Download Immune-Mediated Adverse Reactions Management Guide

Immune-Mediated Adverse Reactions Management Guide
OPDIVO® is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or
after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving OPDIVO.
OPDIVO, in combination with YERVOY® (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic
melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this
indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
OPDIVO (10 mg/mL) and YERVOY (5 mg/mL) are injections for intravenous (IV) use.
OPDIVO is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior
anti-angiogenic therapy.
OPDIVO is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after
autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin. This indication is approved
under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification
and description of clinical benefit in confirmatory trials.
OPDIVO is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN)
with disease progression on or after a platinum-based therapy.
OPDIVO is indicated for treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease
progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or
adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor
response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of
clinical benefit in confirmatory trials.
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
REGIMEN
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY® can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions
may involve any organ system; however, the most common severe immune-mediated adverse reactions are
enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The
majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred
weeks to months after discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate
clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid
function tests at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immunemediated reactions.
Please see Important Safety Information for OPDIVO® and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
REGIMEN
Explore the Following Sections to Learn More About
the Management of Immune-Mediated Adverse Reactions
Summary of Immune-Mediated Adverse Reactions
and Infusion Reactions..................................................................................................4–5
Signs, Symptoms, and Management
of Immune-Mediated Adverse Reactions ............................................................. 6–22
Immune-Mediated Pneumonitis and
Pulmonary Adverse Reactions ............................................................................7–8
Immune-Mediated Colitis and
Gastrointestinal Adverse Reactions .................................................................. 9–10
Immune-Mediated Hepatitis and
Hepatic Adverse Reactions................................................................................11–12
Immune-Mediated Endocrinopathies .............................................................. 13–14
Immune-Mediated Nephritis and
Renal Dysfunction Adverse Reactions ............................................................. 15–16
Immune-Mediated Skin Adverse Reactions ..................................................... 17–18
Immune-Mediated Encephalitis and
Neurological-Related Adverse Reactions ........................................................ 19–20
Other Immune-Mediated Adverse Reactions ........................................................ 21
Infusion Reactions ................................................................................................22
Clinical Trial Data Including Efficacy and Frequency/Onset
of Immune-Mediated Adverse Reactions .............................................................23–41
OPDIVO® in Previously Treated Metastatic NSCLC ......................................... 24–27
OPDIVO + YERVOY® Regimen in Metastatic Melanoma..................................28–32
OPDIVO in Advanced RCC Previously Treated
With Anti-Angiogenic Therapy ....................................................................... 33–36
OPDIVO in Adults With Relapsed or Progressed cHL
After Auto-HSCT and Post-HSCT Brentuximab Vedotin ..................................37–41
OPDIVO in Recurrent or Metastatic SCCHN With
Disease Progression on or After Platinum-Based Therapy ............................. 42–45
OPDIVO in Previously Treated Patients With
Locally Advanced or Metastatic Urothelial Carcinoma .................................. 46–49
Important Safety Information .................................................................................50–53
Auto-HSCT=autologous hematopoietic stem cell transplantation; cHL=classical Hodgkin lymphoma; HSCT=hematopoietic stem cell
transplantation; NSCLC=non-small cell lung cancer; RCC=renal cell carcinoma; SCCHN=squamous cell carcinoma of the head and neck.
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
3
REGIMEN
Summary of Immune-Mediated Adverse Reactions With
OPDIVO® as a Single Agent or the OPDIVO + YERVOY® Regimen
Clinically significant adverse reactions of OPDIVO as a single agent were evaluated in 1994 patients enrolled in Checkmate 037,
017, 057, 066, 025, 067, 205, and 039, or a single-arm trial in NSCLC (n=117), administering OPDIVO as a single agent1
Clinically significant adverse reactions of OPDIVO administered with YERVOY were evaluated in 407 patients with melanoma
enrolled in Checkmate 067 (n=313) or a phase 2 randomized study (n=94), administering OPDIVO with YERVOY, supplemented
by immune-mediated adverse reaction reports in ongoing clinical trials1
Please see pages 6–22 for respective management of immune-mediated adverse reactions in patients treated with OPDIVO
Frequency and Onset of Immune-Mediated Adverse Reactions1
OPDIVO (N=1994)
OPDIVO + YERVOY (N=407)
All Grades
n (%)
Median Time to Onset
months (range)
All Grades
n (%)
Median Time to Onset
months (range)
Pneumonitis*
61 (3.1%)
3.5 (1 day to 22.3 months)
25 (6%)
1.6 (24 days to 10.1 months)
Colitis
58 (2.9%)
5.3 (2 days to 20.9 months)
107* (26%)
1.6 (3 days to 15.2 months)
Hepatitis
35 (1.8%)
3.3 (6 days to 9 months)
51 (13%)
2.1 (15 days to 11 months)
12 (0.6%)
4.9 (1.4 months to 11 months)
36 (9%)
2.7 (27 days to 5.5 months)
Adrenal insufficiency
20 (1%)
4.3 (15 days to 21 months)
21 (5%)
3.0 (21 days to 9.4 months)
Hypothyroidism/
thyroiditis
171 (9%)
2.9 (1 day to 16.6 months)
89 (22%)
2.1 (1 day to 10.1 months)
Hyperthyroidism
54 (2.7%)
1.5 (1 day to 14.2 months)
34 (8%)
23 days (3 days to 3.7 months)
Diabetes
17† (0.9%)
4.4 (15 days to 22 months)
6 (1.5%)
2.5 (1.3 months to 4.4 months)
Nephritis/Renal
Dysfunction
23 (1.2%)
4.6 (23 days to 12.3 months)
9 (2.2%)
2.7 (9 days to 7.9 months)
Skin*
171 (9%)
2.8 (<1 day to 25.8 months)
Encephalitis
3‡ (0.2%)
-
Endocrinopathies
Hypophysitis
92 (22.6%) 18 days (1 day to 9.7 months)
1 (0.2%)
1.7
*Fatal cases have been reported.1 †Two cases of diabetic ketoacidosis occurred.1 ‡Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation
of OPDIVO and administration of corticosteroids.1
Other Immune-Mediated Adverse Reactions1
Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids,
and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO the following clinically significant
immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial
and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome,
hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis
(Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
4
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Summary of Infusion Reactions With OPDIVO®
or the OPDIVO + YERVOY® Regimen
Clinically significant adverse reactions of OPDIVO as a single agent were evaluated in 1994 patients enrolled in Checkmate 037,
017, 057, 066, 025, 067, 205, and 039, or a single-arm trial in NSCLC (n=117), administering OPDIVO as a single agent1
Clinically significant adverse reactions of OPDIVO administered with YERVOY were evaluated in 407 patients with melanoma
enrolled in Checkmate 067 (n=313) or a phase 2 randomized study (n=94), administering OPDIVO with YERVOY, supplemented
by immune-mediated adverse reaction reports in ongoing clinical trials1
OPDIVO can cause severe infusion reactions, which have been reported in less than 1.0% of patients in clinical trials1
Frequency and Onset of Infusion Reactions1
OPDIVO (N=1994)
Infusion Reactions
OPDIVO + YERVOY (N=407)
All Grades
n (%)
Median Time to Onset
months (range)
All Grades
n (%)
Median Time to Onset
months (range)
127 (6.4%)
-
10 (2.5%)
-
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
5
REGIMEN
Signs, Symptoms, and Management
of Immune-Mediated Adverse Reactions
This section contains guidance for the management of select immune-mediated adverse reactions,
which includes adverse reaction management algorithms from the clinical trials of OPDIVO® and the
OPDIVO + YERVOY® Regimen.1,2
For ease of use, this guidance is organized by body system and contains both management
and follow-up information.
A general principle is that differential diagnoses should be diligently evaluated according to standard medical practice.
Non-inflammatory etiologies should be considered and appropriately treated2
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral equivalent
of the recommended intravenous (IV) doses may be considered for ambulatory patients with low-grade toxicity.
The lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent
dose of oral corticosteroids2
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or therapeutic procedure,
is recommended2
The frequency and severity of the related adverse events covered by these algorithms will depend on the
immuno-oncology agent or regimen being used2
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
6
REGIMEN
Immune-Mediated Pneumonitis
Immune-Mediated Pneumonitis1
OPDIVO® can cause immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear
alternate etiology
Fatal cases have been reported
Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis
OPDIVO as a Single Agent1
Immune-mediated pneumonitis led to permanent discontinuation of OPDIVO in 1.1%, and withholding of OPDIVO in
1.3% of patients. Approximately 89% of patients with pneumonitis received high-dose corticosteroids (at least 40 mg
prednisone equivalents per day) for a median duration of 26 days (range: 1 day to 6 months). Complete resolution of
symptoms following corticosteroid taper occurred in 67% of patients. Approximately 8% of patients had recurrence
of pneumonitis after re-initiation of OPDIVO
For more information on immune-mediated pneumonitis for patients with cHL, see page 39
OPDIVO + YERVOY® Regimen1
Immune-mediated pneumonitis led to permanent discontinuation or withholding of OPDIVO with YERVOY in
2.2% and 3.7% of patients, respectively. Approximately 84% of patients with pneumonitis received high-dose
corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 30 days (range: 5 days
to 11.8 months). Complete resolution occurred in 68% of patients. Approximately 13% of patients had recurrence
of pneumonitis after re-initiation of OPDIVO with YERVOY
Signs and symptoms of pneumonitis may include1
Radiographic changes
New or worsening cough
Chest pain
Shortness of breath
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
7
REGIMEN
Management of Immune-Mediated Pulmonary
Adverse Reactions
Immune-Mediated Pulmonary Adverse Reactions1,2
When OPDIVO® is administered in combination with YERVOY®, if OPDIVO is withheld, YERVOY should also be withheld.
Grade 1*
(Radiographic changes only)
Grade 2*
(Mild to moderate new symptoms)
Grade 3–4*
(Severe new symptoms; new/worsening
hypoxia; life-threatening)
Monitoring
Every 2 to 3 days
Daily
Hospitalize
Treatment With
OPDIVO or
OPDIVO + YERVOY
Regimen
Continue treatment
Withhold dose†
Permanently discontinue
Consult
Consider pulmonary and
infectious disease
Pulmonary and infectious disease
Pulmonary and infectious disease
Steroids‡
-
1 to 2 mg/kg/day prednisone equivalents 1 to 2 mg/kg/day prednisone equivalents§
followed by corticosteroid taper
followed by corticosteroid taper
Pulmonary Tests
-
Consider bronchoscopy, lung biopsy
Consider bronchoscopy, lung biopsy
Follow-up1,2
Re-image at least
every 3 weeks
If worsens
• Treat as Grade 2 or 3–4
Re-image every 1–3 days
-
If improved to baseline
If improved to baseline
• Taper steroids before
resuming treatmentII
• Taper steroids
If not improving after 2 weeks
or worsening
If persists or worsens after 2 days
• Treat as Grade 3–4
• Add non-corticosteroid
immunosuppressive medication
*Grades correspond to those listed in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.1,3 † Resume treatment when adverse
reaction returns to Grade 0 or 1.1 ‡Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier,
once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral
corticosteroids.2 §Add prophylactic antibiotics for opportunistic infections.2 IIConsider adding prophylactic antibiotics.2
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
8
REGIMEN
Immune-Mediated Colitis
Immune-Mediated Colitis1
OPDIVO® can cause immune-mediated colitis, defined as requiring use of corticosteroids with no clear
alternate etiology
Monitor patients for signs and symptoms of colitis
OPDIVO as a Single Agent1
Immune-mediated colitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 1%
of patients. Approximately 91% of patients with colitis received high-dose corticosteroids (at least 40 mg
prednisone equivalents per day) for a median duration of 23 days (range: 1 day to 9.3 months). Four patients
required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 74% of patients.
Approximately 16% of patients had recurrence of colitis after re-initiation of OPDIVO
OPDIVO + YERVOY® Regimen1
Immune-mediated colitis led to permanent discontinuation or withholding of OPDIVO with YERVOY in 16% and 7%
of patients, respectively. Approximately 96% of patients with colitis received high-dose corticosteroids (at least 40 mg
prednisone equivalents per day) for a median duration of 1.1 month (range: 1 day to 12 months). Approximately
23% of patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in
75% of patients. Approximately 28% of patients had recurrence of colitis after re-initiation of OPDIVO with YERVOY
Signs and symptoms of colitis may include1
Diarrhea (loose stools) or more bowel
movements than usual
Blood in stools or dark, tarry, sticky stools
Severe stomach-area (abdomen) pain or tenderness
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
9
REGIMEN
Management of Immune-Mediated Gastrointestinal
Adverse Reactions
Immune-Mediated Gastrointestinal Adverse Reactions1,2
When OPDIVO® is administered in combination with YERVOY®, if OPDIVO is withheld, YERVOY should also be withheld.
Grade 1*
(Diarrhea: <4 stools
per day over baseline;
colitis: asymptomatic)
Grade 2*
(Diarrhea: 4-6 stools per day
over baseline; IV fluids indicated
<24 hours; not interfering with ADL;
colitis: abdominal pain, blood
in stool)
Grade 3–4*
(Diarrhea [G3]: ≥7 stools per day over
baseline; incontinence; IV fluids ≥24 hours;
interfering with ADL; colitis [G3]: severe
abdominal pain, medical intervention
indicated, peritoneal signs;
[G4] life-threatening, perforation)
Continue treatment
†
Withhold dose
Grade 3:
Withhold dose†
Grade 4:
Permanently discontinue
Treatment With
OPDIVO + YERVOY Continue treatment
Regimen
Withhold dose†
Permanently discontinue
Symptomatic
Treatment
Administer
Treatment With
OPDIVO
Administer
Steroids‡
-
GI Tests
-
-
For Grade 2 colitis of >5 days
• 0.5 to 1 mg/kg/day prednisone
equivalents followed by
corticosteroid taper§
-
1 to 2 mg/kg/day prednisone equivalentsII
followed by corticosteroid taper
Consider lower-GI endoscopy
Follow-up1,2
If improved to Grade 1
• Resume treatment
Educate patient to report • If steroids have been administered,
taper steroids before resuming
worsening immediately
treatment
• Permanently discontinue for recurrent
colitis upon re-initiation of OPDIVO
or the OPDIVO + YERVOY Regimen
If improved from Grade 3 while
administering single-agent OPDIVO
• When at Grade 1, taper steroids
before resuming treatment
If symptoms worsen
• Treat as Grade 2 or 3–4
If symptoms persist >3 to 5 days
or recur after improvement
• Add non-corticosteroid
immunosuppressive medication
Close monitoring for
worsening symptoms
If worsening or no improvement
occurs despite initiation of
corticosteroids, increase dose to 1 to
2 mg/kg/day prednisone equivalents
• Permanently discontinue for recurrent
colitis upon re-initiation of OPDIVO
*Grades correspond to those listed in the NCI CTCAE version 4.0.1,3 †Resume treatment when adverse reaction returns to Grade 0 or 1.1 ‡Patients on IV steroids may be switched to an
equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should
be taken into account when switching to the equivalent dose of oral corticosteroids.2 §Consider prophylactic antibiotics for opportunistic infections.2 || Add prophylactic antibiotics for
opportunistic infections.2
ADL=activities of daily living; G3=Grade 3; G4=Grade 4; GI=gastrointestinal.
Important Safety Information About YERVOY
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal
signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511),
5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50–53
50-53 and
and the
the US
US Full
Full Prescribing
Prescribing Information
Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
10
REGIMEN
Immune-Mediated Hepatitis
Immune-Mediated Hepatitis1
OPDIVO® can cause immune-mediated hepatitis, defined as requiring use of corticosteroids and no clear
alternate etiology
Monitor patients for abnormal liver tests prior to and periodically during treatment
OPDIVO as a Single Agent1
Immune-mediated hepatitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 1%
of patients. All patients with hepatitis received high-dose corticosteroids (at least 40 mg prednisone equivalents)
for a median duration of 23 days (range: 1 day to 2 months). Two patients required the addition of mycophenolic acid
to high-dose corticosteroids. Complete resolution occurred in 74% of patients. Approximately 29% of patients had
recurrence of hepatitis after re-initiation of OPDIVO
OPDIVO + YERVOY® Regimen1
Immune-mediated hepatitis led to permanent discontinuation or withholding of OPDIVO with YERVOY in 6% and
5% of patients, respectively. Approximately 92% of patients with hepatitis received high-dose corticosteroids
(at least 40 mg prednisone equivalents per day) for a median duration of 1.1 month (range: 1 day to 13.2 months).
Complete resolution occurred in 75% of patients. Approximately 11% of patients had recurrence of hepatitis after
re-initiation of OPDIVO with YERVOY
Signs and symptoms of hepatitis may include1
Transaminase elevation
Total bilirubin elevation
Yellowing of the skin or the
whites of the eyes
Severe nausea or vomiting
Pain on the right side of the
stomach area (abdomen)
Drowsiness
Dark urine (tea colored)
Bleeding or bruising more easily than normal
Feeling less hungry than usual
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
11
REGIMEN
Management of Immune-Mediated Hepatic
Adverse Reactions
Immune-Mediated Hepatic Adverse Reactions1,2
When OPDIVO® is administered in combination with YERVOY®, if OPDIVO is withheld, YERVOY should also be withheld.
Grade 1*
(AST or ALT >ULN to
3.0x ULN and/or T. bili
>ULN to 1.5x ULN)
Grade 2*
(AST or ALT >3.0 to ≤5x ULN
or T. bili >1.5 to ≤3x ULN)
Grade 3–4*
(AST or ALT >5x ULN
or T. bili >3x ULN)
Treatment With
OPDIVO or
OPDIVO + YERVOY
Regimen
Continue treatment
Withhold dose†
Permanently discontinue
Monitoring
Monitor LFTs prior
to and periodically
during treatment
Increase frequency of monitoring
to every 3 days
Increase frequency of monitoring
to every 1 to 2 days
Consult
Steroids‡
-
-
For moderate (Grade 2) transaminase
elevations
• 0.5 to 1 mg/kg/day
prednisone equivalents
Gastroenterology
For severe (Grade 3) or life-threatening
(Grade 4) transaminase elevations with or
without concomitant T. bili elevations
• 1 to 2 mg/kg/day prednisone equivalents§
followed by corticosteroid taper
Follow-up1,2
Continue
monitoring LFTs
If improved to Grade 1 or baseline
• Resume treatment
• If steroids have been administered,
taper steroids before resuming
treatment
• Resume routine LFT monitoring
If improved to Grade 2
If symptoms worsen
• Treat as Grade 2 or 3–4
If AST/ALT >5x and/or T. bili >3x ULN
• Treat as Grade 3–4
If no improvement in 3–5 days,
worsens, or rebounds
• Add non-corticosteroid
immunosuppressive medication
• Taper steroids
*Grades correspond to those listed in the NCI CTCAE version 4.0.1,3 †Resume treatment when adverse reaction returns to Grade 0 or 1.1 ‡Patients on IV steroids may be switched
to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral
corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.2 §Add prophylactic antibiotics for opportunistic infections.2
ALT=alanine aminotransferase; AST=aspartate aminotransferase; LFT=liver function test; T. bili=total bilirubin; ULN=upper limit of normal.
Important Safety Information About YERVOY
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations
>5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2%
and hospitalization in 0.4%.
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
12
REGIMEN
Immune-Mediated Endocrinopathies
Immune-Mediated Endocrinopathies1
OPDIVO® can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune
thyroid disorders, and type 1 diabetes mellitus
Monitor patients for signs and symptoms of hypophysitis and adrenal insufficiency and for hyperglycemia
Monitor thyroid function prior to and periodically during treatment
OPDIVO as a Single Agent1
Hypophysitis led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO in 0.2%
of patients. Approximately 67% of patients with hypophysitis received hormone replacement therapy
and 33% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median
duration of 14 days (range: 5 to 26 days)
Adrenal insufficiency led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO in 0.5%
of patients. Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy
and 25% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median
duration of 11 days (range: 1 day to 1 month)
In patients receiving OPDIVO as a single agent, approximately 79% of patients with hypothyroidism received
levothyroxine and 4% also required corticosteroids. Resolution occurred in 35% of patients
In patients receiving OPDIVO as a single agent, approximately 26% of patients with hyperthyroidism received
methimazole, 9% received carbimazole, 4% received propylthiouracil, and 9% received corticosteroids.
Resolution occurred in 76% of patients
OPDIVO + YERVOY® Regimen1
Hypophysitis led to permanent discontinuation or withholding of OPDIVO with YERVOY in 1.0% and 3.9%
of patients, respectively. Approximately 75% of patients with hypophysitis received hormone replacement
therapy and 56% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for
a median duration of 19 days (range: 1 day to 2.0 months)
Adrenal insufficiency led to permanent discontinuation or withholding of OPDIVO with YERVOY in 0.5% and
1.7% of patients, respectively. Approximately 57% of patients with adrenal insufficiency received hormone
replacement therapy and 33% received high-dose corticosteroids (at least 40 mg prednisone equivalents
per day) for a median duration of 9 days (range: 1 day to 2.7 months)
In patients receiving OPDIVO with YERVOY, approximately 73% of patients with hypothyroidism or thyroiditis
received levothyroxine. Resolution occurred in 45% of patients
In patients receiving OPDIVO with YERVOY, approximately 29% of patients with hyperthyroidism received
methimazole and 24% received carbimazole. Resolution occurred in 94% of patients
OPDIVO with YERVOY was withheld in a patient and permanently discontinued in a second patient who
developed diabetes
Signs and symptoms of endocrinopathies may include1
Headaches that will not go away
or unusual headaches
Extreme tiredness
Weight gain or weight loss
Dizziness or fainting
Changes in mood or behavior, such
as decreased sex drive, irritability,
or forgetfulness
Hair loss
Feeling cold
Constipation
Voice gets deeper
Excessive thirst
or lots of urine
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
13
REGIMEN
Management of Immune-Mediated Endocrinopathies
Immune-Mediated Endocrinopathies1,2
When OPDIVO® is administered in combination with YERVOY®, if OPDIVO is withheld, YERVOY should also be withheld.
Hypophysitis
Adrenal Insufficiency
Hypothyroidism/Thyroiditis
or Hyperthyroidism
Type 1 Diabetes Mellitus
Treatment
With OPDIVO
or OPDIVO
+ YERVOY
Regimen
• Grade 2 or 3:
Withhold dose*
• Grade 4:
Permanently discontinue
• Grade 2:
Withhold dose*
• Grade 3–4:
Permanently discontinue
There are no recommended
dose modifications
for hypothyroidism or
hyperthyroidism
• Grade 3 hyperglycemia:
Withhold dose until
metabolic control
is achieved*
• Grade 4 hyperglycemia:
Permanently discontinue
Monitoring
• Evaluate endocrine function
• Consider pituitary scan
• Repeat labs in 1 to 3 weeks/MRI in 1 month if symptoms
persist but normal lab/pituitary scan
Monitor thyroid function
prior to and periodically
during treatment
Monitor for hyperglycemia
Consult
Consider endocrinology
Consider endocrinology
Consider endocrinology
†
Steroids
Additional
Therapeutic
Management
≥Grade 2: 1 mg/kg/day
prednisone equivalents
followed by corticosteroid
taper
Grade 3–4: 1 to 2 mg/kg/day
prednisone equivalents
followed by corticosteroid
taper
Administer hormone
replacement therapy as
clinically indicated
–
–
• Administer hormonereplacement therapy
for hypothyroidism
• Initiate medical
management for control
of hyperthyroidism
-
–
Follow-up1,2
If improved (with or without hormone replacement)
• Taper steroids before resuming treatment‡
Continue standard monitoring
• Patients with adrenal insufficiency may need to continue
steroids with mineralocorticoid component‡
–
When Grade 3 hyperglycemia
returns to Grade 0 or 1,
resume treatment
*Resume treatment when adverse reaction returns to Grade 0 or 1.1 †Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or
earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.2
‡
Consider prophylactic antibiotics for opportunistic infections.2
MRI=magnetic resonance imaging.
Important Safety Information About YERVOY
In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring
hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients.
All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency,
hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
14
REGIMEN
Immune-Mediated Nephritis
and Renal Dysfunction
Immune-Mediated Nephritis and Renal Dysfunction1
OPDIVO® can cause immune-mediated nephritis, defined as renal dysfunction or ≥Grade 2 increased creatinine,
requirement for corticosteroids, and no clear alternate etiology
Monitor patients for elevated serum creatinine prior to and periodically during treatment
OPDIVO as a Single Agent1
Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of OPDIVO in 0.3%
and withholding of OPDIVO in 0.8% of patients. All patients received high-dose corticosteroids (at least
40 mg prednisone equivalents per day) for a median duration of 21 days (range: 1 day to 15.4 months).
Complete resolution occurred in 48% of patients. No patients had recurrence of nephritis or renal
dysfunction after re-initiation of OPDIVO
OPDIVO + YERVOY® Regimen1
Immune-mediated nephritis and renal dysfunction led to permanent discontinuation or withholding of
OPDIVO with YERVOY in 0.7% and 0.5% of patients, respectively. Approximately 67% of patients received
high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of
13.5 days (range: 1 day to 1.1 months). Complete resolution occurred in all patients. Two patients
resumed OPDIVO with YERVOY without recurrence of nephritis or renal dysfunction
Signs and symptoms of nephritis and renal dysfunction may include1
Increase in serum creatinine
Decrease in the amount of urine
Blood in the urine
Swelling in the ankles
Loss of appetite
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
15
REGIMEN
Management of Immune-Mediated Renal
Adverse Reactions
Immune-Mediated Renal Adverse Reactions1,2
When OPDIVO® is administered in combination with YERVOY®, if OPDIVO is withheld, YERVOY should also be withheld.
Grade 1*
(Creatinine >ULN and
>baseline but ≤1.5x baseline)
Grade 2–3*
(Creatinine >1.5x to ≤6x ULN)
Grade 4*
(Creatinine >6x ULN)
Treatment With
OPDIVO or
OPDIVO + YERVOY
Regimen
Continue treatment
Withhold dose†
Permanently discontinue
Monitoring
Monitor creatinine weekly
Monitor creatinine every
2 to 3 days
Monitor creatinine daily
Consult
-
-
Nephrology
Steroids
-
0.5 to 1 mg/kg/day prednisone
equivalents followed by a
corticosteroid taper
Renal Tests
-
Consider renal biopsy
Consider renal biopsy
If improved to baseline
• Resume routine creatinine
monitoring
If improved to Grade 1
• Taper steroids before resuming
treatment with routine creatinine
monitoring§
If improved to Grade 1
• Taper steroidsII
If worsens
• Treat as Grade 2–3 or 4
If worsening or no improvement
• 1 to 2 mg/kg/day prednisone
equivalents
‡
1 to 2 mg/kg/day prednisone
equivalents followed by
a corticosteroid taper
Follow-up1,2
-
*Grades correspond to those listed in the NCI CTCAE version 4.0.1,3 †Resume treatment when adverse reaction returns to Grade 0 or 1.1 ‡Patients on IV steroids may be switched to an
equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should
be taken into account when switching to the equivalent dose of oral corticosteroids.2 §Consider prophylactic antibiotics for opportunistic infections.2 IIAdd prophylactic antibiotics for
opportunistic infections.2
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
16
REGIMEN
Immune-Mediated Skin Adverse Reactions
Immune-Mediated Skin Adverse Reactions1
OPDIVO® can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN),
some cases with fatal outcome
OPDIVO as a Single Agent1
Immune-mediated rash led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.8%
of patients. Approximately 16% of patients with rash received high-dose corticosteroids (at least 40 mg prednisone
equivalents per day) for a median duration of 12 days (range: 1 day to 8.9 months) and 85% received topical
corticosteroids. Complete resolution occurred in 48% of patients. Recurrence of rash occurred in 1.4% of patients
who resumed OPDIVO after resolution of rash
OPDIVO + YERVOY® Regimen1
Immune-mediated rash led to permanent discontinuation or withholding of OPDIVO with YERVOY in 0.5% and 3.9%
of patients, respectively. Approximately 17% of patients with rash received high-dose corticosteroids (at least 40 mg
prednisone equivalents per day) for a median duration of 14 days (range: 2 days to 4.7 months). Complete resolution
occurred in 47% of patients. Approximately 6% of patients who resumed OPDIVO and YERVOY after resolution had
recurrence of rash
Signs and symptoms of skin adverse reactions may include1
Rash
Itching
Skin blistering
Ulcers in the mouth or other mucous membranes
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
17
REGIMEN
Management of Immune-Mediated Skin
Adverse Reactions
Immune-Mediated Skin Adverse Reactions1,2
When OPDIVO® is administered in combination with YERVOY®, if OPDIVO is withheld, YERVOY should also be withheld.
Grade 1–2*
(Covering ≤30% BSA)
Grade 3–4*
(Covering >30% BSA; life-threatening consequences)
Treatment With
OPDIVO or
Continue treatment
OPDIVO + YERVOY
Regimen
Symptomatic
Treatment
Administer (eg, antihistamines
and topical steroids)
-
Consult
Steroids‡
Administer symptomatic treatment
(eg, topical steroids)
Skin Test
-
Grade 3 or symptoms/signs of SJS or TEN:
Withhold dose†
Grade 4 or confirmed SJS or TEN:
Permanently discontinue
For symptoms or signs of SJS or TEN
• Refer the patient for specialized care for assessment
and treatment
Dermatology
For immune-mediated rash
• 1 to 2 mg/kg/day of prednisone or equivalent
followed by corticosteroid taper
Consider skin biopsy
Follow-up1,2
If symptoms persist >1–2 weeks or recur
• Consider skin biopsy
If improved to Grade 1
• Taper steroids before resuming treatmentII
• Withhold dose
• Consider 0.5 to 1.0 mg/kg/day methylprednisolone
or equivalent. Once improving, taper steroids,§ and
resume treatment
If symptoms worsen
-
• Treat as Grade 3–4
*Grades correspond to those listed in the NCI CTCAE version 4.0.1,3 †Resume treatment when adverse reaction returns to Grade 0 or 1.1 ‡Patients on IV steroids may be switched to an
equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids
should be taken into account when switching to the equivalent dose of oral corticosteroids.2 § Consider prophylactic antibiotics for opportunistic infections.2 II Add prophylactic
antibiotics for opportunistic infections.2
BSA=body surface area.
Important Safety Information About YERVOY
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis
(eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration,
or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died
as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
18
REGIMEN
Immune-Mediated Encephalitis
Immune-Mediated Encephalitis1
OPDIVO® can cause immune-mediated encephalitis with no clear alternate etiology
OPDIVO as a Single Agent1
Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO
and administration of corticosteroids. In the other 2 patients, encephalitis occurred post-allogeneic HSCT
Signs and symptoms of encephalitis may include1
Headache
Fever
Tiredness or weakness
Confusion
Memory problems
Sleepiness
Seeing or hearing things that are
not really there (hallucinations)
Seizures
Stiff neck
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY® Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
19
REGIMEN
Management of Immune-Mediated Neurological
Adverse Reactions
Immune-Mediated Neurological Adverse Reactions1,2
In patients with new-onset moderate to severe neurologic signs or symptoms, evaluate to rule out infectious or other
causes of moderate to severe neurologic deterioration.
Evaluation may include but may not be limited to consultation with a neurologist, brain MRI, and lumbar puncture.
When OPDIVO® is administered in combination with YERVOY®, if OPDIVO is withheld, YERVOY should also be withheld.
Grade 1*
(Asymptomatic or mild symptoms)
Treatment With
OPDIVO or
Continue treatment
OPDIVO + YERVOY
Regimen
Grade 2*
(New-onset moderate or severe
neurologic signs or symptoms)
Grade 3–4*
(Immune-mediated encephalitis)
Withhold dose†
Permanently discontinue
Consult
-
Consider consulting neurology
Neurology
Steroids‡
-
Treat symptoms per local
guidelines
1 to 2 mg/kg/day prednisone
equivalents followed by
corticosteroid taper§
-
If improved to baseline
• Resume treatment
If improved to Grade 2
• Taper steroids
If worsens or no improvement
• Treat as Grade 3–4
If worsens or atypical presentation
• Consider other
immunosuppressive therapies
Follow-up1,2
If worsens
• Treat as Grade 2 or 3–4
*G
*Grades
d correspondd tto th
those lilisted
t d in
i the
th NCI CTCAE version
i 4.0.
4 0 11,33 †RResume ttreatment
t t when
h adverse
d
reaction
ti returns
t
to
t Grade
G d 0 or 1.1 1 ‡PPatients
ti t on IV steroids
t id may bbe switched
it h d tto an
equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should
2§
2
be taken into account when switching to the equivalent dose of oral corticosteroids. Add prophylactic antibiotics for opportunistic infections.
Important Safety Information About YERVOY
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3)
peripheral motor neuropathy were reported.
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
20
REGIMEN
Management of Other Immune-Mediated
Adverse Reactions
Other Immune-Mediated Adverse Reactions1
OPDIVO® can cause other clinically significant immune-mediated adverse reactions
Immune-mediated adverse reactions may occur after discontinuation of OPDIVO therapy
For any suspected immune-mediated adverse reactions, exclude other causes
Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer
high-dose corticosteroids, and if appropriate, initiate hormone-replacement therapy
Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over
at least 1 month
Consider restarting OPDIVO after completion of corticosteroid taper based on the severity of the event
Signs and symptoms of other immune-mediated adverse reactions may include1
Changes in eyesight
Severe or persistent muscle
or joint pains
Severe muscle weakness
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY® Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
21
REGIMEN
Signs, Symptoms, and Management
of Infusion Reactions
Infusion Reactions1,4
OPDIVO® can cause severe infusion reactions, which have been reported in less than 1.0% of patients
in clinical trials1
Infusion reactions were graded according to the NCI CTCAE version 4.03,4
Mild/moderate symptoms (Grade 1 or 2)1,4
— Interrupt or slow the rate of infusion in patients
— Monitor patients until recovery
Severe/life threatening (Grade 3 or 4)1,4
— Discontinue OPDIVO in such patients
— To manage anaphylaxis, follow institutional protocol
— Patient should be monitored until the treating physician is comfortable that the symptoms will not recur
Signs and symptoms of infusion reactions may include1
Chills or shaking
Itching or rash
Flushing
Difficulty breathing
Dizziness
Fever
Feeling like passing out
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY® Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
22
REGIMEN
Clinical Trial Data Including Efficacy and Frequency/
Onset of Immune-Mediated Adverse Reactions
This section contains clinical trial data including efficacy and the frequency and onset of
immune-mediated adverse reactions organized by indication.
Please see Important Safety Information for OPDIVO® and the OPDIVO + YERVOY® Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
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NSCLC
For previously treated metastatic non-squamous NSCLC1
OPDIVO® Was Approved Based on Superior OS vs
Chemotherapy* in a Study Designed to Include PD-L1
Expressors and Non-Expressors1
Checkmate 057: Overall Survival
1,5
Median OS
100
OPDIVO
DOCETAXEL
90
HR=0.73; 95% CI: 0.60–0.89; P=0.0015
80
PERCENT SURVIVAL (%)
12.2 mos. (95% CI: 9.7–15.0)
9.4 mos. (95% CI: 8.0–10.7)
70
51%
60
95% CI: 45–56
50
40
39%
30
95% CI: 33–45
20
10
0
STUDY MONTH 0
3
6
9
12
15
18
21
24
27
Number at risk
OPDIVO
292
DOCETAXEL
290
232
244
194
194
169
150
146
111
123
88
62
34
32
10
9
5
0
0
HR for OS=0.73 (95% CI: 0.60–0.89, P=0.0015).
Median OS was 12.2 months (95% CI: 9.7–15.0)
for OPDIVO and 9.4 months (95% CI: 8.0–10.7)
for docetaxel1
ORR with OPDIVO was 19% (95% CI: 15–24)
(56/292; 4 complete responses) vs 12% with
docetaxel (95% CI: 9–17) (36/290; 1 complete
response), P=0.02. The median duration
of response was 17 months in the OPDIVO
arm and 6 months in the docetaxel arm1
Median PFS with OPDIVO was 2.3 months
vs 4.2 months with docetaxel; HR=0.92
(95% CI: 0.77–1.11, P=0.39)1
Results were based on the prespecified
interim analysis conducted when 413 events
(93% of the planned number of events for
final analysis) were observed (190 in the
OPDIVO arm and 223 in the docetaxel arm)1
Refer to Figure 7 in the Full Prescribing Information for data on censored patients.1
Study design: OPDIVO was evaluated in a randomized (1:1), open-label, phase 3 study (Checkmate 057) of OPDIVO
3 mg/kg IV q2w† (n=292) vs docetaxel 75 mg/m2 IV q3w (n=290) in patients with metastatic non-squamous NSCLC
who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen.
Appropriate targeted therapy may have been given to patients with known EGFR mutation or ALK translocation.
The primary endpoint of the study was OS. Secondary endpoints included ORR and PFS.1,5
PD-L1 testing is not required for a treatment decision with OPDIVO1
*Docetaxel.1
†
The recommended dose of OPDIVO is 240 mg administered as an IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.1
ALK=anaplastic lymphoma kinase; CI=confidence interval; EGFR=epidermal growth factor receptor; HR=hazard ratio; mos=months; ORR=objective response rate; OS=overall survival;
PD-1=programmed death-1; PD-L1=programmed death ligand 1; PFS=progression-free survival; q2w=every 2 weeks; q3w=every 3 weeks.
Serious Adverse Reactions1
In Checkmate 057 and 017, serious adverse reactions occurred in 46% of patients receiving OPDIVO. The most frequent
serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism,
dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, in the OPDIVO arm, seven deaths
were due to infection including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one
death was due to limbic encephalitis
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
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NSCLC
For previously treated metastatic squamous NSCLC regardless of PD-L1 expression1
OPDIVO® Is the Only PD-1 Inhibitor Approved Based
on Superior Overall Survival vs Chemotherapy*—
A Standard of Care1,6-8
Checkmate 017: Overall Survival1,8
Median OS
100
OPDIVO
DOCETAXEL
90
HR=0.59; 95% CI: 0.44–0.79; P=0.0002
80
PERCENT SURVIVAL (%)
9.2 mos. (95% CI: 7.3–13.3)
6.0 mos. (95% CI: 5.1–7.3)
70
60
42%
50
95% CI: 34–50
40
30
20
24%
95% CI: 17–31
10
0
STUDY MONTH
0
3
6
9
12
15
18
21
24
135
137
113
103
86
68
69
45
52
30
31
14
15
7
7
2
0
0
Number at risk
OPDIVO
DOCETAXEL
HR for OS=0.59 (95% CI: 0.44–0.79,
P=0.0002). Median OS was 9.2 months
(95% CI: 7.3–13.3) for OPDIVO and 6 months
(95% CI: 5.1–7.3) for docetaxel1
ORR with OPDIVO was 20% (95% CI: 14–28)
(27/135; 1 complete response) vs 9% with
docetaxel (95% CI: 5–15) (12/137), P=0.008.
The median duration of response was not
reached in the OPDIVO arm and was
8.4 months in the docetaxel arm1
Median PFS with OPDIVO was 3.5 months
vs 2.8 months with docetaxel; HR=0.62
(95% CI: 0.47–0.81, P=0.0004)1
Results were based on the prespecified
interim analysis conducted when 199 events
(86% of the planned number of events
for final analysis) were observed (86 in the
OPDIVO arm and 113 in the docetaxel arm)1
Refer to Figure 6 in the Full Prescribing Information for data on censored patients.1
Study design: OPDIVO was evaluated in a randomized (1:1), open-label, phase 3 study of OPDIVO 3 mg/kg IV q2w† (n=135)
vs docetaxel 75 mg/m2 IV q3w (n=137) in patients with metastatic squamous NSCLC who had experienced disease
progression during or after one prior platinum doublet-based chemotherapy regimen. The primary endpoint of the study
was OS. Secondary endpoints included ORR and PFS.1,8
PD-L1 testing is not required for a treatment decision with OPDIVO1
*Docetaxel.1
†
The recommended dose of OPDIVO is 240 mg administered as an IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.1
Common Adverse Reactions1
Across both Checkmate 057 and 017, the most common adverse reactions (reported in at least 20% of patients) were fatigue,
musculoskeletal pain, cough, dyspnea, and decreased appetite
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
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NSCLC
Overview of Trials in Previously Treated Metastatic NSCLC
Checkmate 057: OPDIVO® was evaluated in a randomized (1:1), open-label, phase 3 study of OPDIVO 3 mg/kg IV q2w
(n=292) or docetaxel 75 mg/m2 IV q3w (n=290) in patients with metastatic non-squamous NSCLC who had experienced
disease progression during or after one prior platinum doublet-based chemotherapy regimen. Appropriate targeted
therapy may have been given to patients with known EGFR mutation or ALK translocation. The primary endpoint
of the study was OS. Secondary endpoints included ORR and PFS1,5
Checkmate 017: OPDIVO was evaluated in a randomized (1:1), open-label, phase 3 study of OPDIVO 3 mg/kg IV q2w
(n=135) vs docetaxel 75 mg/m2 IV q3w (n=137) in patients with metastatic squamous NSCLC who had experienced
disease progression during or after one prior platinum doublet-based chemotherapy regimen. The primary endpoint
of the study was OS. Secondary endpoints included ORR and PFS1,8
Checkmate 057 and 017: Onset of Select Immune-Mediated Adverse Reactions9
OPDIVO (N=418)
Median Time to Onset (Weeks)
Pneumonitis
range: 2.6 to 85.1 weeks
30.3
Diarrhea/Colitis
range: 4.0 to 91.0 weeks
14.0
Hepatitis*
Endocrinopathies
Hypophysitis†
Adrenal Insufficiency
Hypothyroidism/Thyroiditis
5.1‡
range: 3.7 to 61.1 weeks
12.3
Hyperthyroidism
8.6 range: 4.1 to 12.1 weeks
Diabetes Mellitus
24.5
Nephritis/
Renal Dysfunction
Rash
range: 12.7 to 36.3 weeks
range: 6.7 to 24.1 weeks
9.9
14.7
range: 2.0 to 50.6 weeks
Encephalitis*
Weeks 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 108 112 116 120
*Time to onset is not available.9 †Immune-mediated adverse reaction information not available.9 ‡Represents time to onset.9
Infusion Reactions/Hypersensitivity9
The median time to onset in the OPDIVO arm was 0.1 weeks (range: 0.1 weeks to 2.1 weeks)
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
26
prev
pr
evio
ev
io
ous
u lyy treeat
ated
ed met
ed
etas
asta
as
tati
ta
ticc
ti
NSCLC
Checkmate 057 and 017: Frequency of Immune-Mediated Adverse Reactions9
All Grades
n/N (%)
Pulmonary
Gastrointestinal
Hepatic
Grade 1
n/N
Grade 2
n/N
Grades 3–5
n/N
Immune-Mediated Pneumonitis
13/418 (3.1%)
-
7/418
Grade 3: 6/418
Immune-Mediated Diarrhea/Colitis
9/418 (2.2%)
2/418
3/418
Grade 3: 4/418
Immune-Mediated Hepatitis
1/418 (0.2%)
-
-
1/418
Immune-Mediated Adrenal Insufficiency
1/418 (0.2%)
-
-
Grade 3: 1/418
Immune-Mediated Hypothyroidism/Thyroiditis
27/418 (6.5%)
3/418
24/418
-
Endocrinopathies
Immune-Mediated Hyperthyroidism
4/418 (1.0%)
1/418
3/418
-
Immune-Mediated Diabetes Mellitus
2/418 (0.5%)
Renal
Skin
Neurological
-
1/418
1/418
Immune-Mediated Nephritis and Renal Dysfunction
3/418 (0.7%)
1/418
1/418
Grade 3: 1/418
Immune-Mediated Rash
21/418 (5.0%)
15/418
5/418
Grade 3: 1/418
-
Grade 5: 1/418
Encephalitis
1/418 (0.2%)
-
Checkmate 057 and 017: Frequency of Infusion Reactions9
Infusion Reactions
Infusion Reactions/Hypersensitivity
3/418 (0.7%)
-
3/418
-
Please see Important Safety Information for OPDIVO® on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
27
REGIMEN
meta
me
tast
staticc
melan
noma
For previously untreated patients with metastatic melanoma1
Superior Efficacy With the First and Only
Combination of Immune Checkpoint Inhibitors1
Progression-Free Survival1
Median PFS
OPDIVO® + YERVOY® Regimen
11.5 mos. (95% CI: 8.9–16.7)
6.9 mos. (95% CI: 4.3–9.5)
OPDIVO Monotherapy
2.9 mos. (95% CI: 2.8–3.4)
YERVOY Monotherapy
1.0
0.9
PROBABILITY OF PFS
0.8
0.7
0.6
(95% CI: 0.34–0.51)
11.5 HR=0.42
P<0.0001
0.5
2.9
0.4
6.9
HR=0.57 (95% CI: 0.47–0.69)
P<0.0001
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6
8
9 10 11 12 13 14 15 16 17 18 19 20 21
MONTHS*
Number of subjects at risk
OPDIVO + YERVOY Regimen 314
OPDIVO Monotherapy 316
YERVOY Monotherapy 315
7
219
177
137
173
147
77
151
124
54
65
50
24
11
9
4
1
1
0
0
0
0
*Assessed per investigator.
Serious Adverse Reactions1
In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent
discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions
(72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm relative to the OPDIVO arm
In Checkmate 067, the most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and
the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%)
Common Adverse Reactions1
In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm were fatigue, rash,
diarrhea, nausea, pyrexia, vomiting, and dyspnea. The most common (≥20%) adverse reactions in the OPDIVO arm were
fatigue, rash, diarrhea, and nausea
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
28
REGIMEN
meta
me
tast
staticc
melan
noma
~60%
reduced risk of progression or death
with the OPDIVO® + YERVOY® Regimen
vs YERVOY alone (HR=0.42)1
Approved across BRAF status1
Study design: The OPDIVO + YERVOY Regimen was evaluated in a double-blind, randomized study of previously
untreated, unresectable, or metastatic melanoma. Patients were randomized (1:1:1) to receive the OPDIVO + YERVOY
Regimen (OPDIVO 1 mg/kg and YERVOY 3 mg/kg q3w x 4 doses, followed by OPDIVO monotherapy 3 mg/kg q2w),*
or OPDIVO 3 mg/kg q2w, or YERVOY 3 mg/kg q3w x 4 doses followed by placebo q2w.1
Major efficacy outcome measures were investigator-assessed PFS and OS. Additional efficacy outcome measures
were confirmed ORR and duration of response.1
*The recommended dose of OPDIVO is 1 mg/kg administered as an IV infusion over 60 minutes, followed by YERVOY on the same day, every 3 weeks for 4 doses. The
recommended subsequent dose of OPDIVO, as a single agent, is 240 mg administered as an IV infusion over 60 minutes every 2 weeks until disease progression or
unacceptable toxicity.1
Adverse Reactions Leading to Discontinuation1
In Checkmate 067, the most frequent adverse reactions leading to discontinuation of both drugs in the OPDIVO plus YERVOY
arm and of OPDIVO in the OPDIVO arm, respectively, were diarrhea (8% and 1.9%), colitis (8% and 0.6%), increased ALT
(4.8% and 1.3%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%)
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
29
REGIMEN
meta
me
tast
staticc
melan
noma
Overview of Trials in Previously Untreated Metastatic Melanoma1,10
Checkmate 067: The OPDIVO® + YERVOY® Regimen was evaluated in a double-blind, randomized study of previously
untreated, unresectable, or metastatic melanoma. Patients were randomized (1:1:1) to receive the OPDIVO + YERVOY
Regimen (OPDIVO 1 mg/kg and YERVOY 3 mg/kg q3w x 4 doses, followed by OPDIVO monotherapy 3 mg/kg q2w) or
OPDIVO 3 mg/kg q2w or YERVOY 3 mg/kg q3w x 4 doses followed by placebo q2w1
Major efficacy outcome measures were investigator-assessed PFS and OS. Additional efficacy outcome measures
were confirmed ORR and duration of response1
Checkmate 069: The OPDIVO + YERVOY Regimen was evaluated in a double-blind, randomized study of previously
untreated, unresectable, or metastatic melanoma. Patients were randomized (2:1) to receive the OPDIVO + YERVOY
Regimen (OPDIVO 1 mg/kg and YERVOY 3 mg/kg q3w x 4 doses, followed by OPDIVO monotherapy 3 mg/kg q2w)
or YERVOY 3 mg/kg q3w x 4 doses followed by placebo q2w10
Major efficacy outcome measures were investigator-assessed ORR in patients with BRAF V600 wild-type melanoma.
Secondary endpoints were investigator-assessed PFS in patients with BRAF V600 wild-type tumors, the proportion
of patients achieving an objective response among patients with BRAF V600 mutation-positive tumors, and PFS
for patients with BRAF V600 mutation-positive tumors10
Checkmate 067 and 069: Onset of Select Immune-Mediated Adverse Reactions1
OPDIVO + YERVOY Regimen (N=407)
Median Time to Onset (Months)
Pneumonitis
1.6
Diarrhea/Colitis
1.6
Hepatitis
range: 24 days to 10.1 months
range: 3 days
to 15.2 months
range: 15 days to 11 months
2.1
Endocrinopathies
Hypophysitis
range: 27 days to 5.5 months
2.7
Adrenal Insufficiency
Hyperthyroidism*
range: 21 days to 9.4 months
3.0
Hypothyroidism/Thyroiditis
range: 1 day to 10.1 months
2.1
range: 3 days to 3.7 months
23
Diabetes Mellitus
range: 1.3 to 4.4 months
2.5
Nephritis and
Renal Dysfunction
range: 9 days to 7.9 months
2.7
range: 1 day to 9.7 months
18
Rash*
Encephalitis
1.7†
Months 0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
*Median time to onset reported in days.1 †Represents time to onset.1
Hypersensitivity/Infusion-Related Reactions11
The median time to onset in the OPDIVO + YERVOY arm was 0.7 months
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
30
REGIMEN
meta
me
tast
staticc
melan
noma
Checkmate 067 and 069: Frequency of Immune-Mediated Adverse Reactions1,11
All Grades n/N (%)
Grades 3–4 n/N
Grade 5 n/N
Immune-Mediated Pneumonitis
Pulmonary
25/407 (6.1%)
Grade 3: 7/407
-
Immune-Mediated Diarrhea/Colitis
Gastrointestinal
107/407 (26.3%)
62/407
-
Immune-Mediated Hepatitis
Hepatic
51/407 (12.5%)
45/407
-
Immune-Mediated Hypophysitis
36/407 (8.8%)
Grade 3: 8/407
-
Immune-Mediated Adrenal Insufficiency
Grade 3: 7/407
Grade 4: 1/407
21/407 (5.2%)
-
Immune-Mediated Hypothyroidism/Thyroiditis
Endocrinopathies
89/407 (21.9%)
Grade 3: 6/407
-
Immune-Mediated Hyperthyroidism
34/407 (8.4%)
Grade 3: 4/407
-
Immune-Mediated Diabetes Mellitus
6/407 (1.5%)
4/407*
-
Immune-Mediated Nephritis and Renal Dysfunction
Renal
9/407 (2.2%)
7/407
-
Immune-Mediated Rash
Skin
92/407 (22.6%)
Grade 3: 15/407
-
Encephalitis
Neurological
1/407 (0.2%)
-
-
*One patient with Grade 3 diabetes mellitus and three patients with Grade 4 diabetic ketoacidosis.11
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
31
REGIMEN
meta
me
tast
staticc
melan
noma
Checkmate 067 and 069: Infusion-Related Reactions1
All Grades n/N (%)
Grades 3–4 n/N
Grade 5 n/N
Hypersensitivity/Infusion-Related Reactions
Infusion Reactions
10/407 (2.5%)
-
-
Important Safety Information About YERVOY®
Immune-Mediated Colitis
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above
baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients.
Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died
as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.
Immune-Mediated Hepatitis
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations
>5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure
in 0.2% and hospitalization in 0.4%.
Please see Important Safety Information for OPDIVO® and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
32
2L advvaan
nced
ceed
renal cell carcinoma
prev
pr
evio
ev
ious
io
usly
us
lyy treeat
a ed
d witth an
nti
t -aang
ngio
ioge
io
geni
ge
nicc th
ni
ther
erap
er
apyy
ap
The First and Only PD-1 Inhibitor to Demonstrate
Significant Overall Survival of More Than 2 Years1
Checkmate 025: Overall Survival1,12
100
Median OS
90
25 mos. (95% CI: 21.7–NE)
OPDIVO®
19.6 mos. (95% CI: 17.6–23.1)
EVEROLIMUS
HR=0.73; 95% CI: 0.60–0.89; P=0.0018
PERCENT SURVIVAL (%)
80
25
70
months
60
95% CI: 21.7–NE
50
19.6
40
months
30
95% CI: 17.6–23.1
20
10
0
0
3
6
9
OPDIVO
EVEROLIMUS
12
15
18
21
24
27
30
33
73
61
29
20
3
2
0
0
OVERALL SURVIVAL (MONTHS)
Number at risk
410
411
389
366
359
324
337
287
305
265
275
241
213
187
139
115
See OS Figure for advanced RCC in the Full Prescribing Information for data on censored patients.1
2L=second line; NE=not estimable.
Serious Adverse Reactions1
In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent
serious adverse reactions reported in at least 2% of patients were acute kidney injury, pleural effusion, pneumonia,
diarrhea, and hypercalcemia
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
33
2L advvaan
nced
ceed
renal cell carcinoma
prev
pr
evio
ev
ious
io
usly
us
lyy treeat
a ed
d witth an
nti
t -aang
ngio
ioge
io
geni
ge
nicc th
ni
ther
erap
er
apyy
ap
Median OS was 25.0 months for OPDIVO®
and 19.6 months for everolimus1
HR=0.73; 95% CI: 0.60–0.89; P=0.00181
77% of OPDIVO patients received only 1 prior anti-angiogenic therapy1
OPDIVO demonstrated a 27% reduction in the risk of death vs everolimus, HR=0.73; 95% CI: 0.60–0.89; P=0.00181
Results were based on the prespecified interim analysis conducted when 398 events (70% of the planned number
of events for final analysis) were observed1,12
OS benefit was observed regardless of PD-L1 expression level1
Study design: Checkmate 025 was a randomized (1:1), open-label study of OPDIVO 3 mg/kg IV over 60 minutes q2w*
(n=410) vs everolimus 10 mg daily, administered orally (n=411) in patients with advanced RCC who had experienced disease
progression during or after 1 or 2 prior anti-angiogenic therapy regimens. The primary endpoint was OS.1,12
*The recommended dose of OPDIVO is 240 mg administered as an IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.1
Common Adverse Reactions1
In Checkmate 025, the most common adverse reactions (reported in at least 20% of patients) were asthenic conditions,
cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
34
2L advvaan
nced
ceed
renal cell carcinoma
prev
pr
evio
ev
ious
io
usly
us
lyy treeat
a ed
d witth an
nti
t -aang
ngio
ioge
io
geni
ge
nicc th
ni
ther
erap
er
apyy
ap
Overview of Trial in Advanced RCC Previously Treated With Anti-Angiogenic Therapy
Checkmate 025: OPDIVO® was evaluated in a randomized (1:1), open-label study of OPDIVO 3 mg/kg IV over 60 minutes
q2w (n=410) vs everolimus 10 mg daily, administered orally (n=411) in patients with advanced RCC who had experienced
disease progression during or after 1 or 2 prior anti-angiogenic therapy regimens. The primary endpoint was OS1,12
Checkmate 025: Onset of Select Immune-Mediated Adverse Reactions13
OPDIVO (N=406)
Median Time to Onset (Weeks)
Pneumonitis
range:
0.3 to 97.1 weeks
16.6
Diarrhea/Colitis
range: 0.3 to 67.9 weeks
20.9
Hepatitis
range: 2.0 to 23.0 weeks
16.0
Endocrinopathies
Hypothyroidism/Thyroiditis
range: 2.1 to 59.0 weeks
20.1
range: 3.4 to 61.7 weeks
13.0
Diabetes Mellitus
range: 10.1 to 95.0 weeks
34.1
Nephritis and
Renal Dysfunction
Rash
range: 3.1 to 91.0 weeks
25.3
Adrenal Insufficiency
Hyperthyroidism
range: 14.1 to 39.9 weeks
27.0
Hypophysitis
23.7
range: 4.6 to 53.6 weeks
13.7
range:
0.3 to 112.0
weeks
Encephalitis*
Weeks 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 108 112 116 120
*Immune-mediated adverse reaction information not available.13
Hypersensitivity/Infusion-Related Reactions13
The median time to onset in the OPDIVO group was 6.29 weeks (range: 0.1 to 120.1 weeks)
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
35
2L advvaan
nced
ceed
renal cell carcinoma
prev
pr
evio
ev
ious
io
usly
us
lyy treeat
a ed
d witth an
nti
t -aang
ngio
ioge
io
geni
ge
nicc th
ni
ther
erap
er
apyy
ap
Checkmate 025: Frequency of Immune-Mediated Adverse Reactions13
All Grades n/N (%)
Grade 1 n/N
Grade 2 n/N
Grades 3–5 n/N
Immune-Mediated Pneumonitis
Pulmonary
18/406 (4.4%)
1/406
12/406
Grade 3: 4/406
Grade 4: 1/406
Immune-Mediated Diarrhea/Colitis
Gastrointestinal
13/406 (3.2%)
1/406
7/406
Grade 3: 5/406
Immune-Mediated Hepatitis Requiring Systemic Immunosuppression
Hepatic
6/406 (1.5%)
-
1/406
Grade 3: 5/406
Immune-Mediated Hypophysitis
2/406 (0.5%)
1/406
-
Grade 3: 1/406
Immune-Mediated Adrenal Insufficiency
8/406 (2%)
1/406
4/406
Grade 3: 3/406
Immune-Mediated Hypothyroidism/Thyroiditis
Endocrinopathies
33/406 (8.1%)
14/406
17/406
Grade 3: 2/406
Immune-Mediated Hyperthyroidism
10/406 (2.5%)
5/406
5/406
-
Immune-Mediated Diabetes Mellitus
6/406* (1.5%)
1/406
2/406
Grade 3: 3/406
Immune-Mediated Nephritis and Renal Dysfunction
Renal
12/406 (3.0%)
-
7/406
Grade 3: 4/406
Grade 4: 1/406
Immune-Mediated Rash
Skin
30/406 (7.4%)
19/406
7/406
Grade 3: 4/406
Checkmate 025: Frequency of Infusion Reactions13
Hypersensitivity/Infusion-Related Reactions
Infusion Reactions
25/406 (6.2%)
-
-
Grade 4: 1/406
*Most events (4) were diabetes mellitus; there was 1 event of diabetic ketoacidosis and 1 event of type 1 diabetes mellitus.13
Please see Important Safety Information for OPDIVO® on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
36
Forr ad
Fo
adul
ults
ul
tss wit
ith
h re
rela
laaps
laps
psed
ed or pr
prog
ogre
og
ress
re
ssed
ss
ed
d
classical hodgkin lymphoma
a te
af
terr au
uto
to-H
-H
HSC
SCT
T an
nd po
post
s -H
st
HSC
SCT
T br
bren
entu
en
tuxi
tu
xima
xi
mab
ma
b ve
vedo
doti
do
tin
ti
n
OPDIVO® Demonstrated Impressive Response Rates1
65%
(62/95) of patients
achieved an objective response1
OPDIVO Delivered a High ORR1
100
80
65%
ORR
CR: 7% (7/95)1
PR: 58% (55/95)1
ORR (%)
(95% CI: 55–75)
60
7% CR
The median time to response was
2.1 months (range 0.7 to 5.7 months).1
58% PR
Patients received a median of
17 doses of OPDIVO (range 3 to 48),
with a median duration of therapy of
8.3 months (range 1.9 to 24 months).1
(95% CI: 3–15)
40
(95% CI: 47–68)
20
0
ORR was evaluated by an independent radiographic review committee (IRRC).1
Study design: The efficacy of OPDIVO as a single agent was evaluated in 95 patients with cHL in Checkmate 205
and Checkmate 039 after failure of auto-HSCT and post-transplantation brentuximab vedotin.1
The combined analysis included1:
Checkmate 205 was a phase 2, single-arm, open-label, multicenter, multicohort study
Checkmate 039 was a phase 1, open-label, multicenter, dose-escalation study
Efficacy was evaluated by ORR, and an additional outcome measure was duration of response. Patients received
3 mg/kg of OPDIVO administered IV over 60 minutes every 2 weeks until disease progression,
maximal clinical benefit, or unacceptable toxicity.1
CR=complete response; PR=partial response.
Serious Adverse Reactions1
In Checkmate 205 and 039, serious adverse reactions occurred in 21% of patients. The most frequent serious adverse reactions
reported in at least 1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash, and pneumonitis.
Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT
Common Adverse Reactions1
In Checkmate 205 and 039, the most common adverse reactions (reported in at least 20%) among all patients (safety
population), were fatigue, upper respiratory tract infection, pyrexia, diarrhea, and cough
Among the subset of patients in the efficacy population, the most common adverse reactions also included rash,
musculoskeletal pain, pruritus, nausea, arthralgia, and peripheral neuropathy. Serious adverse reactions occurred in 27%
of these patients
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
37
Forr ad
Fo
adul
ults
ul
tss wit
ith
h re
rela
laaps
laps
psed
ed or pr
prog
ogre
og
ress
re
ssed
ss
ed
d
classical hodgkin lymphoma
a te
af
terr au
uto
to-H
-H
HSC
SCT
T an
nd po
post
s -ttraansspl
st
plan
anta
an
tati
ta
tion
ti
on bre
rent
ntux
nt
uxim
ux
imab
im
ab ved
edot
otin
ot
in
OPDIVO® ORRs Were Maintained Over Time1
AMONG RESPONDERS, MEDIAN DoR WAS
8.7 MONTHS1
(95% CI: 6.8–NE)
range (0.0+, 23.1+)
0
2
4
6
8
10
Median DoR (months)
DoR=duration of response.
Immune-Mediated Pneumonitis1
In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving
OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and
Grade 2 (n=8)
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
38
Forr ad
Fo
adul
ults
ul
tss wit
ith
h re
rela
laaps
laps
psed
ed or pr
prog
ogre
og
ress
re
ssed
ss
ed
d
classical hodgkin lymphoma
a te
af
terr au
uto
to-H
-H
HSC
SCT
T an
nd po
post
s -ttraansspl
st
plan
anta
an
tati
ta
tion
ti
on bre
rent
ntux
nt
uxim
ux
imab
im
ab ved
edot
otin
ot
in
Overview of Trials in Adults With Relapsed or Progressed cHL After Auto-HSCT and
Post-HSCT Brentuximab Vedotin
Checkmate 205 and 039: The efficacy of OPDIVO® as a single agent was evaluated in the combined analysis of 95
patients with cHL in Checkmate 205 (phase 2, single-arm, open-label, multicohort study) and Checkmate 039
(phase 1, open-label, multicenter, dose-escalation study) after failure of auto-HSCT and post-transplantation
brentuximab vedotin. Patients received OPDIVO 3 mg/kg IV every 2 weeks until disease progression, maximal
clinical benefit, or unacceptable toxicity. Efficacy was evaluated by ORR and an additional outcome measure was DoR.
ORR was evaluated by an IRRC1
— The safety of OPDIVO 3 mg/kg every 2 weeks was evaluated in 263 adult patients with cHL (240 patients
in Checkmate 205 and 23 patients in Checkmate 039)1
Checkmate 205 and 039: Onset of Select Immune-Mediated Adverse Reactions1,14
OPDIVO (N=263)
Median Time to Onset (Weeks)
Pneumonitis*
range: 1 day to 10.1 months
2.2
7.0†
Diarrhea/Colitis
Hepatitis
9.4
range: 6.7 to 26.0 weeks
Endocrinopathies
Hypophysitis‡
6.1†
Adrenal Insufficiency
Hypothyroidism/Thyroiditis
12.1
6.9 range: 5.1 to 11.0 weeks
Hyperthyroidism
Diabetes Mellitus
range: 0.1 to 26.1 weeks
2.1
†
Nephritis/
Renal Dysfunction‡
Rash
7.3
range: 0.1 to 36.1 weeks
Encephalitis§
Weeks 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 108 112 116 120
*Median time to onset and range for pneumonitis reported in months.1 †Represents time to onset.14 ‡Immune-mediated adverse reaction information not available.14 §Time to onset is
not available.1
Hypersensitivity/Infusion-Related Reactions14
Median time to onset is not available
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
39
Forr ad
Fo
adul
ults
ul
tss wit
ith
h re
rela
laaps
laps
psed
ed or pr
prog
ogre
og
ress
re
ssed
ss
ed
d
classical hodgkin lymphoma
a te
af
terr au
uto
to-H
-H
HSC
SCT
T an
nd po
post
s -ttraansspl
st
plan
anta
an
tati
ta
tion
ti
on bre
rent
ntux
nt
uxim
ux
imab
im
ab ved
edot
otin
ot
in
Checkmate 205 and 039: Frequency of Immune-Mediated Adverse Reactions1,14
All Grades n/N (%)
Grade 1 n/N
Grade 2 n/N
Grades 3–5 n/N
Immune-Mediated Pneumonitis
Pulmonary
9/263 (3.4%)
-
8/263
Grade 3: 1/263
Immune-Mediated Diarrhea/Colitis
Gastrointestinal
1/263 (0.4%)
-
-
Grade 3: 1/263
Immune-Mediated Hepatitis
Hepatic
6/263 (2.3%)
-
1/263
Grade 3: 5/263
Immune-Mediated Adrenal Insufficiency
1/263 (0.4%)
-
1/263
-
Immune-Mediated Hypothyroidism/Thyroiditis
25/263 (9.5%)
Endocrinopathies
9/263
16/263
-
Immune-Mediated Hyperthyroidism
3/263 (1.1%)
-
3/263
-
Immune-Mediated Diabetes Mellitus
1/263 (0.4%)
1/263
-
-
Nephritis and Renal Dysfunction
Renal
9/263* (3.4%)
-
-
-
3/263
Grade 3: 3/263
Immune-Mediated Rash
Skin
14/263 (5.3%)
8/263
Immune-Mediated Encephalitis
Neurological
†
2/263 (0.8%)
-
-
Grade 3: 2/263
*In addition to the 9 patients reported here, 1 patient had Grade 3 autoimmune nephritis treated with corticosteroids.14 †Encephalitis occurred after allogeneic HSCT after OPDIVO® therapy;
one case of Grade 3 lymphocytic encephalitis without an identified infectious cause, which occurred and resolved on steroids and one case of Grade 3 suspected viral encephalitis, which
was resolved with antiviral treatment.1
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
40
Forr ad
Fo
adul
ults
ul
tss wit
ith
h re
rela
laaps
laps
psed
ed or pr
prog
ogre
og
ress
re
ssed
ss
ed
d
classical hodgkin lymphoma
a te
af
terr au
uto
to-H
-H
HSC
SCT
T an
nd po
post
s -ttraansspl
st
plan
anta
an
tati
ta
tion
ti
on bre
rent
ntux
nt
uxim
ux
imab
im
ab ved
edot
otin
ot
in
Checkmate 205 and 039: Frequency of Infusion Reactions14
All Grades n/N (%)
Grade 1 n/N
Grade 2 n/N
Grades 3–5 n/N
Hypersensitivity/Infusion Reactions
Infusion Reactions
38/263 (14.4%)
-
-
-
Checkmate 205 and 039: Complications of Allogeneic HSCT After OPDIVO®1
Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes
were evaluated in 17 patients from Checkmate 205 and 039 who underwent allogeneic HSCT after discontinuing
OPDIVO (15 with reduced-intensity conditioning, two with myeloablative conditioning). The median age at HSCT was
33 (range: 18 to 56), and a median of 9 doses of OPDIVO had been administered (range: 4 to 16). Six of 17 patients
(35%) died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or
refractory GVHD. Grade 3 or higher acute GVHD was reported in 5/17 patients (29%). Hyperacute GVHD, defined as
GVHD occurring within 14 days after stem cell infusion, was reported in 2 patients (20%). A steroid-requiring febrile
syndrome, without an identified infectious cause, was reported in six patients (35%) within the first 6 weeks
post-transplantation, with five patients responding to steroids. Two cases of encephalitis were reported: one case
of Grade 3 lymphocytic encephalitis without an identified infectious cause, which occurred and resolved on steroids,
and one case of Grade 3 suspected viral encephalitis which was resolved with antiviral treatment. Hepatic
veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic HSCT
and died of GVHD and multi-organ failure
Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients
with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute
GVHD have also been reported
These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT
Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe
(Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse
reactions, and intervene promptly
GVHD=graft-versus-host disease.
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
41
recu
re
curr
cu
rrrent
ent or
en
o met
etas
a ta
as
tati
ticc
ti
squamous cell carcinoma of the head and neck
w th
wi
th dissea
e see pro
rogr
grres
essi
sion
si
o on or aft
on
fter
er a pla
lati
tinu
ti
numnu
m-ba
mbase
ba
sed
se
d th
ther
erap
er
apyy
ap
The Opportunity for Survival: OPDIVO® More Than
Doubled 1-Year Overall Survival vs Standard of Care
Options15*
Checkmate 141: Superior Overall Survival1,15
Median OS
PROBABILITY OF SURVIVAL (%)
100
7.5 mos. (95% CI: 5.5–9.1)
5.1 mos. (95% CI: 4.0–6.0)
OPDIVO
IC
90
HR=0.70; 95% CI: 0.53–0.92; P=0.0101
80
70
36%
60
1-Year OS
50
95% CI: 29–43
40
30
20
17%
10
95% CI: 9–27
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
MONTHS
Number at risk
OPDIVO
IC
240
121
167
87
109
42
52
17
24
5
7
1
0
0
*IC of cetuximab (n=15) 400 mg/m2 loading dose IV followed by 250 mg/m2 IV weekly, methotrexate (n=52) 40 to 60 mg/m2 IV weekly, or docetaxel (n=54)
30 to 40 mg/m2 IV weekly.1
IC=investigator’s choice.
Serious Adverse Reactions1
In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent
serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, dyspnea,
respiratory failure, respiratory tract infection, and sepsis
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
42
recu
re
curr
cu
rrrent
ent or
en
o met
etas
a ta
as
tati
ticc
ti
squamous cell carcinoma of the head and neck
w th
wi
th dissea
e see pro
rogr
grres
essi
sion
si
o on or aft
on
fter
er a pla
lati
tinu
ti
numnu
m-ba
mbase
ba
sed
se
d th
ther
erap
er
apyy
ap
The only I-O therapy with superior
overall survival vs IC1*
For OPDIVO® vs IC, the HR for PFS was 0.89 (95% CI: 0.70–1.13)1
ORR with OPDIVO was 13.3% (95% CI: 9.3–18.3) vs 5.8% (95% CI: 2.4–11.6) for IC1
Checkmate 141 results were based on a prespecified interim analysis conducted when 78% of the planned number of
events for final analysis occurred1
Study design: Checkmate 141 was a randomized (2:1), active-controlled, open-label, multicenter, phase 3 study of OPDIVO
3 mg/kg IV over 60 minutes every 2 weeks (n=240) vs IC (n=121) of cetuximab (n=15) 400 mg/m2 loading dose IV followed
by 250 mg/m2 weekly, methotrexate (n=52) 40 to 60 mg/m2 IV weekly, or docetaxel (n=54) 30 to 40 mg/m2 IV weekly
in patients with recurrent or metastatic SCCHN who had experienced disease progression during or within 6 months of
receiving platinum-based therapy. The primary endpoint was OS. Secondary endpoints were PFS and ORR.1
*IC of cetuximab (n=15) 400 mg/m2 loading dose IV followed by 250 mg/m2 IV weekly, methotrexate (n=52) 40 to 60 mg/m2 IV weekly, or docetaxel (n=54) 30 to 40 mg/m2 IV weekly.1
I-O=Immuno-Oncology.
Common Adverse Reactions1
In Checkmate 141, the most common adverse reactions occurring in ≥10% of OPDIVO-treated patients and at a higher
incidence than investigator’s choice were cough and dyspnea
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
43
recu
re
curr
cu
rrrent
ent or
en
o met
etas
a ta
as
tati
ticc
ti
squamous cell carcinoma of the head and neck
w th
wi
th dissea
e see pro
rogr
grres
essi
sion
si
o on or aft
on
fter
er a pla
lati
tinu
ti
numnu
m-ba
mbase
ba
sed
se
d th
ther
erap
er
apyy
ap
Overview of Trial in Recurrent or Metastatic SCCHN With Disease Progression on or After a
Platinum-Based Therapy
Checkmate 141: OPDIVO® was evaluated in a randomized (2:1), active-controlled, open-label, multicenter, phase 3 study
of OPDIVO 3 mg/kg IV over 60 minutes every 2 weeks (n=240) vs IC (n=121) of cetuximab (n=15) 400 mg/m2 loading dose
IV followed by 250 mg/m2 weekly, methotrexate (n=52) 40 to 60 mg/m2 IV weekly, or docetaxel (n=54) 30 to 40 mg/m2
IV weekly in patients with recurrent or metastatic SCCHN who had experienced disease progression during or within
6 months of receiving platinum-based therapy. The primary endpoint was OS. Secondary endpoints were PFS and ORR1
Checkmate 141: Onset of Select Immune-Mediated Adverse Reactions16
OPDIVO (N=236)
Median Time to Onset (Weeks)
Pneumonitis
4.9
Diarrhea/Colitis
range: 3.0 to 6.6 weeks
12.3 range: 8.0 to 16.4 weeks
Hepatitis
19.1*
Endocrinopathies
Hypophysitis
5.6 range: 5.1 to 5.9 weeks
Adrenal Insufficiency
5.1*
Hypothyroidism/Thyroiditis
11.7
Hyperthyroidism
9.6
range: 0.1 to 25.1 weeks
range: 2.1 to 18.0 weeks
†
Diabetes Mellitus
Nephritis and
Renal Dysfunction†
Rash
4.1
range: 1.0 to 22.9 weeks
Encephalitis†
Weeks 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 108 112 116 120
*Represents time to onset.16 †Immune-mediated adverse reaction information not available.16
Hypersensitivity/Infusion-Related Reactions16
The median time to onset is not available
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
44
recu
re
curr
cu
rrrent
ent or
en
o met
etas
a ta
as
tati
ticc
ti
squamous cell carcinoma of the head and neck
w th
wi
th dissea
e see pro
rogr
grres
essi
sion
si
o on or aft
on
fter
er a pla
lati
tinu
ti
numnu
m-ba
mbase
ba
sed
se
d th
ther
erap
er
apyy
ap
Checkmate 141: Frequency of Immune-Mediated Adverse Reactions16
All Grades n/N (%)
Grade 1 n/N
Grade 2 n/N
Grades 3–5 n/N
Immune-Mediated Pneumonitis
Pulmonary
2/236 (0.8%)
-
-
Grade 3: 2/236
Immune-Mediated Diarrhea/Colitis
Gastrointestinal
2/236 (0.8%)
1/236
1/236
-
Immune-Mediated Hepatitis
Hepatic
1/236 (0.4%)
-
-
Grade 3: 1/236
Immune-Mediated Hypophysitis
2/236 (0.8%)
-
1/236
Grade 4: 1/236
Immune-Mediated Adrenal Insufficiency
1/236 (0.4%)
Endocrinopathies
-
-
Grade 3: 1/236
Immune-Mediated Hypothyroidism/Thyroiditis
19/236 (8.1%)
9/236
10/236
-
Immune-Mediated Hyperthyroidism
3/236 (1.3%)
2/236
1/236
-
Immune-Mediated Rash
Skin
12/235 (5.1%)
8/236
4/236
-
Checkmate 141: Frequency of Infusion Reactions16
Hypersensitivity/Infusion-Related Reactions
Infusion Reactions
4/236 (1.7%)
-
-
-
Please see Important Safety Information for OPDIVO® on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
45
Forr pr
Fo
p ev
e io
ious
usly
us
lyy treat
reeat
a ed pat
a ie
ient
ntss wi
nt
with
th loc
ocal
ally
al
ly adv
dvan
ance
an
ced
ce
d or
metastatic urothelial carcinoma
OPDIVO® Demonstrated an ORR of 19.6%1
19.6% ORR
(53/270)
PR: 17.0% (n=46) QCR: 2.6% (n=7)
PR=partial response; CR=complete response.
ORR by PD-L1 Expression Status
Æ1%
(124/270)
25% ORR
(31/124)
<1%
(146/270)
15.1% ORR
19.6% (53/270) of patients
achieved an objective response1
CR: 2.6% (n=7)
PR: 17.0% (n=46)
Efficacy was evaluated in 270 patients with
6 months’ follow-up by confirmed ORR as
determined by an IRRC1
OPDIVO delivered a 25% ORR in patients with
PD-L1 expression ≥1% (31/124) and 15.1% in
patients with PD-L1 expression <1% (22/146)1
46% of patients had PD-L1 expression ≥1%
(124/270), and 54% of patients had PD-L1
expression <1% (146/270)1
(22/146)
PR: 20.2% (n=25) QCR: 4.8% (n=6) PR:14.4% (n=21) QCR: 0.7% (n=1) Study design: The efficacy of OPDIVO was evaluated in a phase 2, single-arm study of 270 patients with locally advanced
or mUC who have disease progression during or following platinum-containing chemotherapy or have disease
progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy,
regardless of PD-L1 status.1
The primary endpoint was ORR.* Patients received OPDIVO 3 mg/kg every 2 weeks† until disease progression or
unacceptable toxicity.1,17
*ORR was evaluated by an independent radiographic review committee (IRRC) with RECIST 1.1.1 ,17
†
The recommended dose of OPDIVO is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or until unacceptable toxicity.
Serious Adverse Reactions1
In Checkmate 275, serious adverse reactions occurred in 54% of patients. The most frequent serious adverse reactions (≥2%)
were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
46
Forr pr
Fo
p ev
e io
ious
usly
us
lyy treat
reeat
a ed pat
a ie
ient
ntss wi
nt
with
th loc
ocal
ally
al
ly adv
dvan
ance
an
ced
ce
d or
metastatic urothelial carcinoma
Median Duration of Response Was 10.3 Months1
(Range: 1.9+ to 12.0+ months)
Time
(mos)
0
1
2
3
4
5
6
7
8
9
10
11
12
Median Duration of Response
10.3 months
range (1.9+ to 12.0+)
The median time to response was 1.9 months (range: 1.6 to 7.2 months)1
Common Adverse Reactions1
In Checkmate 275, the most common adverse reactions (≥20%) were fatigue (46%), musculoskeletal pain (30%),
nausea (22%), and decreased appetite (22%)
Additional Safety Information
OPDIVO was discontinued due to adverse reactions in 17% of patients
46% of patients receiving OPDIVO had a drug delay for an adverse reaction
Treatment-related death occurred in 4 patients due to pneumonitis or cardiovascular failure
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
47
Forr pr
Fo
p ev
e io
ious
usly
us
lyy treat
reeat
a ed pat
a ie
ient
ntss wi
nt
with
th loc
ocal
ally
al
ly adv
dvan
ance
an
ced
ce
d or
metastatic urothelial carcinoma
Overview of Checkmate 275: A Clinical Trial Evaluating Objective Response Rate
Checkmate 275: The efficacy of OPDIVO® was evaluated in a phase 2, single-arm study of 270 patients with locally
advanced or mUC who have disease progression during or following platinum-containing chemotherapy or have
disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy,
regardless of PD-L1 status. Patients received OPDIVO 3 mg/kg every 2 weeks until disease progression or unacceptable
toxicity. The primary endpoint was ORR by IRRC with RECIST 1.11,17
— The safety of OPDIVO was studied in 270 adult patients with previously treated locally advanced or mUC1
Checkmate 275: Onset of Select Immune-Mediated Adverse Reactions17
OPDIVO (N=270)
Median Time to Onset (Weeks)
Pneumonitis
8.9
Diarrhea/Colitis
10.0
Hepatitis
range: 2.3 to 28.7 weeks
range: 3.4 to 12.6 weeks
range: 2.9 to 21.0 weeks
4.1
Endocrinopathies
25.6
Hypophysitis
Adrenal Insufficiency
30.5
Hypothyroidism/Thyroiditis
Hyperthyroidism
Diabetes Mellitus
range: 29.1 to 31.9 weeks
range: 0.1 to 30 weeks
11.4
range: 2.1 to 25.6 weeks
4.8
10.1*
Nephritis/
Renal Dysfunction
Rash
range: 24.1 to 27.1 weeks
range: 1.1 to 41.6 weeks
21.4
9.2
range: 1.7 to 30.1 weeks
Encephalitis†
Weeks 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 108 112 116 120
*
Represents time to onset.18 †Immune-mediated adverse reaction information not available.17
Hypersensitivity/Infusion-Related Reactions17
The median time to onset was 2.1 weeks
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
48
Forr pr
Fo
p ev
e io
ious
usly
us
lyy treat
reeat
a ed pat
a ie
ient
ntss wi
nt
with
th loc
ocal
ally
al
ly adv
dvan
ance
an
ced
ce
d or
metastatic urothelial carcinoma
Checkmate 275: Frequency of Immune-Mediated Adverse Reactions17
All Grades n/N (%)
Grade 1 n/N
Grade 2 n/N
Grades 3–5 n/N
Immune-Mediated Pneumonitis
Pulmonary
10/270 (3.7%)
3/270
3/270
Grade 3: 3/270
Grade 5: 1/270
Immune-Mediated Diarrhea/Colitis
Gastrointestinal
7/270 (2.6%)
-
2/270
Grade 3: 4/270
Grade 4: 1/270
Immune-Mediated Hepatitis
Hepatic
3/270 (1.1%)
1/270
1/270
Grade 3: 1/270
Immune-Mediated Hypophysitis
2/270 (0.7%)
-
1/270
Grade 3: 1/270
Immune-Mediated Adrenal Insufficiency
2/270 (0.7%)
-
2/270
-
Immune-Mediated Hypothyroidism/Thyroiditis
Endocrinopathies
29/270 (10.7%)
9/270
20/270
-
Immune-Mediated Hyperthyroidism
12/270 (4.4%)
5/270
7/270
-
Immune-Mediated Diabetes Mellitus
1/270 (0.3%)
-
1/270
-
Immune-Mediated Nephritis and Renal Dysfunction
Renal
2/270 (0.7%)
-
-
Grade 3: 2/270
9/270
6/270
Grade 3: 3/270
Grade 1 n/N
Grade 2 n/N
Grades 3–5 n/N
Immune-Mediated Rash
Skin
18/270 (6.7%)
Checkmate 275: Frequency of Infusion Reactions17
All Grades n/N (%)
Hypersensitivity/Infusion Reactions
Infusion Reactions
1/270 (0.4%)
-
-
Grade 3: 1/270
Please see Important Safety Information for OPDIVO on pages 50-53 and the US Full Prescribing Information for OPDIVO at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
49
REGIMEN
IMPORTANT SAFETY INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY® can result in severe and fatal immune-mediated
adverse reactions. These immune-mediated reactions
may involve any organ system; however, the most
common severe immune-mediated adverse reactions
are enterocolitis, hepatitis, dermatitis (including toxic
epidermal necrolysis), neuropathy, and endocrinopathy.
The majority of these immune-mediated reactions
initially manifested during treatment; however, a minority
occurred weeks to months after discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis,
dermatitis, neuropathy, and endocrinopathy and evaluate
clinical chemistries including liver function tests (LFTs),
adrenocorticotropic hormone (ACTH) level, and thyroid
function tests at baseline and before each dose.
Permanently discontinue YERVOY and initiate
systemic high-dose corticosteroid therapy for severe
immune-mediated reactions.
Immune-Mediated Pneumonitis
OPDIVO® can cause immune-mediated pneumonitis. Fatal
cases have been reported. Monitor patients for signs with
radiographic imaging and for symptoms of pneumonitis.
Administer corticosteroids for Grade 2 or more severe
pneumonitis. Permanently discontinue for Grade 3 or 4 and
withhold until resolution for Grade 2. In patients receiving
OPDIVO monotherapy, fatal cases of immune-mediated
pneumonitis have occurred. Immune-mediated pneumonitis
occurred in 3.1% (61/1994) of patients. In patients receiving
OPDIVO with YERVOY, immune-mediated pneumonitis
occurred in 6% (25/407) of patients.
In Checkmate 205 and 039, pneumonitis, including interstitial
lung disease, occurred in 4.9% (13/263) of patients receiving
OPDIVO. Immune-mediated pneumonitis occurred in 3.4%
(9/263) of patients receiving OPDIVO: Grade 3 (n=1) and
Grade 2 (n=8).
Immune-Mediated Colitis
OPDIVO can cause immune-mediated colitis. Monitor
patients for signs and symptoms of colitis. Administer
corticosteroids for Grade 2 (of more than 5 days duration), 3, or
4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and
permanently discontinue for Grade 4 or recurrent colitis upon
re-initiation of OPDIVO. When administered with YERVOY,
withhold OPDIVO and YERVOY for Grade 2 and permanently
discontinue for Grade 3 or 4 or recurrent colitis. In patients
receiving OPDIVO monotherapy, immune-mediated colitis
occurred in 2.9% (58/1994) of patients. In patients receiving
OPDIVO with YERVOY, immune-mediated colitis occurred in
26% (107/407) of patients including three fatal cases.
Immune-Mediated Colitis (cont’d)
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal (diarrhea of ≥7 stools above
baseline, fever, ileus, peritoneal signs; Grade 3-5) immunemediated enterocolitis occurred in 34 (7%) patients. Across
all YERVOY-treated patients in that study (n=511), 5 (1%)
developed intestinal perforation, 4 (0.8%) died as a result
of complications, and 26 (5%) were hospitalized for severe
enterocolitis.
Immune-Mediated Hepatitis
OPDIVO can cause immune-mediated hepatitis. Monitor
patients for abnormal liver tests prior to and periodically
during treatment. Administer corticosteroids for Grade 2 or
greater transaminase elevations. Withhold for Grade 2 and
permanently discontinue for Grade 3 or 4 immune-mediated
hepatitis. In patients receiving OPDIVO monotherapy, immunemediated hepatitis occurred in 1.8% (35/1994) of patients. In
patients receiving OPDIVO with YERVOY, immune-mediated
hepatitis occurred in 13% (51/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, lifethreatening, or fatal hepatotoxicity (AST or ALT elevations >5x
the ULN or total bilirubin elevations >3x the ULN; Grade 3-5)
occurred in 8 (2%) patients, with fatal hepatic failure in 0.2%
and hospitalization in 0.4%.
Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of
fatal Guillain-Barré syndrome and 1 case of severe (Grade 3)
peripheral motor neuropathy were reported.
Immune-Mediated Endocrinopathies
OPDIVO can cause immune-mediated hypophysitis, immunemediated adrenal insufficiency, autoimmune thyroid disorders,
and Type 1 diabetes mellitus. Monitor patients for signs
and symptoms of hypophysitis, signs and symptoms of
adrenal insufficiency, thyroid function prior to and periodically
during treatment, and hyperglycemia. Administer hormone
replacement as clinically indicated and corticosteroids for
Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and
permanently discontinue for Grade 4 hypophysitis. Administer
corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold
for Grade 2 and permanently discontinue for Grade 3 or 4
adrenal insufficiency. Administer hormone-replacement
therapy for hypothyroidism. Initiate medical management for
control of hyperthyroidism. Withhold OPDIVO for Grade 3 and
permanently discontinue for Grade 4 hyperglycemia.
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
50
REGIMEN
IMPORTANT SAFETY INFORMATION (cont’d)
Immune-Mediated Endocrinopathies (cont’d)
Immune-Mediated Skin Adverse Reactions
and Dermatitis (cont’d)
In patients receiving OPDIVO® monotherapy, hypophysitis
occurred in 0.6% (12/1994) of patients. In patients receiving
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407)
life-threatening, or fatal immune-mediated dermatitis
of patients. In patients receiving OPDIVO monotherapy,
(eg, Stevens-Johnson syndrome, toxic epidermal necrolysis,
adrenal insufficiency occurred in 1% (20/1994) of patients. In
or rash complicated by full thickness dermal ulceration, or
patients receiving OPDIVO with YERVOY, adrenal insufficiency
necrotic, bullous, or hemorrhagic manifestations; Grade 3-5)
occurred in 5% (21/407) of patients. In patients receiving
occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result
OPDIVO monotherapy, hypothyroidism or thyroiditis resulting
of toxic epidermal necrolysis. 1 additional patient required
in hypothyroidism occurred in 9% (171/1994) of patients.
hospitalization for severe dermatitis.
Hyperthyroidism occurred in 2.7% (54/1994) of patients
Immune-Mediated Encephalitis
receiving OPDIVO monotherapy. In patients receiving OPDIVO
OPDIVO can cause immune-mediated encephalitis.
with YERVOY, hypothyroidism or thyroiditis resulting in
Evaluation of patients with neurologic symptoms may
hypothyroidism occurred in 22% (89/407) of patients.
include, but not be limited to, consultation with a
Hyperthyroidism occurred in 8% (34/407) of patients
neurologist, brain MRI, and lumbar puncture. Withhold
receiving OPDIVO with YERVOY. In patients receiving OPDIVO
OPDIVO in patients with new-onset moderate to severe
monotherapy, diabetes occurred in 0.9% (17/1994) of patients.
neurologic signs or symptoms and evaluate to rule out
In patients receiving OPDIVO with YERVOY, diabetes occurred in
other causes. If other etiologies are ruled out, administer
1.5% (6/407) of patients.
corticosteroids and permanently discontinue OPDIVO for
In a separate Phase 3 study of YERVOY 3 mg/kg, severe to
immune-mediated encephalitis. In patients receiving OPDIVO
life-threatening immune-mediated endocrinopathies (requiring
monotherapy, encephalitis occurred in 0.2% (3/1994) of
hospitalization, urgent medical intervention, or interfering with
patients. Fatal limbic encephalitis occurred in one patient
activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients.
after 7.2 months of exposure despite discontinuation of
All 9 patients had hypopituitarism, and some had additional
OPDIVO and administration of corticosteroids. Encephalitis
concomitant endocrinopathies such as adrenal insufficiency,
occurred in one patient receiving OPDIVO with YERVOY
hypogonadism, and hypothyroidism. 6 of the 9 patients were
(0.2%) after 1.7 months of exposure.
hospitalized for severe endocrinopathies.
Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. Monitor
patients for elevated serum creatinine prior to and periodically
during treatment. Administer corticosteroids for Grades 2-4
increased serum creatinine. Withhold OPDIVO for Grade 2 or 3
and permanently discontinue for Grade 4 increased serum
creatinine. In patients receiving OPDIVO monotherapy,
immune-mediated nephritis and renal dysfunction occurred in
1.2% (23/1994) of patients. In patients receiving OPDIVO with
YERVOY, immune-mediated nephritis and renal dysfunction
occurred in 2.2% (9/407) of patients.
Immune-Mediated Skin Adverse Reactions
and Dermatitis
OPDIVO can cause immune-mediated rash, including
Stevens-Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN), some cases with fatal outcome. Administer
corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3
and permanently discontinue for Grade 4 rash. For symptoms
or signs of SJS or TEN, withhold OPDIVO and refer the
patient for specialized care for assessment and treatment;
if confirmed, permanently discontinue. In patients receiving
OPDIVO monotherapy, immune-mediated rash occurred in
9% (171/1994) of patients. In patients receiving OPDIVO with
YERVOY, immune-mediated rash occurred in 22.6% (92/407)
of patients.
Other Immune-Mediated Adverse Reactions
Based on the severity of adverse reaction, permanently
discontinue or withhold treatment, administer high-dose
corticosteroids, and, if appropriate, initiate hormonereplacement therapy. Across clinical trials of OPDIVO
the following clinically significant immune-mediated
adverse reactions occurred in <1.0% of patients receiving
OPDIVO: uveitis, iritis, pancreatitis, facial and abducens
nerve paresis, demyelination, polymyalgia rheumatica,
autoimmune neuropathy, Guillain-Barré syndrome,
hypopituitarism, systemic inflammatory response
syndrome, gastritis, duodenitis, sarcoidosis, histiocytic
necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis,
myocarditis, rhabdomyolysis, motor dysfunction, vasculitis,
and myasthenic syndrome.
Infusion Reactions
OPDIVO can cause severe infusion reactions, which have been
reported in <1.0% of patients in clinical trials. Discontinue
OPDIVO in patients with Grade 3 or 4 infusion reactions.
Interrupt or slow the rate of infusion in patients with Grade 1 or
2. In patients receiving OPDIVO monotherapy, infusion-related
reactions occurred in 6.4% (127/1994) of patients. In patients
receiving OPDIVO with YERVOY, infusion-related reactions
occurred in 2.5% (10/407) of patients..
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
51
REGIMEN
IMPORTANT SAFETY INFORMATION (cont’d)
Complications of Allogeneic HSCT after OPDIVO®
Complications, including fatal events, occurred in patients
who received allogeneic HSCT after OPDIVO. Outcomes were
evaluated in 17 patients from Checkmate 205 and 039, who
underwent allogeneic HSCT after discontinuing OPDIVO
(15 with reduced-intensity conditioning, 2 with myeloablative
conditioning). Thirty-five percent (6/17) of patients died
from complications of allogeneic HSCT after OPDIVO. Five
deaths occurred in the setting of severe or refractory GVHD.
Grade 3 or higher acute GVHD was reported in 29% (5/17)
of patients. Hyperacute GVHD was reported in 20% (n=2)
of patients. A steroid-requiring febrile syndrome, without
an identified infectious cause, was reported in 35% (n=6) of
patients. Two cases of encephalitis were reported: Grade 3
(n=1) lymphocytic encephalitis without an identified infectious
cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic
veno-occlusive disease (VOD) occurred in one patient, who
received reduced-intensity conditioned allogeneic HSCT and
died of GVHD and multi-organ failure. Other cases of hepatic
VOD after reduced-intensity conditioned allogeneic HSCT have
also been reported in patients with lymphoma who received a
PD-1 receptor blocking antibody before transplantation. Cases
of fatal hyperacute GVHD have also been reported. These
complications may occur despite intervening therapy between
PD-1 blockade and allogeneic HSCT.
Follow patients closely for early evidence of transplantrelated complications such as hyperacute GVHD, severe
(Grade 3 to 4) acute GVHD, steroid-requiring febrile
syndrome, hepatic VOD, and other immune-mediated
adverse reactions, and intervene promptly.
Embryo-Fetal Toxicity
Based on their mechanisms of action, OPDIVO and YERVOY®
can cause fetal harm when administered to a pregnant
woman. Advise pregnant women of the potential risk to a
fetus. Advise females of reproductive potential to use effective
contraception during treatment with an OPDIVO- or YERVOYcontaining regimen and for at least 5 months after the last
dose of OPDIVO.
Lactation
It is not known whether OPDIVO or YERVOY is present in
human milk. Because many drugs, including antibodies,
are excreted in human milk and because of the potential
for serious adverse reactions in nursing infants from an
OPDIVO-containing regimen, advise women to discontinue
breastfeeding during treatment. Advise women to discontinue
nursing during treatment with YERVOY and for 3 months
following the final dose.
Serious Adverse Reactions
In Checkmate 037, serious adverse reactions occurred in 41%
of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse
reactions occurred in 42% of patients receiving OPDIVO. The
most frequent Grade 3 and 4 adverse drug reactions reported
in 2% to <5% of patients receiving OPDIVO were abdominal
pain, hyponatremia, increased aspartate aminotransferase,
and increased lipase. In Checkmate 066, serious adverse
reactions occurred in 36% of patients receiving OPDIVO
(n=206). Grade 3 and 4 adverse reactions occurred in 41% of
patients receiving OPDIVO. The most frequent Grade 3 and 4
adverse reactions reported in ≥2% of patients receiving
OPDIVO were gamma-glutamyltransferase increase (3.9%) and
diarrhea (3.4%). In Checkmate 067, serious adverse reactions
(73% and 37%), adverse reactions leading to permanent
discontinuation (43% and 14%) or to dosing delays (55% and
28%), and Grade 3 or 4 adverse reactions (72% and 44%) all
occurred more frequently in the OPDIVO plus YERVOY arm
(n=313) relative to the OPDIVO arm (n=313). The most frequent
(≥10%) serious adverse reactions in the OPDIVO plus YERVOY
arm and the OPDIVO arm, respectively, were diarrhea (13% and
2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In
Checkmate 017 and 057, serious adverse reactions occurred in
46% of patients receiving OPDIVO (n=418). The most frequent
serious adverse reactions reported in at least 2% of patients
receiving OPDIVO were pneumonia, pulmonary embolism,
dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory
failure. In Checkmate 025, serious adverse reactions occurred in
47% of patients receiving OPDIVO (n=406). The most frequent
serious adverse reactions reported in ≥2% of patients were
acute kidney injury, pleural effusion, pneumonia, diarrhea, and
hypercalcemia. In Checkmate 205 and 039, among all patients
(safety population [n=263]), adverse reactions leading to
discontinuation (4.2%) or to dosing delays (23%) occurred.
The most frequent serious adverse reactions reported in ≥1%
of patients were infusion-related reaction, pneumonia, pleural
effusion, pyrexia, rash and pneumonitis. Ten patients died from
causes other than disease progression, including 6 who died
from complications of allogeneic HSCT. Serious adverse
reactions occurred in 21% of patients in the safety
population (n=263) and 27% of patients in the subset of
patients evaluated for efficacy (efficacy population [n=95]).
In Checkmate 141, serious adverse reactions occurred in 49%
of patients receiving OPDIVO. The most frequent serious
adverse reactions reported in at least 2% of patients receiving
OPDIVO were pneumonia, dyspnea, respiratory failure,
respiratory tract infection, and sepsis. In Checkmate 275,
serious adverse reactions occurred in 54% of patients receiving
OPDIVO (n=270). The most frequent serious adverse reactions
reported in at least 2% of patients receiving OPDIVO were
urinary tract infection, sepsis, diarrhea, small intestine
obstruction, and general physical health deterioration.
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
52
REGIMEN
IMPORTANT SAFETY INFORMATION (cont’d)
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%)
reported with OPDIVO (n=268) was rash (21%). In Checkmate 066,
the most common adverse reactions (≥20%) reported with
OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs
39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%),
and pruritus (23% vs 12%). In Checkmate 067, the
most common (≥20%) adverse reactions in the OPDIVO
plus YERVOY arm (n=313) were fatigue (59%), rash (53%),
diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%),
and dyspnea (20%). The most common (≥20%) adverse
reactions in the OPDIVO (n=313) arm were fatigue (53%),
rash (40%), diarrhea (31%), and nausea (28%). In Checkmate
017 and 057, the most common adverse reactions (≥20%)
in patients receiving OPDIVO (n=418) were fatigue,
musculoskeletal pain, cough, dyspnea, and decreased appetite.
In Checkmate 025, the most common adverse reactions
(≥20%) reported in patients receiving OPDIVO (n=406) vs
everolimus (n=397) were asthenic conditions (56% vs 57%),
cough (34% vs 38%), nausea (28% vs 29%), rash (28%
vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%),
constipation (23% vs 18%), decreased appetite (23% vs 30%),
back pain (21% vs 16%), and arthralgia (20% vs 14%).
In Checkmate 205 and 039, among all patients (safety
population [n=263]) and the subset of patients in the efficacy
population (n=95), respectively, the most common adverse
reactions (≥20%) were fatigue (32% and 43%), upper
respiratory tract infection (28% and 48%), pyrexia (24%
and 35%), diarrhea (23% and 30%), and cough (22% and
35%). In the subset of patients in the efficacy population
(n=95), the most common adverse reactions also included
rash (31%), musculoskeletal pain (27%), pruritus (25%),
nausea (23%), arthralgia (21%), and peripheral neuropathy (21%).
In Checkmate 141, the most common adverse reactions
(≥10%) in patients receiving OPDIVO were cough and
dyspnea at a higher incidence than investigator’s choice. In
Checkmate 275, the most common adverse reactions
(≥20%) reported in patients receiving OPDIVO (n=270) were
fatigue (46%), musculoskeletal pain (30%), nausea (22%),
and decreased appetite (22%).
In a separate Phase 3 study of YERVOY® 3 mg/kg, the most
common adverse reactions (≥5%) in patients who received
YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%),
pruritus (31%), rash (29%), and colitis (8%).
Checkmate Trials and Patient Populations
Checkmate 067 - advanced melanoma alone or in
combination with YERVOY; Checkmate 017 - squamous
non-small cell lung cancer (NSCLC); Checkmate 057 non-squamous NSCLC; Checkmate 025 - renal cell
carcinoma; Checkmate 205/039 - classical Hodgkin
lymphoma; Checkmate 141 - squamous cell carcinoma of
the head and neck; Checkmate 275 - metastatic urothelial
carcinoma.
References: 1. OPDIVO® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2017. 2. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and
ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-2017 [supplementary appendix]. 3. National Cancer Institute.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.
pdf. Published June 14, 2010. Accessed October 7, 2016. 4. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous
non—small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639 [protocol]. 5. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in
advanced nonsquamous non—small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639. 6. Referenced with permission from the NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2016. © National Comprehensive Network, Inc 2016. All rights reserved.
Accessed February 3, 2016. To view the most recent and complete version of the guideline, go to NCCN.org. NATIONAL COMPREHENSIVE CANCER
NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
7. AlphaImpact Rx. BrandImpact Treatment Report. Week Ending 9-11-2015. Princeton, NJ: Bristol-Myers Squibb Company. 8. Brahmer J, Reckamp KL,
Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non—small-cell lung cancer. N Engl J Med. 2015;373(2):123-135. 9. Data on file.
NIVO 196. Princeton, NJ: Bristol-Myers Squibb Company; 2016. 10. Hodi FS, Chesney J, Pavlick AC, et al. Combined nivolumab and ipilimumab versus
ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial.
Lancet Oncol. 2016; http://dx.doi.org/10.1016/S1470-2045(16)30366-7. 11. Data on file. NIVO 194. Princeton, NJ: Bristol-Myers Squibb Company; 2016.
12. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813.
13. Data on file. NIVO 195. Princeton, NJ: Bristol-Myers Squibb Company; 2016. 14. Data on file. NIVO 119. Princeton, NJ: Bristol-Myers Squibb Company; 2016.
15. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. doi:10.1056/
NEJMoa1602252. 16. Data on file. NIVO 197. Princeton, NJ: Bristol-Myers Squibb Company; 2016. 17. Data on File. NIVO 215. Bristol-Myers Squibb Company,
Princeton, NJ; 2016.
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50-53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
53
REGIMEN
Treatment Modifications in Response
to Immune-Mediated Adverse Reactions1
Adverse Reaction
Severity*
Treatment Modification
Adverse Reaction
Grade 2 diarrhea or colitis
Withhold dose†
Serum creatinine >1.5 and up to
Nephritis and
6x the ULN
Renal Dysfunction
Serum creatinine >6x the ULN
Grade 3 diarrhea or colitis
Colitis
Pneumonitis
Hepatitis
Single-agent OPDIVO®
Withhold dose†
Administered with YERVOY®
Permanently discontinue
Grade 4 diarrhea or colitis
Permanently discontinue
Grade 2 pneumonitis
Withhold dose†
Grade 3 or 4 pneumonitis
Permanently discontinue
AST/or ALT more than 3 and up to
5x the ULN or total bilirubin more
than 1.5 and up to 3x the ULN
Withhold dose†
Encephalitis
Withhold dose†
Grade 4 hypophysitis
Permanently discontinue
Adrenal
Insufficiency
Grade 2 adrenal insufficiency
Withhold dose†
Grade 3 or 4 adrenal insufficiency
Permanently discontinue
Type 1 Diabetes
Mellitus
Grade 3 hyperglycemia
Withhold dose†
Grade 4 hyperglycemia
Permanently discontinue
Treatment Modification
Withhold dose†
Permanently discontinue
Grade 3 rash or suspected SJS
or TEN
Withhold dose†
Grade 4 rash or confirmed SJS
or TEN
Permanently discontinue
New-onset moderate or severe
neurologic signs or symptoms
Withhold dose†
Immune-mediated encephalitis
Permanently discontinue
Other Grade 3 adverse reaction
AST or ALT more than 5x the upper
limit of normal or total bilirubin
Permanently discontinue
more than 3x the ULN
Grade 2 or 3 hypophysitis
Hypophysitis
Skin
Severity*
Other
First occurrence
Withhold dose†
Recurrence of same Grade 3
adverse reactions
Permanently discontinue
Life-threatening or Grade 4
adverse reaction
Permanently discontinue
Requirement for ≥10 mg per day
prednisone or equivalent for
>12 weeks
Permanently discontinue
Persistent Grade 2 or 3 adverse
reactions lasting 12 weeks
or longer
Permanently discontinue
*Toxicity was graded per NCI CTCAE. Version 4.0. †Resume treatment when adverse reaction returns to Grade 0 or 1.
SJS=Stevens-Johnson syndrome; TEN=toxic epidermal necrolysis.
When OPDIVO is administered in combination with YERVOY, if OPDIVO is withheld, YERVOY should also be withheld
There are no recommended dose modifications for hypothyroidism or hyperthyroidism
Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions
Discontinue OPDIVO in patients with severe or life-threatening infusion reactions
OPDIVO as a single agent1
For previously treated metastatic NSCLC, advanced RCC previously treated with anti-angiogenic therapy, metastatic melanoma: and
previously treated locally advanced or metastatic urothelial carcinoma: The recommended dose of OPDIVO is 240 mg administered as
an IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
For adults with cHL after auto-HSCT and post-HSCT brentuximab vedotin and recurrent or metastatic SCCHN with disease progression
on or after platinum-based therapy: The recommended dose of OPDIVO is 3 mg/kg administered as an IV infusion over 60 minutes
every 2 weeks until disease progression or unacceptable toxicity.
OPDIVO in combination with YERVOY1
The recommended dose of OPDIVO is 1 mg/kg administered as an IV infusion over 60 minutes, followed by YERVOY on the same day,
every 3 weeks for 4 doses. The recommended subsequent dose of OPDIVO, as a single agent, is 240 mg administered as an IV infusion
over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
Review the Full Prescribing Information for OPDIVO and the OPDIVO + YERVOY Regimen prior to initiation.
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages 50–53 and the US Full Prescribing Information
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY, at the end of this document.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
Please visit OPDIVO.com/hcp or call 1-855-OPDIVO-1 (1-855-673-4861) for more information.
OPDIVO®,
YERVOY®,
andthe
the related
logos Prescribing
are trademarks ofInformation
Bristol-Myers Squibb Company.
Please see Important Safety Information for OPDIVO and the OPDIVO + YERVOY Regimen on pages
50-53
and
US Full
©2017
Squibb
All rights reserved.
for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY,
atBristol-Myers
the end of
thisCompany.
document.
Printed in USA. 1506US1604559-02-01 02/17
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
54
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use OPDIVO safely
and effectively. See full prescribing information for OPDIVO.
OPDIVO (nivolumab) injection, for intravenous use
Initial U.S. Approval: 2014
-----------------------------RECENT MAJOR CHANGES ---------------------------Indications and Usage (1)
2/2017
Dosage and Administration (2)
2/2017
Warnings and Precautions (5)
10/2016
----------------------------- INDICATIONS AND USAGE ----------------------------OPDIVO is a programmed death receptor-1 (PD-1) blocking antibody indicated for the
treatment of patients with:
• BRAF V600 wild-type unresectable or metastatic melanoma, as a single agent. (1.1)
• BRAF V600 mutation-positive unresectable or metastatic melanoma, as a single agent.
This indication is approved under accelerated approval based on progression-free
survival. Continued approval for this indication may be contingent upon verification
and description of clinical benefit in the confirmatory trials. (1.1)
• Unresectable or metastatic melanoma, in combination with ipilimumab. This
indication is approved under accelerated approval based on progression-free
survival. Continued approval for this indication may be contingent upon verification
and description of clinical benefit in the confirmatory trials. (1.1)
• Metastatic non-small cell lung cancer and progression on or after platinum-based
chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have
disease progression on FDA-approved therapy for these aberrations prior to receiving
OPDIVO. (1.2)
• Advanced renal cell carcinoma who have received prior anti-angiogenic therapy. (1.3)
• Classical Hodgkin lymphoma that has relapsed or progressed after autologous
hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab
vedotin. This indication is approved under accelerated approval based on overall
response rate. Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory trials. (1.4)
• Recurrent or metastatic squamous cell carcinoma of the head and neck with disease
progression on or after a platinum-based therapy. (1.5)
• Locally advanced or metastatic urothelial carcinoma who:
• have disease progression during or following platinum-containing chemotherapy
• have disease progression within 12 months of neoadjuvant or adjuvant treatment
with platinum-containing chemotherapy.
This indication is approved under accelerated approval based on tumor response rate
and duration of response. Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory trials. (1.6)
-------------------------- DOSAGE AND ADMINISTRATION -------------------------Administer as an intravenous infusion over 60 minutes.
• Unresectable or metastatic melanoma
• OPDIVO 240 mg every 2 weeks. (2.1)
• OPDIVO with ipilimumab: OPDIVO 1 mg/kg, followed by ipilimumab on the same
day, every 3 weeks for 4 doses, then OPDIVO 240 mg every 2 weeks. (2.1)
• Metastatic non-small cell lung cancer
• OPDIVO 240 mg every 2 weeks. (2.2)
• Advanced renal cell carcinoma
• OPDIVO 240 mg every 2 weeks. (2.3)
• Classical Hodgkin lymphoma
• OPDIVO 3 mg/kg every 2 weeks. (2.4)
• Recurrent or metastatic squamous cell carcinoma of the head and neck
• OPDIVO (nivolumab) 3 mg/kg every 2 weeks. (2.5)
• Locally advanced or metastatic urothelial carcinoma
• OPDIVO 240 mg every 2 weeks (2.6)
-------------------------DOSAGE FORMS AND STRENGTHS -----------------------Injection: 40 mg/4 mL and 100 mg/10 mL solution in a single-dose vial. (3)
------------------------------- CONTRAINDICATIONS ------------------------------None. (4)
-------------------------- WARNINGS AND PRECAUTIONS -------------------------• Immune-mediated pneumonitis: Withhold for moderate and permanently discontinue
for severe or life-threatening pneumonitis. (5.1)
• Immune-mediated colitis: Withhold OPDIVO when given as a single agent for
moderate or severe and permanently discontinue for life-threatening colitis. Withhold
OPDIVO when given with ipilimumab for moderate and permanently discontinue for
severe or life-threatening colitis. (5.2)
• Immune-mediated hepatitis: Monitor for changes in liver function. Withhold for
moderate and permanently discontinue for severe or life-threatening transaminase
or total bilirubin elevation. (5.3)
• Immune-mediated endocrinopathies: Withhold for moderate or severe and
permanently discontinue for life-threatening hypophysitis. Withhold for moderate and
permanently discontinue for severe or life-threatening adrenal insufficiency. Monitor
for changes in thyroid function. Initiate thyroid hormone replacement as needed.
Monitor for hyperglycemia. Withhold for severe and permanently discontinue for
life-threatening hyperglycemia. (5.4)
• Immune-mediated nephritis and renal dysfunction: Monitor for changes in renal
function. Withhold for moderate or severe and permanently discontinue for
life-threatening serum creatinine elevation. (5.5)
• Immune-mediated skin adverse reactions: Withhold for severe and permanently
discontinue for life-threatening rash. (5.6)
• Immune-mediated encephalitis: Monitor for changes in neurologic function. Withhold
for new-onset moderate to severe neurological signs or symptoms and permanently
discontinue for immune-mediated encephalitis. (5.7)
• Infusion reactions: Discontinue OPDIVO for severe and life-threatening infusion
reactions. Interrupt or slow the rate of infusion in patients with mild or moderate
infusion reactions. (5.9)
• Complications of allogeneic HSCT after OPDIVO: Monitor for hyperacute graft-versushost-disease (GVHD), grade 3-4 acute GVHD, steroid-requiring febrile syndrome,
hepatic veno-occlusive disease, and other immune-mediated adverse reactions.
Transplant-related mortality has occurred. (5.10)
• Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use
of effective contraception. (5.11, 8.1, 8.3)
------------------------------- ADVERSE REACTIONS ------------------------------Most common adverse reactions (≥20%) in patients were:
• OPDIVO as a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea,
nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain,
arthralgia, upper respiratory tract infection, pyrexia. (6.1)
• OPDIVO with ipilimumab: fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and
dyspnea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at
1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-------------------------- USE IN SPECIFIC POPULATIONS -------------------------Lactation: Discontinue breastfeeding. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 2/2017
FULL PRESCRIBING INFORMATION: CONTENTS*
1
2
INDICATIONS AND USAGE
1.1
Unresectable or Metastatic Melanoma
1.2
Metastatic Non-Small Cell Lung Cancer
1.3
Renal Cell Carcinoma
1.4
Classical Hodgkin Lymphoma
1.5
Squamous Cell Carcinoma of the Head and Neck
1.6
Urothelial Carcinoma
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage for Melanoma
2.2
Recommended Dosage for NSCLC
2.3
Recommended Dosage for RCC
2.4
Recommended Dosage for cHL
2.5
Recommended Dosage for SCCHN
2.6
Recommended Dosage for Urothelial Carcinoma
3
4
5
2.7
Dose Modifications
2.8
Preparation and Administration
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
5.1
Immune-Mediated Pneumonitis
5.2
Immune-Mediated Colitis
5.3
Immune-Mediated Hepatitis
5.4
Immune-Mediated Endocrinopathies
5.5
Immune-Mediated Nephritis and Renal Dysfunction
5.6
Immune-Mediated Skin Adverse Reactions
5.7
Immune-Mediated Encephalitis
5.8
Other Immune-Mediated Adverse Reactions
5.9
Infusion Reactions
5.10 Complications of Allogeneic HSCT after OPDIVO
5.11 Embryo-Fetal Toxicity
(Continued)
FULL PRESCRIBING INFORMATION: CONTENTS* (Continued)
6
12
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Immunogenicity
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
13
14
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
CLINICAL STUDIES
14.1 Unresectable or Metastatic Melanoma
14.2 Metastatic Non-Small Cell Lung Cancer (NSCLC)
14.3 Renal Cell Carcinoma
14.4 Classical Hodgkin Lymphoma
14.5 Recurrent or Metastatic Squamous Cell Carcinoma of the
Head and Neck (SCCHN)
14.6 Urothelial Carcinoma
HOW SUPPLIED/STORAGE AND HANDLING
PATIENT COUNSELING INFORMATION
10
OVERDOSAGE
16
17
11
DESCRIPTION
*Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Unresectable or Metastatic Melanoma
• OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with
BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies
(14.1)].
• OPDIVO as a single agent is indicated for the treatment of patients with BRAF V600
mutation-positive unresectable or metastatic melanoma [see Clinical Studies (14.1)].
This indication is approved under accelerated approval based on progression-free
survival. Continued approval for this indication may be contingent upon verification
and description of clinical benefit in the confirmatory trials.
• OPDIVO, in combination with ipilimumab, is indicated for the treatment of patients
with unresectable or metastatic melanoma [see Clinical Studies (14.1)].
This indication is approved under accelerated approval based on progression-free
survival. Continued approval for this indication may be contingent upon verification
and description of clinical benefit in the confirmatory trials.
1.2
Metastatic Non-Small Cell Lung Cancer
OPDIVO is indicated for the treatment of patients with metastatic non-small cell lung
cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients
with EGFR or ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving OPDIVO [see Clinical
Studies (14.2)].
1.3
Renal Cell Carcinoma
This indication is approved under accelerated approval based on tumor response rate
and duration of response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in confirmatory trials [see Clinical
Studies (14.6)].
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage for Melanoma
The recommended dose of OPDIVO (nivolumab) as a single agent is 240 mg
administered as an intravenous infusion over 60 minutes every 2 weeks until disease
progression or unacceptable toxicity.
The recommended dose of OPDIVO is 1 mg/kg administered as an intravenous infusion
over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for 4 doses
[see Clinical Studies (14.1)]. The recommended subsequent dose of OPDIVO, as a
single agent, is 240 mg administered as an intravenous infusion over 60 minutes every
2 weeks until disease progression or unacceptable toxicity. Review the Full Prescribing
Information for ipilimumab prior to initiation.
2.2
Recommended Dosage for NSCLC
The recommended dose of OPDIVO is 240 mg administered as an intravenous infusion
over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
2.3
Recommended Dosage for RCC
The recommended dose of OPDIVO is 240 mg administered as an intravenous infusion
over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
OPDIVO is indicated for the treatment of patients with advanced renal cell carcinoma
(RCC) who have received prior anti-angiogenic therapy [see Clinical Studies (14.3)].
2.4
1.4
The recommended dose of OPDIVO is 3 mg/kg administered as an intravenous infusion
over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
Classical Hodgkin Lymphoma
OPDIVO is indicated for the treatment of patients with classical Hodgkin lymphoma
(cHL) that has relapsed or progressed after autologous hematopoietic stem cell
transplantation (HSCT) and post-transplantation brentuximab vedotin [see Clinical
Studies (14.4)]. This indication is approved under accelerated approval based on overall
response rate. Continued approval for this indication may be contingent upon verification
and description of clinical benefit in confirmatory trials [see Clinical Studies (14.4)].
2.5
Squamous Cell Carcinoma of the Head and Neck
OPDIVO is indicated for the treatment of patients with recurrent or metastatic squamous
cell carcinoma of the head and neck (SCCHN) with disease progression on or after
platinum-based therapy [see Clinical Studies (14.5)].
1.6
Urothelial Carcinoma
OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or
metastatic urothelial carcinoma who:
Recommended Dosage for SCCHN
The recommended dose of OPDIVO is 3 mg/kg administered as an intravenous infusion
over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
2.6
1.5
Recommended Dosage for cHL
Recommended Dosage for Urothelial Carcinoma
The recommended dose of OPDIVO is 240 mg administered as an intravenous infusion
over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
2.7
Dose Modifications
Recommendations for OPDIVO modifications are provided in Table 1. When OPDIVO is
administered in combination with ipilimumab, if OPDIVO is withheld, ipilimumab should
also be withheld.
•
have disease progression during or following platinum-containing chemotherapy
There are no recommended dose modifications for hypothyroidism or hyperthyroidism.
•
have disease progression within 12 months of neoadjuvant or adjuvant
treatment with platinum-containing chemotherapy.
Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions.
Discontinue OPDIVO in patients with severe or life-threatening infusion reactions.
OPDIVO® (nivolumab)
Table 1:
Recommended Dose Modifications for OPDIVO
Adverse Reaction
Severity*
Grade 2 diarrhea or colitis
Colitis
Grade 3 diarrhea or colitis
Pneumonitis
Hepatitis
Hypophysitis
Adrenal Insufficiency
Type 1 Diabetes Mellitus
Nephritis and Renal
Dysfunction
Skin
Encephalitis
Other
OPDIVO® (nivolumab)
Preparation
Dose Modification
Withhold
dosea
Withhold dosea when
administered as a single
agent
Permanently discontinue
when administered with
ipilimumab
Grade 4 diarrhea or colitis
Permanently discontinue
Grade 2 pneumonitis
Withhold dosea
Grade 3 or 4 pneumonitis
Permanently discontinue
Aspartate aminotransferase
(AST)/or alanine
aminotransferase (ALT) more
than 3 and up to 5 times the
upper limit of normal or total
bilirubin more than 1.5 and up
to 3 times the upper limit of
normal
Withdraw the required volume of OPDIVO and transfer into an intravenous
container.
•
Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose
Injection, USP to prepare an infusion with a final concentration ranging from
1 mg/mL to 10 mg/mL.
•
Mix diluted solution by gentle inversion. Do not shake.
•
Discard partially used vials or empty vials of OPDIVO.
Storage of Infusion
The product does not contain a preservative.
After preparation, store the OPDIVO infusion either:
Withhold dosea
•
at room temperature for no more than 4 hours from the time of preparation.
This includes room temperature storage of the infusion in the IV container and
time for administration of the infusion or
•
under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from
the time of infusion preparation.
Do not freeze.
Administration
AST or ALT more than 5 times
the upper limit of normal or total
bilirubin more than 3 times the
upper limit of normal
Permanently discontinue
Grade 2 or 3 hypophysitis
Withhold dosea
Grade 4 hypophysitis
Permanently discontinue
Grade 2 adrenal insufficiency
Withhold dosea
Flush the intravenous line at end of infusion.
Permanently discontinue
When administered in combination with ipilimumab, infuse OPDIVO first followed by
ipilimumab on the same day. Use separate infusion bags and filters for each infusion.
Grade 3 hyperglycemia
Withhold dosea
3
Grade 4 hyperglycemia
Permanently discontinue
Grade 3 or 4 adrenal
insufficiency
Administer the infusion over 60 minutes through an intravenous line containing a
sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer
to 1.2 micrometer).
Do not coadminister other drugs through the same intravenous line.
DOSAGE FORMS AND STRENGTHS
Injection: 40 mg/4 mL (10 mg/mL) and 100 mg/10 mL (10 mg/mL) solution in a
single-dose vial.
Serum creatinine more than
1.5 and up to 6 times the upper
limit of normal
Withhold
Serum creatinine more than 6
times the upper limit of normal
Permanently discontinue
None.
Grade 3 rash or suspected
Stevens-Johnson syndrome
(SJS) or toxic epidermal
necrolysis (TEN)
Withhold dosea
5
WARNINGS AND PRECAUTIONS
5.1
Immune-Mediated Pneumonitis
Grade 4 rash or confirmed SJS
or TEN
Permanently discontinue
New-onset moderate or severe
neurologic signs or symptoms
Withhold dosea
Immune-mediated encephalitis
Permanently discontinue
Other Grade 3 adverse reaction
First occurrence
Recurrence of same
Grade 3 adverse reactions
Withhold dosea
Permanently discontinue
Life-threatening or Grade 4
adverse reaction
Permanently discontinue
Requirement for 10 mg per
day or greater prednisone
or equivalent for more than
12 weeks
Permanently discontinue
Persistent Grade 2 or 3 adverse
reactions lasting 12 weeks or
longer
Permanently discontinue
dosea
4
* Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse
Events. Version 4.0 (NCI CTCAE v4).
a Resume treatment when adverse reaction returns to Grade 0 or 1.
2.8
•
Preparation and Administration
Visually inspect drug product solution for particulate matter and discoloration prior to
administration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard
the vial if the solution is cloudy, discolored, or contains extraneous particulate matter
other than a few translucent-to-white, proteinaceous particles. Do not shake the vial.
CONTRAINDICATIONS
OPDIVO can cause immune-mediated pneumonitis, defined as requiring use of
corticosteroids and no clear alternate etiology. Fatal cases have been reported.
Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis.
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for
moderate (Grade 2) or more severe (Grade 3-4) pneumonitis, followed by corticosteroid
taper. Permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4)
pneumonitis and withhold OPDIVO until resolution for moderate (Grade 2) pneumonitis
[see Dosage and Administration (2.7)].
OPDIVO as a Single Agent
In patients receiving OPDIVO as a single agent, immune-mediated pneumonitis
occurred in 3.1% (61/1994) of patients. The median time to onset of immune-mediated
pneumonitis was 3.5 months (range: 1 day to 22.3 months). Immune-mediated
pneumonitis led to permanent discontinuation of OPDIVO in 1.1%, and withholding of
OPDIVO in 1.3% of patients. Approximately 89% of patients with pneumonitis received
high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median
duration of 26 days (range: 1 day to 6 months). Complete resolution of symptoms
following corticosteroid taper occurred in 67% of patients. Approximately 8% of
patients had recurrence of pneumonitis after re-initiation of OPDIVO.
OPDIVO with Ipilimumab
In patients receiving OPDIVO with ipilimumab, immune-mediated pneumonitis occurred
in 6% (25/407) of patients. The median time to onset of immune-mediated pneumonitis
was 1.6 months (range: 24 days to 10.1 months). Immune-mediated pneumonitis led to
permanent discontinuation or withholding of OPDIVO with ipilimumab in 2.2% and 3.7%
of patients, respectively. Approximately 84% of patients with pneumonitis received
high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median
duration of 30 days (range: 5 days to 11.8 months). Complete resolution occurred in
68% of patients. Approximately 13% of patients had recurrence of pneumonitis after
re-initiation of OPDIVO with ipilimumab.
OPDIVO® (nivolumab)
5.2
Immune-Mediated Colitis
OPDIVO can cause immune-mediated colitis, defined as requiring use of corticosteroids
with no clear alternate etiology.
Monitor patients for signs and symptoms of colitis. Administer corticosteroids at a dose
of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe
(Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of
0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate
(Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs
despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone
equivalents.
Withhold OPDIVO for moderate or severe (Grade 2 or 3) colitis. Permanently discontinue
OPDIVO for life-threatening (Grade 4) or for recurrent colitis upon re-initiation of OPDIVO
[see Dosage and Administration (2.7)].
When administered in combination with ipilimumab, withhold OPDIVO and ipilimumab
for moderate colitis (Grade 2). Permanently discontinue OPDIVO and ipilimumab for
severe or life-threatening (Grade 3 or 4) colitis or for recurrent colitis [see Dosage and
Administration (2.7)].
OPDIVO as a Single Agent
In patients receiving OPDIVO as a single agent, immune-mediated colitis occurred
in 2.9% (58/1994) of patients; the median time to onset was 5.3 months (range:
2 days to 20.9 months). Immune-mediated colitis led to permanent discontinuation
of OPDIVO in 0.7% and withholding of OPDIVO in 1% of patients. Approximately 91%
of patients with colitis received high-dose corticosteroids (at least 40 mg prednisone
equivalents per day) for a median duration of 23 days (range: 1 day to 9.3 months).
Four patients required addition of infliximab to high-dose corticosteroids. Complete
resolution occurred in 74% of patients. Approximately 16% of patients had recurrence
of colitis after re-initiation of OPDIVO.
OPDIVO with Ipilimumab
In patients receiving OPDIVO with ipilimumab, immune-mediated colitis occurred
in 26% (107/407) of patients including three fatal cases. The median time to
onset of immune-mediated colitis was 1.6 months (range: 3 days to 15.2 months).
Immune-mediated colitis led to permanent discontinuation or withholding of OPDIVO
with ipilimumab in 16% and 7% of patients, respectively. Approximately 96% of patients
with colitis received high-dose corticosteroids (at least 40 mg prednisone equivalents
per day) for a median duration of 1.1 month (range: 1 day to 12 months). Approximately
23% of patients required addition of infliximab to high-dose corticosteroids. Complete
resolution occurred in 75% of patients. Approximately 28% of patients had recurrence
of colitis after re-initiation of OPDIVO with ipilimumab.
5.3
Immune-Mediated Hepatitis
OPDIVO can cause immune-mediated hepatitis, defined as requiring use of
corticosteroids and no clear alternate etiology. Monitor patients for abnormal liver
tests prior to and periodically during treatment. Administer corticosteroids at a
dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper
for severe (Grade 3) or life-threatening (Grade 4) transaminase elevations, with or
without concomitant elevation in total bilirubin. Administer corticosteroids at a dose
of 0.5 to 1 mg/kg/day prednisone equivalents for moderate (Grade 2) transaminase
elevations. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue
OPDIVO for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis
[see Dosage and Administration (2.7)].
OPDIVO as a Single Agent
In patients receiving OPDIVO as a single agent, immune-mediated hepatitis occurred in
1.8% (35/1994) of patients; the median time to onset was 3.3 months (range: 6 days to
9 months). Immune-mediated hepatitis led to permanent discontinuation of OPDIVO in
0.7% and withholding of OPDIVO in 1% of patients. All patients with hepatitis received
high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median
duration of 23 days (range: 1 day to 2 months). Two patients required the addition of
mycophenolic acid to high-dose corticosteroids. Complete resolution occurred in 74%
of patients. Approximately 29% of patients had recurrence of hepatitis after re-initiation
of OPDIVO.
OPDIVO with Ipilimumab
In patients receiving OPDIVO with ipilimumab, immune-mediated hepatitis occurred in
13% (51/407) of patients; the median time to onset was 2.1 months (range: 15 days to
11 months). Immune-mediated hepatitis led to permanent discontinuation or withholding
of OPDIVO with ipilimumab in 6% and 5% of patients, respectively. Approximately 92%
of patients with hepatitis received high-dose corticosteroids (at least 40 mg prednisone
equivalents per day) for a median duration of 1.1 month (range: 1 day to 13.2 months).
Complete resolution occurred in 75% of patients. Approximately 11% of patients had
recurrence of hepatitis after re-initiation of OPDIVO with ipilimumab.
OPDIVO® (nivolumab)
5.4
Immune-Mediated Endocrinopathies
Hypophysitis
OPDIVO can cause immune-mediated hypophysitis. Monitor patients for signs and
symptoms of hypophysitis. Administer hormone replacement as clinically indicated
and corticosteroids at a dose of 1 mg/kg/day prednisone equivalents followed by
corticosteroid taper for moderate (Grade 2) or greater hypophysitis. Withhold OPDIVO
for moderate (Grade 2) or severe (Grade 3). Permanently discontinue OPDIVO for
life-threatening (Grade 4) hypophysitis [see Dosage and Administration (2.7)].
In patients receiving OPDIVO as a single agent, hypophysitis occurred in 0.6% (12/1994)
of patients; the median time to onset was 4.9 months (range: 1.4 to 11 months).
Hypophysitis led to permanent discontinuation of OPDIVO in 0.1% and withholding
of OPDIVO in 0.2% of patients. Approximately 67% of patients with hypophysitis
received hormone replacement therapy and 33% received high-dose corticosteroids
(at least 40 mg prednisone equivalents per day) for a median duration of 14 days
(range: 5 to 26 days).
In patients receiving OPDIVO with ipilimumab, hypophysitis occurred in 9% (36/407)
of patients; the median time to onset was 2.7 months (range: 27 days to 5.5 months).
Hypophysitis led to permanent discontinuation or withholding of OPDIVO with
ipilimumab in 1.0% and 3.9% of patients, respectively. Approximately 75% of patients
with hypophysitis received hormone replacement therapy and 56% received high-dose
corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of
19 days (range: 1 day to 2.0 months).
Adrenal Insufficiency
OPDIVO can cause immune-mediated adrenal insufficiency. Monitor patients for
signs and symptoms of adrenal insufficiency. Administer corticosteroids at a dose
of 1 to 2 mg/kg/day prednisone equivalents followed by a corticosteroid taper for
severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Withhold OPDIVO
for moderate (Grade 2) and permanently discontinue OPDIVO for severe (Grade 3) or
life-threatening (Grade 4) adrenal insufficiency [see Dosage and Administration (2.7)].
In patients receiving OPDIVO as a single agent, adrenal insufficiency occurred in
1% (20/1994) of patients and the median time to onset was 4.3 months (range: 15 days
to 21 months). Adrenal insufficiency led to permanent discontinuation of OPDIVO in
0.1% and withholding of OPDIVO in 0.5% of patients. Approximately 85% of patients
with adrenal insufficiency received hormone replacement therapy and 25% received
high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median
duration of 11 days (range: 1 day to 1 month).
In patients receiving OPDIVO with ipilimumab, adrenal insufficiency occurred in
5% (21/407) of patients and the median time to onset was 3.0 months (range: 21 days
to 9.4 months). Adrenal insufficiency led to permanent discontinuation or withholding
of OPDIVO with ipilimumab in 0.5% and 1.7% of patients, respectively. Approximately
57% of patients with adrenal insufficiency received hormone replacement therapy
and 33% received high-dose corticosteroids (at least 40 mg prednisone equivalents
per day) for a median duration of 9 days (range: 1 day to 2.7 months).
Hypothyroidism and Hyperthyroidism
OPDIVO can cause autoimmune thyroid disorders. Monitor thyroid function prior to and
periodically during OPDIVO treatment. Administer hormone-replacement therapy for
hypothyroidism. Initiate medical management for control of hyperthyroidism. There are
no recommended dose adjustments of OPDIVO for hypothyroidism or hyperthyroidism.
In patients receiving OPDIVO as a single agent, hypothyroidism or thyroiditis resulting
in hypothyroidism occurred in 9% (171/1994) of patients; the median time to onset
was 2.9 months (range: 1 day to 16.6 months). Approximately 79% of patients with
hypothyroidism received levothyroxine and 4% also required corticosteroids. Resolution
occurred in 35% of patients.
Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO as a single
agent; the median time to onset was 1.5 months (range: 1 day to 14.2 months).
Approximately 26% of patients with hyperthyroidism received methimazole, 9%
received carbimazole, 4% received propylthiouracil, and 9% received corticosteroids.
Resolution occurred in 76% of patients.
In patients receiving OPDIVO with ipilimumab, hypothyroidism or thyroiditis resulting
in hypothyroidism occurred in 22% (89/407) of patients; the median time to onset
was 2.1 months (range: 1 day to 10.1 months). Approximately 73% of patients with
hypothyroidism or thyroiditis received levothyroxine. Resolution occurred in 45%
of patients.
Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with ipilimumab:
the median time to onset was 23 days (range: 3 days to 3.7 months). Approximately
29% of patients with hyperthyroidism received methimazole and 24% received
carbimazole. Resolution occurred in 94% of patients.
OPDIVO® (nivolumab)
Type 1 Diabetes Mellitus
OPDIVO can cause Type 1 diabetes mellitus. Monitor for hyperglycemia. Withhold
OPDIVO in cases of severe (Grade 3) hyperglycemia until metabolic control is achieved.
Permanently discontinue OPDIVO for life-threatening (Grade 4) hyperglycemia [see
Dosage and Administration (2.7)].
In patients receiving OPDIVO as a single agent, diabetes occurred in 0.9% (17/1994)
of patients including two cases of diabetic ketoacidosis. The median time to onset was
4.4 months (range: 15 days to 22 months).
In patients receiving OPDIVO with ipilimumab, diabetes occurred in 1.5% (6/407)
of patients; the median time to onset was 2.5 months (range: 1.3 to 4.4 months).
OPDIVO with ipilimumab was withheld in a patient and permanently discontinued in a
second patient who developed diabetes.
OPDIVO® (nivolumab)
Complete resolution occurred in 47% of patients. Approximately 6% of patients who
resumed OPDIVO and ipilimumab after resolution had recurrence of rash.
5.7
Immune-Mediated Encephalitis
OPDIVO can cause immune-mediated encephalitis with no clear alternate etiology.
Evaluation of patients with neurologic symptoms may include, but not be limited to,
consultation with a neurologist, brain MRI, and lumbar puncture.
Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or
symptoms and evaluate to rule out infectious or other causes of moderate to severe
neurologic deterioration. If other etiologies are ruled out, administer corticosteroids at
a dose of 1 to 2 mg/kg/day prednisone equivalents for patients with immune-mediated
encephalitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for
immune-mediated encephalitis [see Dosage and Administration (2.7)].
5.5
Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO can cause immune-mediated nephritis, defined as renal dysfunction or
≥Grade 2 increased creatinine, requirement for corticosteroids, and no clear alternate
etiology. Monitor patients for elevated serum creatinine prior to and periodically
during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone
equivalents followed by corticosteroid taper for life-threatening (Grade 4) increased
serum creatinine. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day
prednisone equivalents for moderate (Grade 2) or severe (Grade 3) increased serum
creatinine, if worsening or no improvement occurs, increase dose of corticosteroids to
1 to 2 mg/kg/day prednisone equivalents.
OPDIVO as a Single Agent
Withhold OPDIVO for moderate (Grade 2) or severe (Grade 3) increased serum
creatinine. Permanently discontinue OPDIVO for life-threatening (Grade 4) increased
serum creatinine. [see Dosage and Administration (2.7) and Adverse Reactions (6.1)].
5.8
OPDIVO as a Single Agent
In patients receiving OPDIVO as a single agent, immune-mediated nephritis and renal
dysfunction occurred in 1.2% (23/1994) of patients; the median time to onset was
4.6 months (range: 23 days to 12.3 months). Immune-mediated nephritis and renal
dysfunction led to permanent discontinuation of OPDIVO in 0.3% and withholding of
OPDIVO in 0.8% of patients. All patients received high-dose corticosteroids (at least
40 mg prednisone equivalents per day) for a median duration of 21 days (range: 1 day
to 15.4 months). Complete resolution occurred in 48% of patients. No patients had
recurrence of nephritis or renal dysfunction after re-initiation of OPDIVO.
OPDIVO with Ipilimumab
In patients receiving OPDIVO with ipilimumab, immune-mediated nephritis and renal
dysfunction occurred in 2.2% (9/407) of patients; the median time to onset was
2.7 months (range: 9 days to 7.9 months). Immune-mediated nephritis and renal
dysfunction led to permanent discontinuation or withholding of OPDIVO with ipilimumab
in 0.7% and 0.5% of patients, respectively. Approximately 67% of patients received
high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median
duration of 13.5 days (range: 1 day to 1.1 months). Complete resolution occurred in
all patients. Two patients resumed OPDIVO with ipilimumab without recurrence of
nephritis or renal dysfunction.
5.6
Immune-Mediated Skin Adverse Reactions
OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS)
and toxic epidermal necrolysis (TEN), some cases with fatal outcome. For symptoms
or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care
for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue
OPDIVO [see Dosage and Administration (2.7)].
For immune-mediated rash, administer corticosteroids at a dose of 1 to 2 mg/kg/day
prednisone equivalents followed by a corticosteroid taper for severe (Grade 3)
or life-threatening (Grade 4) rash. Withhold OPDIVO for severe (Grade 3) rash and
permanently discontinue OPDIVO for life-threatening (Grade 4) rash.
OPDIVO as a Single Agent
In patients receiving OPDIVO as a single agent, immune-mediated rash occurred in
9% (171/1994) of patients; the median time to onset was 2.8 months (range: <1 day to
25.8 months). Immune-mediated rash led to permanent discontinuation of OPDIVO in
0.3% and withholding of OPDIVO in 0.8% of patients. Approximately 16% of patients with
rash received high-dose corticosteroids (at least 40 mg prednisone equivalents per day)
for a median duration of 12 days (range: 1 days to 8.9 months) and 85% received
topical corticosteroids. Complete resolution occurred in 48% of patients. Recurrence of
rash occurred in 1.4% of patients who resumed OPDIVO after resolution of rash.
OPDIVO with Ipilimumab
In patients receiving OPDIVO with ipilimumab, immune-mediated rash occurred in
22.6% (92/407) of patients; the median time to onset was 18 days (range: 1 day to
9.7 months). Immune-mediated rash led to permanent discontinuation or withholding
of OPDIVO with ipilimumab in 0.5% and 3.9% of patients, respectively. Approximately
17% of patients with rash received high-dose corticosteroids (at least 40 mg prednisone
equivalents per day) for a median duration of 14 days (range: 2 days to 4.7 months).
In patients receiving OPDIVO as a single agent, encephalitis occurred in 0.2% (3/1994).
Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite
discontinuation of OPDIVO and administration of corticosteroids. In the other two patients
encephalitis occurred post-allogeneic HSCT [see Warnings and Precautions (5.10)].
OPDIVO with Ipilimumab
Encephalitis occurred in one patient receiving OPDIVO with ipilimumab (0.2%) after
1.7 months of exposure.
Other Immune-Mediated Adverse Reactions
OPDIVO can cause other clinically significant immune-mediated adverse reactions.
Immune-mediated adverse reactions may occur after discontinuation of OPDIVO
therapy. For any suspected immune-mediated adverse reactions, exclude other causes.
Based on the severity of the adverse reaction, permanently discontinue or withhold
OPDIVO, administer high-dose corticosteroids, and if appropriate, initiate hormonereplacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid
taper and continue to taper over at least 1 month. Consider restarting OPDIVO after
completion of corticosteroid taper based on the severity of the event [see Dosage and
Administration (2.7)].
Across clinical trials of OPDIVO administered as a single agent or in combination with
ipilimumab, the following clinically significant immune-mediated adverse reactions
occurred in less than 1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial
and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune
neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response
syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis
(Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction,
vasculitis, and myasthenic syndrome.
5.9
Infusion Reactions
OPDIVO can cause severe infusion reactions, which have been reported in less than
1.0% of patients in clinical trials. Discontinue OPDIVO in patients with severe or
life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with
mild or moderate infusion reactions [see Dosage and Administration (2.7)].
OPDIVO as a Single Agent
In patients receiving OPDIVO as a single agent, infusion-related reactions occurred in
6.4% (127/1994) of patients.
OPDIVO with Ipilimumab
In patients receiving OPDIVO with ipilimumab, infusion-related reactions occurred in
2.5% (10/407) of patients.
5.10
Complications of Allogeneic HSCT after OPDIVO
Complications, including fatal events, occurred in patients who received allogeneic
HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Trials 8 and 9 who
underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity
conditioning, two with myeloablative conditioning). The median age at HSCT was 33
(range: 18 to 56), and a median of 9 doses of OPDIVO had been administered (range: 4 to
16). Six of 17 patients (35%) died from complications of allogeneic HSCT after OPDIVO.
Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher
acute GVHD was reported in 5/17 patients (29%). Hyperacute GVHD, defined as GVHD
occurring within 14 days after stem cell infusion, was reported in 2 patients (20%). A
steroid-requiring febrile syndrome, without an identified infectious cause, was reported
in six patients (35%) within the first 6 weeks post-transplantation, with five patients
responding to steroids. Two cases of encephalitis were reported: one case of Grade 3
lymphocytic encephalitis without an identified infectious cause, which occurred and
resolved on steroids, and one case of Grade 3 suspected viral encephalitis which was
resolved with antiviral treatment. Hepatic veno-occlusive disease (VOD) occurred in one
patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD
and multi-organ failure.
OPDIVO® (nivolumab)
Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT
have also been reported in patients with lymphoma who received a PD-1 receptor
blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also
been reported.
These complications may occur despite intervening therapy between PD-1 blockade
and allogeneic HSCT.
Follow patients closely for early evidence of transplant-related complications such as
hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome,
hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.
5.11
Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies, OPDIVO can cause
fetal harm when administered to a pregnant woman. In animal reproduction studies,
administration of nivolumab to cynomolgus monkeys from the onset of organogenesis
through delivery resulted in increased abortion and premature infant death. Advise
pregnant women of the potential risk to a fetus. Advise females of reproductive potential
to use effective contraception during treatment with an OPDIVO-containing regimen
and for at least 5 months after the last dose of OPDIVO [see Use in Specific Populations
(8.1, 8.3)].
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of
the labeling.
•
•
•
•
•
•
•
•
•
•
6.1
Immune-Mediated Pneumonitis [see Warnings and Precautions (5.1)]
Immune-Mediated Colitis [see Warnings and Precautions (5.2)]
Immune-Mediated Hepatitis [see Warnings and Precautions (5.3)]
Immune-Mediated Endocrinopathies [see Warnings and Precautions (5.4)]
Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and
Precautions (5.5)]
Immune-Mediated Skin Adverse Reactions [see Warnings and Precautions (5.6)]
Immune-Mediated Encephalitis [see Warnings and Precautions (5.7)]
Other Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.8)]
Infusion Reactions [see Warnings and Precautions (5.9)]
Complications of Allogeneic HSCT after OPDIVO [see Warnings and
Precautions (5.10)]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in
the clinical trials of another drug and may not reflect the rates observed in practice.
The data in the Warnings and Precautions section reflect exposure to OPDIVO, as a
single agent, for clinically significant adverse reactions in 1994 patients enrolled in
Trials 1 through 8 or a single-arm trial in NSCLC (n=117) administering OPDIVO as a
single agent [see Warnings and Precautions (5.1, 5.8)]. In addition, clinically significant
adverse reactions of OPDIVO administered with ipilimumab were evaluated in
407 patients with melanoma enrolled in Trial 6 (n=313) or a Phase 2 randomized study
(n=94), administering OPDIVO with ipilimumab, supplemented by immune-mediated
adverse reaction reports in ongoing clinical trials [see Warnings and Precautions
(5.1, 5.8)].
The data described below reflect exposure to OPDIVO as a single agent in Trials 1, 4, and
6, and to OPDIVO with ipilimumab in Trial 6, which are randomized, active-controlled
trials conducted in patients with unresectable or metastatic melanoma. Also described
below are single-agent OPDIVO data from Trials 2 and 3, which are randomized trials
in patients with metastatic NSCLC, Trial 5, which is a randomized trial in patients with
advanced RCC, Trials 7 and 8, which are open-label, multiple-cohort trials in patients
with cHL, Trial 9, a randomized trial in patients with recurrent or metastatic SCCHN, and
Trial 10, which is a single-arm trial in patients with urothelial carcinoma.
Unresectable or Metastatic Melanoma
OPDIVO® (nivolumab)
In Trial 1, patients had documented disease progression following treatment
with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial
excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse
reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse
reactions that had not resolved or were inadequately controlled within 12 weeks of
the initiating event, patients with a condition requiring chronic systemic treatment with
corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive
medications, a positive test for hepatitis B or C, and a history of HIV.
The trial population characteristics in the OPDIVO group and the chemotherapy
group were similar: 66% male, median age 59.5 years, 98% white, baseline Eastern
Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with
M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma,
73% received two or more prior therapies for advanced or metastatic disease, and 18%
had brain metastasis. There were more patients in the OPDIVO group with elevated LDH
at baseline (51% vs. 38%).
OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent
of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse
reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse
reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3
and 4 adverse reactions reported in 2% to less than 5% of patients receiving OPDIVO
were abdominal pain, hyponatremia, increased aspartate aminotransferase, and
increased lipase.
Table 2 summarizes the adverse reactions that occurred in at least 10% of
OPDIVO-treated patients in Trial 1. The most common adverse reaction (reported in at
least 20% of patients) was rash.
Table 2:
Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients
and at a Higher Incidence than in the Chemotherapy Arm (Between
Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 1)
OPDIVO
(n=268)
Adverse Reaction
All
Grades
Chemotherapy
(n=102)
Grades
3-4
All
Grades
Grades
3-4
Percentage (%) of Patients
Skin and Subcutaneous Tissue
Disorders
Rasha
21
0.4
7
0
Pruritus
19
0
3.9
0
17
0
6
0
11
0
2.0
0
10
0
5
0
Respiratory, Thoracic, and
Mediastinal Disorders
Cough
Infections
Upper respiratory tract infectionb
General Disorders and
Administration Site Conditions
Peripheral edema
Toxicity was graded per NCI CTCAE v4.
is a composite term which includes maculopapular rash, erythematous rash, pruritic
rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform
dermatitis.
b Upper respiratory tract infection is a composite term which includes rhinitis, pharyngitis, and
nasopharyngitis.
a Rash
Other clinically important adverse reactions in less than 10% of patients treated with
OPDIVO in Trial 1 were:
Cardiac Disorders: ventricular arrhythmia
Eye Disorders: iridocyclitis
Previously Treated Metastatic Melanoma
General Disorders and Administration Site Conditions: infusion-related reactions
The safety of OPDIVO as a single agent was evaluated in Trial 1, a randomized, open-label
trial in which 370 patients with unresectable or metastatic melanoma received OPDIVO
3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102),
either dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC
6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks [see Clinical Studies (14.1)].
The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months)
in OPDIVO-treated patients and was 2 months (range: 1 day to 9.6+ months) in
chemotherapy-treated patients. In this ongoing trial, 24% of patients received OPDIVO
for greater than 6 months and 3% of patients received OPDIVO for greater than 1 year.
Investigations: increased amylase, increased lipase
Nervous System Disorders: dizziness, peripheral and sensory neuropathy
Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme,
vitiligo, psoriasis
OPDIVO® (nivolumab)
Table 3:
OPDIVO® (nivolumab)
Laboratory Abnormalities Worsening from Baseline Occurring
in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence
than in the Chemotherapy Arm (Between Arm Difference of ≥5%
[All Grades] or ≥2% [Grades 3-4]) (Trial 1)
Percentage of Patients with Worsening Laboratory
Test from Baselinea
OPDIVO
Table 4:
Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients
and at a Higher Incidence than in the Dacarbazine Arm (Between
Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 4)
OPDIVO (n=206)
All
Grades
Adverse Reaction
Chemotherapy
Laboratory
Abnormality
All
Grades
Grades
3-4
All
Grades
Grades
3-4
Increased AST
28
2.4
12
1.0
Increased alkaline
phosphatase
22
2.4
13
1.1
Hyponatremia
25
5
18
1.1
Increased ALT
16
1.6
5
0
Hyperkalemia
15
2.0
6
0
a Each
test incidence is based on the number of patients who had both baseline and at least
one on-study laboratory measurement available: OPDIVO group (range: 252 to 256 patients)
and chemotherapy group (range: 94 to 96 patients).
Previously Untreated Metastatic Melanoma
Trial 4
The safety of OPDIVO was also evaluated in Trial 4, a randomized, double-blind, activecontrolled trial in which 411 previously untreated patients with BRAF V600 wild-type
unresectable or metastatic melanoma received OPDIVO 3 mg/kg every 2 weeks (n=206)
or dacarbazine 1000 mg/m2 every 3 weeks (n=205) [see Clinical Studies (14.1)].
The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in
OPDIVO-treated patients. In this trial, 47% of patients received OPDIVO for greater than
6 months and 12% of patients received OPDIVO for greater than 1 year.
The trial excluded patients with autoimmune disease and patients requiring chronic
systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other
immunosuppressive medications.
The trial population characteristics in the OPDIVO group and dacarbazine group:
59% male, median age 65 years, 99.5% white, 61% with M1c stage disease, 74% with
cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and
37% with elevated LDH at baseline. There were more patients in the OPDIVO group with
ECOG performance status 0 (71% vs. 59%).
All
Grades
Grades
3-4
Percentage (%) of Patients
General Disorders and
Administration Site Conditions
Fatigue
Edemaa
Musculoskeletal and Connective
Tissue Disorders
Musculoskeletal painb
Skin and Subcutaneous Tissue
Disorders
Rashc
Pruritus
Erythema
Vitiligo
Infections
Upper respiratory tract infectiond
49
12
1.9
1.5
39
4.9
3.4
0
32
2.9
25
2.4
28
23
10
11
1.5
0.5
0
0
12
12
2.9
0.5
0
0
0
0
17
0
6
0
Toxicity was graded per NCI CTCAE v4.
a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized
edema, peripheral edema, pulmonary edema, and lymphedema.
b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort,
myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain.
c Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular
rash, papular rash, pustular rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative
dermatitis, acneiform dermatitis, drug eruption, and skin reaction.
d Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis.
Other clinically important adverse reactions in less than 10% of patients treated with
OPDIVO in Trial 4 were:
Nervous System Disorders: peripheral neuropathy
Table 5:
Adverse reactions led to permanent discontinuation of OPDIVO in 7% of patients and
dose interruption in 26% of patients; no single type of adverse reaction accounted for
the majority of OPDIVO discontinuations. Serious adverse reactions occurred in 36%
of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 41% of
patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported
in at least 2% of patients receiving OPDIVO were gamma-glutamyltransferase increase
(3.9%) and diarrhea (3.4%).
Table 4 summarizes selected adverse reactions that occurred in at least 10% of
OPDIVO-treated patients. The most common adverse reactions (reported in at least
20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue,
musculoskeletal pain, rash, and pruritus.
Dacarbazine (n=205)
Grades
3-4
Laboratory Abnormalities Worsening from Baseline Occurring in
≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in
the Dacarbazine Arm (Between Arm Difference of ≥5% [All Grades]
or ≥2% [Grades 3-4]) (Trial 4)
Percentage of Patients with Worsening Laboratory
Test from Baselinea
OPDIVO
Dacarbazine
Laboratory
Abnormality
All
Grades
Grades
3-4
All
Grades
Grades
3-4
Increased ALT
25
3.0
19
0.5
Increased AST
24
3.6
19
0.5
Increased alkaline
phosphatase
21
2.6
14
1.6
Increased bilirubin
13
3.1
6
0
a Each
test incidence is based on the number of patients who had both baseline and
at least one on-study laboratory measurement available: OPDIVO group (range:
194 to 197 patients) and dacarbazine group (range: 186 to 193 patients).
Trial 6
The safety of OPDIVO, administered with ipilimumab or as a single agent, was evaluated
in Trial 6 [see Clinical Studies (14.1)], a randomized (1:1:1), a double-blind trial in which
937 patients with previously untreated, unresectable or metastatic melanoma received:
•
•
•
OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for 4 doses followed
by OPDIVO 3 mg/kg as a single agent every 2 weeks (OPDIVO plus ipilimumab
arm; n=313),
OPDIVO 3 mg/kg every 2 weeks (OPDIVO arm; n=313), or
Ipilimumab 3 mg/kg every 3 weeks for up to 4 doses (ipilimumab arm; n=311).
The median duration of exposure to OPDIVO was 2.8 months (range: 1 day to
18.8 months) for the OPDIVO plus ipilimumab arm and 6.6 months (range: 1 day to
17.3 months) for the OPDIVO arm. In the OPDIVO plus ipilimumab arm, 39% were
exposed to OPDIVO for ≥6 months and 24% exposed for >1 year. In the OPDIVO arm,
53% were exposed for ≥6 months and 32% for >1 year.
OPDIVO® (nivolumab)
OPDIVO® (nivolumab)
Trial 6 excluded patients with autoimmune disease, a medical condition requiring
systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent)
or other immunosuppressive medication within 14 days of the start of study therapy, a
positive test result for hepatitis B or C, or a history of HIV.
Table 7:
Laboratory Abnormalities Worsening from Baseline Occurring
in ≥20% of Patients Treated with OPDIVO with Ipilimumab or
Single-Agent OPDIVO and at a Higher Incidence than in the
Ipilimumab Arm (Between Arm Difference of ≥5% [All Grades] or
≥2% [Grades 3-4]) (Trial 6)
The trial population characteristics were: 65% male, median age 61 years, 97% White,
baseline ECOG performance status 0 (73%) or 1 (27%), 93% with AJCC Stage IV
disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a
history of brain metastasis, and 22% had received adjuvant therapy.
In Trial 6, serious adverse reactions (73% and 37%), adverse reactions leading to
permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and
Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the
OPDIVO plus ipilimumab arm relative to the OPDIVO arm.
The most frequent (≥10%) serious adverse reactions in the OPDIVO plus ipilimumab
arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10%
and 1.6%), and pyrexia (10% and 0.6%). The most frequent adverse reactions leading
to discontinuation of both drugs in the OPDIVO plus ipilimumab arm and of OPDIVO in
the OPDIVO arm, respectively, were diarrhea (8% and 1.9%), colitis (8% and 0.6%),
increased ALT (4.8% and 1.3%), increased AST (4.5% and 0.6%), and pneumonitis (1.9%
and 0.3%). The most common (≥20%) adverse reactions in the OPDIVO plus ipilimumab
arm were fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and dyspnea. The most
common (≥20%) adverse reactions in the OPDIVO arm were fatigue, rash, diarrhea, and
nausea. Table 6 summarizes the incidence of adverse reactions occurring in at least
10% of patients in either OPDIVO-containing arm in Trial 6.
Table 6:
Adverse Reactions Occurring in ≥10% of Patients on the OPDIVO plus
Ipilimumab Arm or the OPDIVO Arm and at a Higher Incidence than
in the Ipilimumab Arm (Between Arm Difference of ≥5% [All Grades]
or ≥2% [Grades 3-4]) (Trial 6)
Percentage (%) of Patients
OPDIVO plus
Ipilimumab
(n=313)
Adverse Reaction
All
Grades
Ipilimumab
(n=311)
OPDIVO
(n=313)
Grades
3-4
All
Grades
Grades
3-4
All
Grades
Grades
3-4
General Disorders and
Administration Site
Conditions
Fatiguea
59
6
53
1.9
50
3.9
Pyrexia
37
1.6
14
0
17
0.6
53
5
40
1.6
42
3.9
Skin and Subcutaneous
Tissue Disorders
Rashb
OPDIVO plus
Ipilimumab
OPDIVO
Ipilimumab
Any
Grade
Grade
3-4
Any
Grade
Grade
3-4
Any
Grade
Grade
3-4
Increased ALT
53
15
23
3.0
28
2.7
Increased AST
47
13
27
3.7
27
1.7
Hyponatremia
42
9
20
3.3
25
7
Laboratory
Abnormality
Chemistry
Increased lipase
41
20
29
9
23
7
Increased alkaline
phosphatase
40
6
24
2.0
22
2.0
Hypocalcemia
29
1.1
13
0.7
21
0.7
Increased amylase
25
9.1
15
1.9
14
1.6
Increased creatinine
23
2.7
16
0.3
16
1.3
Hematology
Anemia
50
2.7
39
2.6
40
6
Lymphopenia
35
4.8
39
4.3
27
3.4
a Each
test incidence is based on the number of patients who had both baseline and at
least one on-study laboratory measurement available: OPDIVO plus ipilimumab (range:
241 to 297); OPDIVO (range: 260 to 306); ipilimumab (range: 253 to 304).
Metastatic Non-Small Cell Lung Cancer
The safety of OPDIVO in metastatic NSCLC was evaluated in Trial 2, a randomized openlabel, multicenter trial in patients with metastatic squamous NSCLC and progression
on or after one prior platinum doublet-based chemotherapy regimen and Trial 3, a
randomized, open-label, multicenter trial in patients with metastatic non-squamous
NSCLC and progression on or after one prior platinum doublet-based chemotherapy
regimen [see Clinical Studies (14.2)]. Patients received 3 mg/kg of OPDIVO administered
intravenously over 60 minutes every 2 weeks or docetaxel administered intravenously
at 75 mg/m2 every 3 weeks. The median duration of therapy in OPDIVO-treated patients
in Trial 2 was 3.3 months (range: 1 day to 21.7+ months) and in Trial 3 was 2.6 months
(range: 0 to 24.0+ months). In Trial 2, 36% of patients received OPDIVO for at least
6 months and 18% of patients received OPDIVO for at least 1 year and in Trial 3,
30% of patients received OPDIVO for greater than 6 months and 20% of patients
received OPDIVO for greater than 1 year.
Trial 2 and Trial 3 excluded patients with active autoimmune disease, medical conditions
requiring systemic immunosuppression, or with symptomatic interstitial lung disease.
Gastrointestinal
Disorders
Diarrhea
52
11
31
3.8
46
8
Nausea
40
3.5
28
0.6
29
1.9
Vomiting
28
3.5
17
1.0
16
1.6
Respiratory, Thoracic
and Mediastinal
Disorders
Dyspnea
Percentage (%) of Patientsa
20
2.2
12
1.3
13
0.6
Toxicity was graded per NCI CTCAE v4.
a Fatigue is a composite term which includes asthenia and fatigue.
b Rash is a composite term which includes pustular rash, dermatitis, acneiform dermatitis,
allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform
dermatitis, drug eruption, erythema, exfoliative rash, erythematous rash, generalized rash,
macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash,
pruritic rash, and seborrheic dermatitis.
Other clinically important adverse reactions in less than 10% of patients treated with either
OPDIVO with ipilimumab or single-agent OPDIVO in Trial 6 were:
Gastrointestinal Disorders: stomatitis, intestinal perforation
Skin and Subcutaneous Tissue Disorders: vitiligo
Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome,
spondyloarthropathy
Nervous System Disorders: neuritis, peroneal nerve palsy
Across both trials, the median age of OPDIVO-treated patients was 61 years (range:
37 to 85); 38% were ≥65 years of age, 61% were male, and 91% were white.
Ten percent of patients had brain metastases and ECOG performance status was 0
(26%) or 1 (74%).
OPDIVO was discontinued in 11% of patients, and was delayed in 28% of patients for
an adverse reaction. Serious adverse reactions occurred in 46% of patients receiving
OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients
receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural
effusion, pneumonitis, and respiratory failure. In Trial 3, in the OPDIVO arm, seven
deaths were due to infection including one case of Pneumocystis jirovecii pneumonia,
four were due to pulmonary embolism, and one death was due to limbic encephalitis.
Across both trials, the most common adverse reactions (reported in at least 20% of
patients) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.
Table 8 summarizes selected adverse reactions occurring more frequently in at least
10% of OPDIVO-treated patients.
OPDIVO® (nivolumab)
Table 8:
OPDIVO® (nivolumab)
Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients
and at a Higher Incidence than Docetaxel (Between Arm Difference
of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trials 2 and 3)
OPDIVO (n=418)
All
Grades
Adverse Reaction
Table 10:
Grade 1-4 Adverse Reactions in >15% of Patients Receiving OPDIVO
(Trial 5)
OPDIVO
(n=406)
Docetaxel (n=397)
Grades
3-4
All
Grades
Grades
3-4
Percentage (%) of Patients
Percentage (%) of Patients
Adverse Reaction
Respiratory, Thoracic, and
Mediastinal Disorders
Cough
31
0.7
24
0
28
1.4
23
1.5
Metabolism and Nutrition Disorders
Decreased appetite
Skin and Subcutaneous Tissue
Disorders
Pruritus
10
0.2
2.0
0
Toxicity was graded per NCI CTCAE v4.
Other clinically important adverse reactions observed in patients treated with OPDIVO
and which occurred at a similar incidence in docetaxel-treated patients and not listed
elsewhere in section 6 include: fatigue/asthenia (48% Grade 1-4, 5% Grade 3-4),
musculoskeletal pain (33%), pleural effusion (4.5%), pulmonary embolism (3.3%).
Table 9:
Laboratory Abnormalities Worsening from Baseline Occurring in
≥10% of OPDIVO-Treated Patients for all NCI CTCAE Grades and at
a Higher Incidence than Docetaxel (Between Arm Difference of ≥5%
[All Grades] or ≥2% [Grades 3-4]) (Trials 2 and 3)
Percentage of Patients with Worsening Laboratory Test
from Baselinea
OPDIVO
Docetaxel
Everolimus
(n=397)
Grades
1-4
Grades
3-4
Grades
1-4
Grades
3-4
98
56
96
62
General Disorders and
Administration Site
Conditions
Asthenic conditionsa
56
6
57
7
Pyrexia
17
0.7
20
0.8
Respiratory, Thoracic and
Mediastinal Disorders
Cough/productive cough
34
0
38
0.5
Dyspnea/exertional
dyspnea
27
3.0
31
2.0
Upper respiratory
infectionb
18
0
11
0
Gastrointestinal Disorders
Nausea
28
0.5
29
1
Diarrheac
25
2.2
32
1.8
Constipation
23
0.5
18
0.5
Vomiting
16
0.5
16
0.5
Rashd
28
1.5
36
1.0
Pruritus/generalized
pruritus
19
0
14
0
23
1.2
30
1.5
Skin and Subcutaneous
Tissue Disorders
All
Grades
Grades
3-4
All
Grades
Grades
3-4
Hyponatremia
35
7
34
4.9
Increased AST
27
1.9
13
0.8
Decreased appetite
Increased alkaline
phosphatase
26
0.7
18
0.8
Increased ALT
22
1.7
17
0.5
Musculoskeletal and
Connective Tissue
Disorders
Increased creatinine
18
0
12
0.5
Arthralgia
20
1.0
14
0.5
N/A
Back pain
21
3.4
16
2.8
Laboratory
Abnormality
Chemistry
Increased TSHb
14
N/A
6
a Each
test incidence is based on the number of patients who had both baseline and at
least one on-study laboratory measurement available: OPDIVO group (range: 405 to
417 patients) and docetaxel group (range: 372 to 390 patients); TSH: OPDIVO group n=314
and docetaxel group n=297.
b Not graded per NCI CTCAE v4.
Renal Cell Carcinoma
The safety of OPDIVO was evaluated in Trial 5, a randomized open-label trial in which
803 patients with advanced RCC who had experienced disease progression during
or after at least one anti-angiogenic treatment regimens received OPDIVO 3 mg/kg
every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.3)].
The median duration of treatment was 5.5 months (range: 1 day to 29.6+ months)
in OPDIVO-treated patients and 3.7 months (range: 6 days to 25.7+ months) in
everolimus-treated patients.
Study therapy was discontinued for adverse reactions in 16% of OPDIVO patients and
19% of everolimus patients. Forty-four percent (44%) of patients receiving OPDIVO had
a drug delay for an adverse reaction. Serious adverse reactions occurred in 47% of
patients receiving OPDIVO. The most frequent serious adverse reactions reported in at
least 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea,
and hypercalcemia.
Rate of death on treatment or within 30 days of the last dose of study drug was 4.7%
on the OPDIVO arm versus 8.6% on the everolimus arm.
The most common adverse reactions (reported in at least 20% of patients) were
asthenic conditions, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased
appetite, back pain, and arthralgia. Table 10 summarizes adverse reactions that
occurred in greater than 15% of OPDIVO-treated patients.
Metabolism and Nutrition
Disorders
Toxicity was graded per NCI CTCAE v4.
a Asthenic conditions covering PTs asthenia, decreased activity, fatigue, and malaise.
b Includes nasopharyngitis, pharyngitis, rhinitis, and viral URI.
c Includes colitis, enterocolitis, and gastroenteritis.
d Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular
rash, maculopapular rash, papular rash, pruritic rash, erythema multiforme, and erythema.
Other clinically important adverse reactions in Trial 5 were:
General Disorders and Administration Site Conditions: peripheral edema/edema
Gastrointestinal Disorders: abdominal pain/discomfort
Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain
Nervous System Disorders: headache/migraine, peripheral neuropathy
Investigations: weight decreased
Skin Disorders: Palmar-plantar erythrodysesthesia
The most common laboratory abnormalities which have worsened compared to
baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia,
increased AST, increased alkaline phosphatase, hyponatremia, elevated triglycerides,
and hyperkalemia. Table 11 summarizes the laboratory abnormalities that occurred in
greater than 15% of OPDIVO-treated patients.
OPDIVO® (nivolumab)
Table 11:
OPDIVO® (nivolumab)
Grade 1-4 Laboratory Values Worsening from Baseline Occurring in
>15% of Patients on OPDIVO (Trial 5)
Table 12:
Non-Hematologic Adverse Reactions Occurring in ≥10% of Patients
with cHL (Trials 7 and 8)
OPDIVO cHL
OPDIVO cHL
Safety Population Efficacy Population
(n=95)
(n=263)
Percentage of Patients with Worsening Laboratory
Test from Baselinea
OPDIVO
Laboratory
Abnormality
Grades
1-4
Everolimus
Grades
3-4
Grades
1-4
Percentage (%) of Patients
Grades
3-4
All
Grades
Grades
3-4
All
Grades
Grades
3-4
Fatigueb
32
1.1
43
1.1
Pyrexia
24
0.8
35
1.1
1.1
Adverse Reactiona
Hematology
Lymphopenia
42
6
53
11
Anemia
39
8
69
16
Chemistry
General Disorders and Administration
Site Conditions
Increased creatinine
42
2.0
45
1.6
Increased AST
33
2.8
39
1.6
Diarrhea
23
0.8
30
Increased alkaline
phosphatase
32
2.3
32
0.8
Nausea
17
0
23
0
Vomiting
15
0.8
16
1.1
Hyponatremia
32
7
26
6
Abdominal painc
11
0.8
13
2.1
Hyperkalemia
30
4.0
20
2.1
Constipation
9
0.4
14
0
Hypocalcemia
23
0.9
26
1.3
Increased ALT
22
3.2
31
0.8
Upper respiratory tract infectiond
28
0.4
48
1.1
Hypercalcemia
19
3.2
6
0.3
Pneumonia/bronchopneumoniae
9
3.0
19
5.3
Lipids
Increased triglycerides
32
1.5
67
11
Increased cholesterol
21
0.3
55
1.4
a Each
test incidence is based on the number of patients who had both baseline and at
least one on-study laboratory measurement available: OPDIVO group (range: 259 to
401 patients) and everolimus group (range: 257 to 376 patients).
In addition, among patients with TSH less than ULN at baseline, a greater proportion of
patients experienced a treatment-emergent elevation of TSH greater than ULN in the
OPDIVO group compared to the everolimus group (26% and 14%, respectively).
Classical Hodgkin Lymphoma
The safety of OPDIVO 3 mg/kg every 2 weeks was evaluated in 263 adult patients with
cHL (240 patients in Trial 7 and 23 patients in Trial 8). Treatment could continue until
disease progression, maximal clinical benefit, or unacceptable toxicity.
The median age was 34 years (range 18 to 72), 98% of patients had received autologous
HSCT, none had received allogeneic HSCT, and 74% had received brentuximab vedotin.
The median number of prior systemic regimens was 4 (range: 1 to 15). Patients received
a median of 10 doses (cycles) of OPDIVO (range: 1 to 48), with a median duration of
therapy of 4.8 months (range: 0.3 to 24 months).
OPDIVO was discontinued due to adverse reactions in 4.2% of patients. Twenty-three
percent (23%) of patients had a dose delay for an adverse reaction. Serious adverse
reactions occurred in 21% of patients. The most frequent serious adverse reactions
reported in at least 1% of patients were infusion-related reaction, pneumonia,
pleural effusion, pyrexia, rash, and pneumonitis. Ten patients died from causes other
than disease progression, including 6 who died from complications of allogeneic HSCT.
The most common adverse reactions (reported in at least 20%) among all patients
(safety population), were fatigue, upper respiratory tract infection, pyrexia, diarrhea,
and cough.
Among the subset of patients in the efficacy population, the most common adverse
reactions also included rash, musculoskeletal pain, pruritus, nausea, arthralgia, and
peripheral neuropathy. Serious adverse reactions occurred in 27% of these patients.
Table 12 summarizes both the adverse reactions that occurred in at least 10% of
patients in the safety population (n=263) and the efficacy population (n=95). There is a
greater incidence of adverse reactions in the subset of patients evaluated for efficacy;
these patients received a median of 17 doses of OPDIVO and a median of 5 prior
systemic regimens [see Clinical Studies (14.4)].
Gastrointestinal Disorders
Infections
Respiratory, Thoracic and Mediastinal
Disorders
Cough/productive cough
22
0
35
0
Dyspnea/exertional dyspnea
10
0.8
16
2.1
Rashf
19
1.5
31
3.2
Pruritus
17
0
25
0
Musculoskeletal paing
19
1.1
27
1.1
Arthralgia
11
0
21
0
Skin and Subcutaneous Tissue Disorders
Musculoskeletal and Connective Tissue
Disorders
Endocrine Disorders
Hypothyroidism/thyroiditis
12
0
17
0
Hyperglycemia/Blood Glucose Increased
9
0.4
14
1.1
Headache
12
0.4
12
1.1
Neuropathy peripheralh
11
0.4
21
0
12
0.4
18
0
Nervous System Disorders
Injury, Poisoning and Procedural
Complications
Infusion-related reaction
Toxicity was graded per NCI CTCAE v4.
a Includes events occurring up to 30 days after last nivolumab dose, regardless of causality.
After an immune-mediate adverse reaction, reactions following nivolumab rechallenge
were included if they occurred up to 30 days after completing the initial nivolumab course.
b Includes asthenia.
c Includes abdominal discomfort and upper abdominal pain.
d Includes nasopharyngitis, pharyngitis, rhinitis, and sinusitis.
e Includes pneumonia bacterial, pneumonia mycoplasmal, pneumocystis jirovecii pneumonia.
f Includes dermatitis, dermatitis acneiform, dermatitis exfoliative, and rash described as
macular, papular, maculopapular, pruritic, exfoliative, or acneiform.
g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort,
myalgia, neck pain, and pain in extremity.
h Includes hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor
neuropathy, peripheral sensory neuropathy, and polyneuropathy.
Additional information regarding clinically important adverse reactions:
Immune-mediated pneumonitis: In Trials 7 and 8, pneumonitis, including interstitial
lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immunemediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO (one
Grade 3 and eight Grade 2). The median time to onset was 2.2 months (range: 1 day
to 10.1 months). All nine patients received systemic corticosteroids, with resolution
in seven. One patient permanently discontinued OPDIVO due to Grade 2 pneumonitis.
Dose delay occurred in three patients. Five patients resumed OPDIVO, of whom none
had recurrence of pneumonitis.
OPDIVO® (nivolumab)
OPDIVO® (nivolumab)
Peripheral neuropathy: In Trials 7 and 8, peripheral neuropathy was observed in
11% (30/263) of all patients receiving OPDIVO. Twenty-two patients (8%) had
new-onset peripheral neuropathy, and four patients had worsening from baseline.
Four additional patients with peripheral neuropathy at baseline (three Grade 1 and one
Grade 2) did not worsen. All events were Grade 1 or 2, except for 1 Grade 3 event (0.4%).
Complications of allogeneic HSCT after OPDIVO: [see Warnings and Precautions (5.10)].
Table 13:
Laboratory Abnormalities Worsening from Baseline Occurring in
≥10% of OPDIVO-Treated cHL Patients (Trials 7 and 8)
OPDIVO cHL
Safety Populationa
OPDIVO cHL
Efficacy Populationb
Percentage (%) of
Patientsc
Grades
3-4
All
Grades
Grades
3-4
All
Grades
Neutropenia
29
3.6
37
6
Thrombocytopenia
28
2.4
33
3.2
Lymphopenia
24
8
32
7
Anemia
22
2.8
27
2.1
Increased ALT
24
2.0
25
2.1
Increased AST
23
2.4
32
3.2
Increased alkaline phosphatase
17
1.6
21
2.1
Increased lipase
16
6.5
28
12
Hyponatremia
14
0.8
15
1.1
Hypokalemia
11
1.6
14
3.2
Hypocalcemia
11
0.4
14
1.1
Hypomagnesemia
10
0.4
15
1.3
Increased creatinine
10
0
15
0
Increased bilirubin
9
0.8
10
0
Laboratory Abnormality
Hematology
Chemistry
a Number of evaluable patients for the safety population ranges from 226 to 253.
b Number of evaluable patients for the efficacy population ranges from 80 to 85.
c
Includes events occurring up to 30 days after last nivolumab dose. After an immunemediate adverse reaction, reactions following nivolumab rechallenge were included if they
occurred within 30 days of completing the initial nivolumab course.
Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
The safety of OPDIVO was evaluated in Trial 9, a randomized, active-controlled, openlabel, multicenter trial in patients with recurrent or metastatic SCCHN with progression
during or within 6 months of receiving prior platinum-based therapy [see Clinical Studies
(14.5)]. Patients received 3 mg/kg of OPDIVO (n=236) administered intravenously (IV)
over 60 minutes every 2 weeks or investigator’s choice of either:
•
cetuximab (n=13), 400 mg/m2 loading dose IV followed by 250 mg/m2 weekly
•
or methotrexate (n=46) 40 to 60 mg/m2 IV weekly, or
•
docetaxel (n=52) 30 to 40 mg/m2 IV weekly.
The median duration of exposure to nivolumab was 1.9 months (range:
1 day to 16.1+ months) in OPDIVO-treated patients. In this trial, 18% of patients
received OPDIVO for greater than 6 months and 2.5% of patients received OPDIVO for
greater than 1 year.
Trial 9 excluded patients with active autoimmune disease, medical conditions
requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the
nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland
or non-squamous histologies (e.g., mucosal melanoma).
The median age of all randomized patients was 60 years (range: 28 to 83); 28% of
patients in the OPDIVO group were ≥65 years of age and 37% in the comparator group
were ≥65 years of age, 83% were male and 83% were White, 12% were Asian, and
4% were Black. Baseline ECOG performance status was 0 (20%) or 1 (78%), 45% of
patients received only one prior line of systemic therapy, the remaining 55% of patients
had two or more prior lines of therapy, and 90% had prior radiation therapy.
OPDIVO was discontinued in 14% of patients and was delayed in 24% of patients for
an adverse reaction. Serious adverse reactions occurred in 49% of patients receiving
OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients
receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract
infection, and sepsis. Adverse reactions and laboratory abnormalities occurring
in patients with SCCHN were generally similar to those occurring in patients with
melanoma and NSCLC. The most common adverse reactions occurring in ≥10% of
OPDIVO-treated patients and at a higher incidence than investigator’s choice were
cough and dyspnea.
The most common laboratory abnormalities occurring in ≥10% of OPDIVOtreated patients and at a higher incidence than investigator’s choice were increased
alkaline phosphatase, increased amylase, hypercalcemia, hyperkalemia, and
increased TSH.
Urothelial Carcinoma
The safety of OPDIVO was evaluated in Trial 10, a single arm study in which 270 patients
with locally advanced or metastatic urothelial carcinoma had disease progression during
or following platinum-containing chemotherapy or had disease progression within
12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
received OPDIVO 3 mg/kg every 2 weeks until disease progression or unacceptable
toxicity. The median duration of treatment was 3.3 months (range: 0 to 13.4+).
Forty-six percent (46%) of patients had a drug delay for an adverse reaction.
Fourteen patients (5.2%) died from causes other than disease progression. This includes
4 patients (1.5%) who died from pneumonitis or cardiovascular failure which was
attributed to treatment with OPDIVO. OPDIVO was discontinued for adverse reactions
in 17% of patients. Serious adverse reactions occurred in 54% of patients. The most
frequent serious adverse reactions reported in at least 2% of patients were urinary
tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health
deterioration.
Twenty-five (9%) patients received an oral prednisone dose equivalent to ≥40 mg daily
for an immune mediated adverse reaction [see Warnings and Precautions (5)].
The most common adverse reactions (reported in at least 20% of patients) were fatigue,
musculoskeletal pain, nausea, and decreased appetite.
Table 14 summarizes adverse reactions that occurred in greater than 10% of patients.
Table 14:
Adverse Reactions Occurring in ≥10% of Patients (Trial 10)
OPDIVO Urothelial Carcinoma
Percentage (%) of Patients
Adverse Reaction
All Grades
Grades 3-4
99
51
General Disorders and
Administration Site Conditions
Asthenia/fatigue/malaise
46
7
Pyrexia/tumor associated fever
17
0.4
Edema/peripheral edema/peripheral
swelling
13
0.4
17
7
Cough/productive cough
18
0
Dyspnea/exertional dyspnea
14
3.3
Nausea
22
0.7
Diarrhea
17
2.6
Constipation
16
0.4
Abdominal paina
13
1.5
Vomiting
12
1.9
Rashb
16
1.5
Pruritus
12
0
Musculoskeletal painc
30
2.6
Arthralgia
10
0.7
(Continued)
Infections and Infestations
Urinary Tract Infection/eschericia/
fungal urinary tract infection
Respiratory, Thoracic and
Mediastinal Disorders
Gastrointestinal Disorders
Skin and Subcutaneous Tissue
Disorders
Musculoskeletal and Connective
Tissue Disorders
OPDIVO® (nivolumab)
OPDIVO® (nivolumab)
Table 14:
Adverse Reactions Occurring in ≥10% of Patients (Trial 10)
(Continued)
OPDIVO Urothelial Carcinoma
Percentage (%) of Patients
All Grades
Grades 3-4
22
2.2
15
0
7
Metabolism and Nutrition Disorders
Decreased appetite
Endocrine Disorders
Thyroid disordersd
Toxicity was graded per NCI CTCAE v4.
a Includes abdominal discomfort, lower and upper abdominal pain.
b Includes dermatitis, dermatitis acneiform, dermatitis bullous, and rash described as
generalized, macular, maculopapular, or pruritic.
c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort,
myalgia, neck pain, pain in extremity and spinal pain.
d Includes autoimmune thyroiditis, blood TSH decrease, blood TSH increase, hyperthyroidism,
hypothyroidism, thyroiditis, thyroxine decreased, thyroxine free increased, thyroxine
increased, tri-iodothyronine free increased, tri-iodothyronine increased.
Table 15:
Laboratory Abnormalities Worsening from Baseline Occurring in
≥10% of Patients (Trial 10)
OPDIVO Urothelial Carcinomaa
Percentage (%) of Patients
Test
The detection of antibody formation is highly dependent on the sensitivity and specificity
of the assay. Additionally, the observed incidence of antibody (including neutralizing
antibody) positivity in an assay may be influenced by several factors including assay
methodology, sample handling, timing of sample collection, concomitant medications,
and underlying disease. For these reasons, comparison of incidence of antibodies to
OPDIVO with the incidences of antibodies to other products may be misleading.
DRUG INTERACTIONS
No formal pharmacokinetic drug-drug interaction studies have been conducted
with OPDIVO.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Based on its mechanism of action and data from animal studies, OPDIVO can cause
fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].
In animal reproduction studies, administration of nivolumab to cynomolgus monkeys
from the onset of organogenesis through delivery resulted in increased abortion and
premature infant death [see Data]. Human IgG4 is known to cross the placental barrier
and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential
to be transmitted from the mother to the developing fetus. The effects of OPDIVO are
likely to be greater during the second and third trimesters of pregnancy. There are no
available human data informing the drug-associated risk. Advise pregnant women of
the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population
is unknown; however, the background risk in the U.S. general population of major
birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized
pregnancies.
All Grades
Grades 3-4
Lymphopenia
42
9
Animal Data
Anemia
40
7
Thrombocytopenia
15
2.4
Leucopenia
11
0
Hyperglycemia
42
2.4
Hyponatremia
41
11
Increased creatinine
39
2.0
Increased alkaline phosphatase
33
5.5
Hypocalcemia
26
0.8
Increased AST
24
3.5
Hyperkalemia
19
1.2
A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining
maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been
shown in murine models of pregnancy to disrupt tolerance to the fetus and to
increase fetal loss. The effects of nivolumab on prenatal and postnatal development
were evaluated in monkeys that received nivolumab twice weekly from the onset of
organogenesis through delivery, at exposure levels of between 9 and 42 times higher
than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC).
Nivolumab administration resulted in a non-dose-related increase in spontaneous
abortion and increased neonatal death. Based on its mechanism of action, fetal
exposure to nivolumab may increase the risk of developing immune-mediated disorders
or altering the normal immune response and immune-mediated disorders have been
reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16
vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were
no apparent malformations and no effects on neurobehavioral, immunological, or
clinical pathology parameters throughout the 6-month postnatal period.
Increased ALT
18
1.2
8.2
Hypomagnesemia
16
0
Risk Summary
Increased lipase
20
7
Increased amylase
18
4.4
It is not known whether OPDIVO is present in human milk. Because many drugs,
including antibodies, are excreted in human milk and because of the potential for
serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue
breastfeeding during treatment with OPDIVO.
Hematology
Data
Chemistry
a Each
test incidence is based on the number of patients who had both baseline and at least
one on-study laboratory measurement available: range: 84 to 256 patients.
8.3
6.2
Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity.
Of 2022 patients who were treated with OPDIVO as a single agent 3 mg/kg
every 2 weeks and evaluable for the presence of anti-nivolumab antibodies,
231 patients (11.4%) tested positive for treatment-emergent anti-nivolumab antibodies
by an electrochemiluminescent (ECL) assay and fifteen patients (0.7%) had neutralizing
antibodies against nivolumab. There was no evidence of altered pharmacokinetic
profile or increased incidence of infusion reactions with anti-nivolumab antibody
development.
Of 394 patients who were treated with OPDIVO with ipilimumab and evaluable for
the presence of anti-nivolumab antibodies, 149 patients (37.8%) tested positive for
treatment-emergent anti-nivolumab antibodies by an ECL assay and 18 patients
(4.6%) had neutralizing antibodies against nivolumab. Of the 391 patients evaluable
for the presence of anti-ipilimumab antibodies, 33 patients (8.4%) tested positive
for treatment-emergent anti-ipilimumab antibodies by an ECL assay and one patient
(0.3%) had neutralizing antibodies against ipilimumab. There was no evidence of
increased incidence of infusion reactions with anti-nivolumab antibody development.
Lactation
Females and Males of Reproductive Potential
Contraception
Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a
pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive
potential to use effective contraception during treatment with OPDIVO and for at least
5 months following the last dose of OPDIVO.
8.4
Pediatric Use
The safety and effectiveness of OPDIVO have not been established in pediatric patients.
8.5
Geriatric Use
Of the 1359 patients randomized to single-agent OPDIVO in Trials 2 through 6,
39% were 65 years or older and 9% were 75 years or older. No overall differences in
safety or effectiveness were reported between elderly patients and younger patients.
In Trial 10 (Urothelial Cancer), 55% of patients were 65 years or older and 14% were
75 years or older. No overall differences in safety or effectiveness were reported
between elderly patients and younger patients.
Trials 1, 7, 8, and 9 did not include sufficient numbers of patients aged 65 years and
older to determine whether they respond differently from younger patients.
OPDIVO® (nivolumab)
Of the 314 patients randomized to OPDIVO administered with ipilimumab in Trial 6,
41% were 65 years or older and 11% were 75 years or older. No overall differences in
safety or effectiveness were reported between elderly patients and younger patients.
8.6
Renal Impairment
Based on a population pharmacokinetic analysis, no dose adjustment is recommended
in patients with renal impairment [see Clinical Pharmacology (12.3)].
8.7
Hepatic Impairment
Based on a population pharmacokinetic analysis, no dose adjustment is recommended
for patients with mild hepatic impairment. OPDIVO has not been studied in patients with
moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)].
10
OVERDOSAGE
There is no information on overdosage with OPDIVO.
11
DESCRIPTION
Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1
and its ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa immunoglobulin that has
a calculated molecular mass of 146 kDa.
OPDIVO is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to
pale-yellow liquid that may contain light (few) particles. OPDIVO injection for intravenous
infusion is supplied in single-dose vials. Each mL of OPDIVO solution contains nivolumab
10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium
chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, USP.
May contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells,
inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands
occurs in some tumors and signaling through this pathway can contribute to inhibition
of active T-cell immune surveillance of tumors. Nivolumab is a human immunoglobulin
G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction
with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune
response, including the anti-tumor immune response. In syngeneic mouse tumor
models, blocking PD-1 activity resulted in decreased tumor growth.
Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition
results in enhanced T-cell function that is greater than the effects of either antibody
alone, and results in improved anti-tumor responses in metastatic melanoma. In murine
syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased
anti-tumor activity.
12.2
Pharmacodynamics
Based on dose/exposure efficacy and safety relationships, there are no clinically
significant differences in safety and efficacy between a nivolumab dose of
240 mg or 3 mg/kg every 2 weeks in patients with melanoma, NSCLC, RCC, and
urothelial carcinoma.
12.3
Pharmacokinetics
Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for
both single-agent OPDIVO and OPDIVO with ipilimumab.
OPDIVO as a single agent: The PK of single-agent nivolumab was studied in patients
over a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple
doses of OPDIVO every 2 or 3 weeks. Nivolumab clearance decreases over time, with
a mean maximal reduction (% coefficient of variation [CV%]) from baseline values of
approximately 24.5% (47.6%) resulting in a geometric mean steady state clearance
(CLss) (CV%) of 8.2 mL/h (53.9%); the decrease in CLss is not considered clinically
relevant. The geometric mean volume of distribution at steady state (Vss) (CV%)
is 6.8 L (27.3%), and geometric mean elimination half-life (t1/2) is 25 days (77.5%).
Steady-state concentrations of nivolumab were reached by approximately 12 weeks
when administered at 3 mg/kg every 2 weeks, and systemic accumulation was
approximately 3.7-fold. The exposure to nivolumab increased dose proportionally over
the dose range of 0.1 to 10 mg/kg administered every 2 weeks.
OPDIVO with ipilimumab: The geometric mean (CV%) CL, Vss, and terminal halflife of nivolumab were 10.0 mL/h (50.3%), 7.92 L (30.1%), and 24.8 days (94.3%),
respectively. When administered in combination, the CL of nivolumab was increased by
24%, whereas there was no effect on the clearance of ipilimumab.
When administered in combination, the clearance of nivolumab increased by 42% in
the presence of anti-nivolumab antibodies. There was no effect of anti-ipilimumab
antibodies on the clearance of ipilimumab.
OPDIVO® (nivolumab)
Specific Populations: The population PK analysis suggested that the following factors
had no clinically important effect on the clearance of nivolumab: age (29 to 87 years),
weight (35 to 160 kg), gender, race, baseline LDH, PD-L1 expression, solid tumor type,
tumor size, renal impairment, and mild hepatic impairment.
Renal Impairment: The effect of renal impairment on the clearance of nivolumab
was evaluated by a population PK analysis in patients with mild (eGFR 60 to
89 mL/min/1.73 m2; n=313), moderate (eGFR 30 to 59 mL/min/1.73 m2; n=140),
or severe (eGFR 15 to 29 mL/min/1.73 m2; n=3) renal impairment. No clinically
important differences in the clearance of nivolumab were found between patients
with renal impairment and patients with normal renal function [see Use in Specific
Populations (8.6)].
Hepatic Impairment: The effect of hepatic impairment on the clearance of nivolumab
was evaluated by population PK analyses in patients with mild hepatic impairment (total
bilirubin [TB] less than or equal to the upper limit of normal [ULN] and AST greater than
ULN or TB less than 1 to 1.5 times ULN and any AST; n=92). No clinically important
differences in the clearance of nivolumab were found between patients with mild
hepatic impairment and patients with normal hepatic function. Nivolumab has not been
studied in patients with moderate (TB greater than 1.5 to 3 times ULN and any AST)
or severe hepatic impairment (TB greater than 3 times ULN and any AST) [see Use in
Specific Populations (8.7)].
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been performed to assess the potential of nivolumab for carcinogenicity
or genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month
and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects
in the male and female reproductive organs; however, most animals in these studies
were not sexually mature.
13.2
Animal Toxicology and/or Pharmacology
In animal models, inhibition of PD-1 signaling increased the severity of some infections
and enhanced inflammatory responses. M. tuberculosis–infected PD-1 knockout
mice exhibit markedly decreased survival compared with wild-type controls, which
correlated with increased bacterial proliferation and inflammatory responses in these
animals. PD-1 knockout mice have also shown decreased survival following infection
with lymphocytic choriomeningitis virus.
14
CLINICAL STUDIES
14.1
Unresectable or Metastatic Melanoma
Previously Treated Metastatic Melanoma
Trial 1 was a multicenter, open-label trial that randomized (2:1) patients with
unresectable or metastatic melanoma to receive either OPDIVO administered
intravenously at 3 mg/kg every 2 weeks or investigator’s choice of chemotherapy,
either single-agent dacarbazine 1000 mg/m2 every 3 weeks or the combination of
carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks. Patients
were required to have progression of disease on or following ipilimumab treatment
and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with
autoimmune disease, medical conditions requiring systemic immunosuppression,
ocular melanoma, active brain metastasis, or a history of Grade 4 ipilimumab-related
adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse
reactions that had not resolved or were inadequately controlled within 12 weeks of the
initiating event. Tumor assessments were conducted 9 weeks after randomization then
every 6 weeks for the first year, and every 12 weeks thereafter.
Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis
of the first 120 patients who received OPDIVO in Trial 1 and in whom the minimum
duration of follow-up was 6 months. The major efficacy outcome measures in this
population were confirmed objective response rate (ORR) as measured by blinded
independent central review using Response Evaluation Criteria in Solid Tumors (RECIST
1.1) and duration of response.
Among the 120 patients treated with OPDIVO, the median age was 58 years (range:
25 to 88), 65% of patients were male, 98% were white, and the ECOG performance score
was 0 (58%) or 1 (42%). Disease characteristics were M1c disease (76%), BRAF V600
mutation positive (22%), elevated LDH (56%), history of brain metastases (18%), and
two or more prior systemic therapies for metastatic disease (68%).
The ORR was 32% (95% confidence interval [CI]: 23, 41), consisting of 4 complete
responses and 34 partial responses in OPDIVO-treated patients. Of 38 patients with
responses, 33 patients (87%) had ongoing responses with durations ranging from
2.6+ to 10+ months, which included 13 patients with ongoing responses of 6 months
or longer.
There were objective responses in patients with and without BRAF V600 mutationpositive melanoma.
OPDIVO® (nivolumab)
OPDIVO® (nivolumab)
Previously Untreated Metastatic Melanoma
Figure 1:
Trial 4
Kaplan-Meier Curves of Overall Survival - Trial 4
1.0
0.9
0.8
Probability of Survival
Trial 4 was a multicenter, double-blind, randomized (1:1) trial conducted in patients with
BRAF V600 wild-type unresectable or metastatic melanoma. Patients were randomized
to receive either OPDIVO 3 mg/kg by intravenous infusion every 2 weeks or dacarbazine
1000 mg/m2 by intravenous infusion every 3 weeks until disease progression or
unacceptable toxicity. Randomization was stratified by PD-L1 status (greater than or
equal to 5% of tumor cell membrane staining by immunohistochemistry vs. less than
5% or indeterminate result) and M stage (M0/M1a/M1b versus M1c). Key eligibility
criteria included histologically confirmed, unresectable or metastatic, cutaneous,
mucosal, or acral melanoma; no prior therapy for metastatic disease; completion
of prior adjuvant or neoadjuvant therapy at least 6 weeks prior to randomization;
ECOG performance status 0 or 1; absence of autoimmune disease; and absence of
active brain or leptomeningeal metastases. The trial excluded patients with ocular
melanoma. Tumor assessments were conducted 9 weeks after randomization then
every 6 weeks for the first year and then every 12 weeks thereafter.
Trial 4 demonstrated a statistically significant improvement in OS for the OPDIVO arm
compared with the dacarbazine arm in an interim analysis based on 47% of the total
planned events for OS. Table 16 and Figure 1 summarize the efficacy results.
0.6
0.5
0.4
0.3
0.2
OPDIVO
Dacarbazine
0.1
The major efficacy outcome measure was overall survival (OS). Additional outcome
measures included investigator-assessed progression-free survival (PFS) and objective
response rate (ORR) per RECIST v1.1.
A total of 418 patients were randomized to OPDIVO (n=210) or dacarbazine (n=208).
The median age was 65 years (range: 18 to 87), 59% were men, and 99.5% were white.
Disease characteristics were M1c stage disease (61%), cutaneous melanoma (74%),
mucosal melanoma (11%), elevated LDH level (37%), PD-L1 greater than or equal to
5% tumor cell membrane expression (35%), and history of brain metastasis (4%).
More patients in the OPDIVO arm had an ECOG performance status of 0 (71% vs. 58%).
0.7
0.0
0
Number at Risk
OPDIVO
210
Dacarbazine
208
3
6
9
12
Overall Survival (Months)
15
18
185
150
105
45
8
0
177
123
82
22
3
0
At the time of analysis, 88% (63/72) of OPDIVO-treated patients had ongoing responses,
which included 43 patients with ongoing response of 6 months or longer.
Trial 6
Table 16:
Efficacy Results - Trial 4
OPDIVO
(n=210)
Dacarbazine
(n=208)
Overall Survival
Deaths (%)
Median, months (95% CI)
50 (24)
96 (46)
Not Reached
10.8 (9.3, 12.1)
Hazard ratio (95% CI)a
0.42 (0.30, 0.60)
p-valueb,c
Trial 6 was a multicenter, double-blind trial that randomized (1:1:1) patients with
previously untreated, unresectable or metastatic melanoma to one of the following
arms: OPDIVO plus ipilimumab, OPDIVO, or ipilimumab. Patients were required to have
completed adjuvant or neoadjuvant treatment at least 6 weeks prior to randomization
and have no prior treatment with anti-CTLA-4 antibody and no evidence of active brain
metastasis, ocular melanoma, autoimmune disease, or medical conditions requiring
systemic immunosuppression.
Patients were randomized to receive:
•
<0.0001
Progression-Free Survival
Disease progression or death (%)
Median, months (95% CI)
108 (51)
5.1 (3.5, 10.8)
Hazard ratio (95% CI)a
Objective Response Rate
163 (78)
•
OPDIVO 3 mg/kg every 2 weeks (OPDIVO arm), or
2.2 (2.1, 2.4)
•
Ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by placebo every
2 weeks (ipilimumab arm).
0.43 (0.34, 0.56)
p-valueb,c
<0.0001
34%
9%
(28, 41)
(5, 13)
Complete response rate
4%
1%
Partial response rate
30%
8%
(95% CI)
a Based on a stratified proportional hazards model.
b Based on stratified log-rank test.
c
OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for 4 doses,
followed by OPDIVO 3 mg/kg as a single agent every 2 weeks (OPDIVO plus
ipilimumab arm),
p-value is compared with the allocated alpha of 0.0021 for this interim analysis.
Randomization was stratified by PD-L1 expression (≥5% vs. <5% tumor cell membrane
expression) as determined by a clinical trial assay, BRAF V600 mutation status, and M
stage per the American Joint Committee on Cancer (AJCC) staging system (M0, M1a,
M1b vs. M1c). Tumor assessments were conducted 12 weeks after randomization then
every 6 weeks for the first year, and every 12 weeks thereafter.
The major efficacy outcome measures were investigator-assessed PFS per RECIST v1.1
and OS. Additional efficacy outcome measures were confirmed ORR and duration
of response.
A total of 945 patients were randomized, 314 patients to the OPDIVO plus ipilimumab
arm, 316 to the OPDIVO arm, and 315 to the ipilimumab arm. The trial population
characteristics were: median age 61 years (range: 18 to 90); 65% male; 97% White;
ECOG performance score 0 (73%) or 1 (27%). Disease characteristics were: AJCC
Stage IV disease (93%); M1c disease (58%); elevated LDH (36%); history of brain
metastases (4%); BRAF V600 mutation-positive melanoma (32%); PD-L1 ≥5% tumor
cell membrane expression as determined by the clinical trials assay (46%); and prior
adjuvant therapy (22%).
Trial 6 demonstrated statistically significant improvements in PFS for patients
randomized to either OPDIVO-containing arm as compared with the ipilimumab arm.
Efficacy results are presented in Table 17 and Figure 2.
OPDIVO® (nivolumab)
Efficacy Results in Trial 6
Figure 3:
OPDIVO plus
Ipilimumab
(n=314)
OPDIVO
(n=316)
Ipilimumab
(n=315)
151
174
234
11.5
(8.9, 16.7)
6.9
(4.3, 9.5)
2.9
(2.8, 3.4)
0.42
0.57
(0.34, 0.51)
(0.47, 0.69)
<0.0001
<0.0001
50%
40%
Progression-free Survival
Disease progression or death
Median in months (95% CI)
Hazard ratioa (vs. ipilimumab)
(95% CI)
p-valueb,c
Confirmed Objective
Response Rate
(95% CI)
14%
(44, 55)
(34, 46)
<0.0001
<0.0001
Complete response
8.9%
8.5%
1.9%
Partial response
41%
31%
12%
p-valued
(10, 18)
Range (months)
OPDIVO + Ipilimumab
OPDIVO
lpilimumab
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
76%
74%
63%
1.2+ to 15.8+
1.3+ to 14.6+
1.0+ to 13.8+
3
6
9
12
15
Progression Free Survival (Months)
Number of Subjects at Risk
OPDIVO + Ipilimumab
123
82
65
OPDIVO
117
50
42
lpilimumab
113
39
19
Duration of Response
Proportion ≥6 months in
duration
Progression-free Survival by PD-L1 Expression (<1%) - Trial 6
1.0
Probability of Progression Free Survival
Table 17:
OPDIVO® (nivolumab)
a Based on a stratified proportional hazards model.
b Based on stratified log-rank test.
18
21
57
26
6
0
0
34
13
2
0
0
12
5
0
0
0
c
p-value is compared with .005 of the allocated alpha for final PFS treatment comparisons.
d Based on the stratified Cochran-Mantel-Haenszel test.
Figure 4:
Progression-free Survival by PD-L1 Expression (≥1%) - Trial 6
Progression-free Survival: Unresectable or Metastatic Melanoma Trial 6
Probability of Progression Free Survival
1.0
OPDIVO + Ipilimumab
OPDIVO
lpilimumab
0.9
0.8
0.7
0.6
0.5
0.4
Probability of Progression Free Survival
1.0
Figure 2:
OPDIVO + Ipilimumab
OPDIVO
lpilimumab
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.3
0.1
0.2
0.0
0
0.1
0.0
0
3
6
9
12
15
18
Progression Free Survival per Investigator (Months)
Number of Subjects at Risk
OPDIVO + Ipilimumab
314
219
173
151
65
11
1
OPDIVO
316
177
147
124
50
9
1
lpilimumab
315
137
77
54
24
4
0
21
0
3
6
9
12
15
Progression Free Survival (Months)
Number of Subjects at Risk
OPDIVO + Ipilimumab
155
113
91
OPDIVO
171
115
97
lpilimumab
164
83
47
18
21
78
32
4
1
0
83
34
7
1
0
36
16
3
0
0
0
0
Figures 3 and 4 present exploratory efficacy subgroup analyses of PFS based on
defined PD-L1 expression levels determined in archival tumor specimens using the
PD-L1 IHC 28-8 pharmDx assay. Tumor samples were available for retrospective
assessment for 97% of the study population; PD-L1 expression status was ascertained
for 89% of the study population while in 6% of patients, melanin precluded evaluation
of PD-L1 expression status. PD-L1 expression status was unknown for 5% of the study
population due to consent withdrawal or missing samples.
The data presented in the figure below summarize the results of exploratory analyses
comparing the two OPDIVO-containing arms in subgroups defined by PD-L1 tumor
expression.
OPDIVO® (nivolumab)
Forest Plot: PFS Based on PD-L1 Expression Comparing
OPDIVO-Containing Arms - Trial 6
PD-L1
#Events/N
Expression
OPDIVO+Ipi : OPDIVO : Ipi
Level
<1%
>=1%
>=1%-<5%
>=5%
59/123
72/155
44/87
28/68
:
:
:
:
76/117 : 85/113
79/171 : 122/164
46/91 : 69/89
33/80 : 53/75
0.56 (0.40, 0.79)
0.95 (0.69, 1.31)
0.93 (0.62, 1.41)
0.96 (0.58, 1.58)
1
2
Unstratified Hazard Ratio (95% CI)
Favors OPDIVO+Ipi
In Trial 2, the median age was 63 years (range: 39 to 85) with 44% ≥65 years of age
and 11% ≥75 years of age. The majority of patients were white (93%) and male (76%);
the majority of patients were enrolled in Europe (57%) with the remainder in US/Canada
(32%) and the rest of the world (11%). Baseline ECOG performance status was 0 (24%)
or 1 (76%) and 92% were former/current smokers. Baseline disease characteristics
of the population as reported by investigators were Stage IIIb (19%), Stage IV (80%),
and brain metastases (6%). All patients received prior therapy with a platinum-doublet
regimen and 99% of patients had tumors of squamous-cell histology.
The trial demonstrated a statistically significant improvement in OS for patients
randomized to OPDIVO as compared with docetaxel at the prespecified interim analysis
when 199 events were observed (86% of the planned number of events for final
analysis) (Table 18 and Figure 6).
Efficacy Results in Trial 2
OPDIVO
(n=135)
Progression-free Survival
Disease progression or death (%)
Median (months)
Hazard ratio (95% CI)a
p-valueb
Docetaxel
(n=137)
0.6
0.5
0.4
0.3
27 (20%)
(14, 28)
3
Number at Risk
OPDIVO
135
113
Docetaxel
137
103
6
9
12
15
Overall Survival (Months)
18
21
24
86
69
52
31
15
7
0
68
45
30
14
7
2
0
Archival tumor specimens were retrospectively evaluated for PD-L1 expression.
Across the study population, 17% (47/272) of patients had non-quantifiable results.
Among the 225 patients with quantifiable results, 47% (106/225) had PD-L1 negative
squamous NSCLC, defined as <1% of tumor cells expressing PD-L1, and 53% (119/225)
had PD-L1 positive squamous NSCLC, defined as ≥1% of tumor cells expressing PD-L1.
In pre-specified exploratory subgroup analyses, the hazard ratios for survival were 0.58
(95% CI: 0.37, 0.92) in the PD-L1 negative subgroup and 0.69 (95% CI: 0.45, 1.05) in
the PD-L1 positive NSCLC subgroup.
Second-line Treatment of Metastatic Non-Squamous NSCLC
Trial 3 was a randomized (1:1), open-label study of 582 patients with metastatic
non-squamous NSCLC who had experienced disease progression during or after
one prior platinum doublet-based chemotherapy regimen. Appropriate prior targeted
therapy in patients with known sensitizing EGFR mutation or ALK translocation was
allowed. Patients received OPDIVO (n=292) administered intravenously at 3 mg/kg
every 2 weeks or docetaxel (n=290) administered intravenously at 75 mg/m2 every
3 weeks. Randomization was stratified by prior maintenance therapy (yes vs. no)
and number of prior therapies (1 vs. 2). The trial excluded patients with autoimmune
disease, medical conditions requiring systemic immunosuppression, symptomatic
interstitial lung disease, or untreated brain metastasis. Patients with treated brain
metastases were eligible if neurologically stable. The first tumor assessments were
conducted 9 weeks after randomization and continued every 6 weeks thereafter. The
major efficacy outcome measure was OS. Additional efficacy outcome measures were
investigator-assessed ORR and PFS. In addition, prespecified analyses were conducted
in subgroups defined by PD-L1 expression.
0
8.4
(3.6, 10.8)
Trial 3 demonstrated a statistically significant improvement in OS for patients
randomized to OPDIVO as compared with docetaxel at the prespecified interim analysis
when 413 events were observed (93% of the planned number of events for final
analysis) (Table 19 and Figure 7).
105 (78%)
122 (89%)
3.5
2.8
0.62 (0.47, 0.81)
0.0004
b Based on stratified log-rank test.
p-value is compared with .0315 of the allocated alpha for this interim analysis.
d Based on the stratified Cochran-Mantel-Haenszel test.
0
12 (9%)
(5, 15)
0.0083
1 (0.7%)
NR
(9.8, NR)
OPDIVO
Docetaxel
In Trial 3, the median age was 62 years (range: 21 to 85) with 42% of patients
≥65 years and 7% of patients ≥75 years. The majority of patients were white (92%)
and male (55%); the majority of patients were enrolled in Europe (46%) followed by the
US/Canada (37%) and the rest of the world (17%). Baseline ECOG performance status
was 0 (31%) or 1 (69%), 79% were former/current smokers, 3.6% had NSCLC with
ALK rearrangement, 14% had NSCLC with EGFR mutation, and 12% had previously
treated brain metastases. Prior therapy included platinum-doublet regimen (100%) and
40% received maintenance therapy as part of the first-line regimen. Histologic subtypes
included adenocarcinoma (93%), large cell (2.4%), and bronchoalveolar (0.9%).
86 (64%)
113 (82%)
6.0
9.2
(5.1, 7.3)
(7.3, 13.3)
0.59 (0.44, 0.79)
0.0002
a Based on a stratified proportional hazards model.
c
0.7
0.0
Trial 2 was a randomized (1:1), open-label study enrolling 272 patients with metastatic
squamous NSCLC who had experienced disease progression during or after one prior
platinum doublet-based chemotherapy regimen. Patients received OPDIVO (n=135)
administered intravenously at 3 mg/kg every 2 weeks or docetaxel (n=137) administered
intravenously at 75 mg/m2 every 3 weeks. Randomization was stratified by prior
paclitaxel vs other prior treatment and region (US/Canada vs. Europe vs. Rest of World).
This study included patients regardless of their PD-L1 status. The trial excluded patients
with autoimmune disease, medical conditions requiring systemic immunosuppression,
symptomatic interstitial lung disease, or untreated brain metastasis. Patients with
treated brain metastases were eligible if neurologically returned to baseline at least
2 weeks prior to enrollment, and either off corticosteroids, or on a stable or decreasing
dose of <10 mg daily prednisone equivalents. The first tumor assessments were
conducted 9 weeks after randomization and continued every 6 weeks thereafter.
The major efficacy outcome measure was OS. Additional efficacy outcome measures
were investigator-assessed ORR and PFS.
Objective Response Rate
(95% CI)
p-valued
Complete response
Median duration of response, months
(95% CI)
0.8
0.1
Second-line Treatment of Metastatic Squamous NSCLC
Overall Survival
Deaths (%)
Median (months)
(95% CI)
Hazard ratio (95% CI)a
p-valueb,c
1.0
0.2
Metastatic Non-Small Cell Lung Cancer (NSCLC)
Table 18:
Overall Survival - Trial 2
0.9
OPDIVO+Ipi vs. OPDIVO
Unstratified HR (95% CI)
0
14.2
Figure 6:
Probability of Survival
Figure 5:
OPDIVO® (nivolumab)
OPDIVO® (nivolumab)
Table 19:
OPDIVO® (nivolumab)
Efficacy Results in Trial 3
Figure 8:
OPDIVO
(n=292)
Docetaxel
(n=290)
Deaths (%)
190 (65%)
223 (77%)
Median (months)
(95% CI)
12.2
(9.7, 15.0)
9.4
(8.0, 10.7)
Median OS (months)
PD-L1 expression level
≥1% (n = 246)
<1% (n = 209)
≥5% (n = 181)
<5% (n = 274)
≥10% (n = 165)
<10% (n = 290)
Overall Survival
Hazard ratio (95% CI)a
0.73 (0.60, 0.89)
p-valueb,c
56 (19%)
(95% CI)
0.25
0.5
Favors OPDIVO
36 (12%)
(15, 24)
(9, 17)
p-valued
4 (1.4%)
1 (0.3%)
Median duration of response (months)
(95% CI)
17
(8.4, NR)
6
(4.4, 7.0)
Figure 9:
2.0
Disease progression or death (%)
Median (months)
Hazard ratio (95%
Forest Plot: PFS Based on PD-L1 Expression - Trial 3
Median PFS (months)
Progression-free Survival
234 (80%)
245 (84%)
2.3
4.2
CI)a
PD-L1 expression level
≥1% (n = 246)
<1% (n = 209)
≥5% (n = 181)
<5% (n = 274)
≥10% (n = 165)
<10% (n = 290)
0.92 (0.77, 1.11)
p-valueb
0.39
a Based on a stratified proportional hazards model.
b Based on stratified log-rank test.
p-value is compared with .0408 of the allocated alpha for this interim analysis.
0.25
0.5
Favors OPDIVO
d Based on the stratified Cochran-Mantel-Haenszel test.
Overall Survival - Trial 3
14.3
Unstratified HR OPDIVO Docetaxel
0.70
4.2
4.5
1.19
2.1
3.6
0.54
5.0
3.8
1.31
2.1
4.2
0.52
5.0
3.6
1.24
2.1
4.2
1.0
2.0
Renal Cell Carcinoma
Trial 5 was a randomized (1:1), open-label study in patients with advanced RCC who had
experienced disease progression during or after one or two prior anti-angiogenic therapy
regimens. Patients had to have a Karnofsky Performance Score (KPS) ≥70% and patients
were included regardless of their PD-L1 status. Trial 5 excluded patients with any
history of or concurrent brain metastases, prior treatment with an mTOR inhibitor, active
autoimmune disease, or medical conditions requiring systemic immunosuppression.
Patients were stratified by region, Memorial Sloan Kettering Cancer Center (MSKCC)
Risk Group and the number of prior anti-angiogenic therapies.
1.0
0.9
0.8
Probability of Survival
1.0
0.02
Complete response
Figure 7:
Unstratified HR OPDIVO Docetaxel
0.59
17.1
9.0
0.90
10.4
10.1
0.43
18.2
8.1
1.01
9.7
10.1
0.40
19.4
8.0
1.00
9.9
10.3
0.0015
Objective Response Rate
c
Forest Plot: OS Based on PD-L1 Expression - Trial 3
0.7
0.6
Patients were randomized to OPDIVO (n=410) administered intravenously at 3 mg/kg
every 2 weeks or everolimus (n=411) administered orally 10 mg daily. The median age
was 62 years (range: 18 to 88) with 40% ≥65 years of age and 9% ≥75 years of age. The
majority of patients were male (75%) and white (88%) and 34% and 66% of patients
had a baseline KPS of 70% to 80% and 90% to 100%, respectively. The majority of
patients (77%) were treated with one prior anti-angiogenic therapy. Patient distribution
by MSKCC risk groups was 34% favorable, 47% intermediate, and 19% poor.
0.5
0.4
0.3
0.2
OPDIVO
Docetaxel
0.1
0.0
0
3
Number at Risk
OPDIVO
292
232
Docetaxel
290
244
6
9
12
15
18
Overall Survival (Months)
21
24
27
194
169
146
123
62
32
9
0
194
150
111
88
34
10
5
0
Archival tumor specimens were evaluated for PD-L1 expression following completion of
the trial. Across the study population, 22% (127/582) of patients had non-quantifiable
results. Of the remaining 455 patients, the proportion of patients in retrospectively
determined subgroups based on PD-L1 testing using the PD-L1 IHC 28-8 pharmDx assay
were: 46% (209/455) PD-L1 negative, defined as <1% of tumor cells expressing PD-L1
and 54% (246/455) had PD-L1 expression, defined as ≥1% of tumor cells expressing
PD-L1. Among the 246 patients with tumors expressing PD-L1, 26% (65/246) had ≥1%,
but <5% tumor cells with positive staining, 7% (16/246) had ≥5% but <10% tumor
cells with positive staining, and 67% (165/246) had greater than or equal to 10% tumor
cells with positive staining. Figure 8 summarizes the results of prespecified analyses
of survival in subgroups determined by percentage of tumor cells expressing PD-L1.
Figure 9 summarizes the results of prespecified analyses of progression-free survival
in subgroups determined by percentage of tumor cells expressing PD-L1.
The first tumor assessments were conducted 8 weeks after randomization and
continued every 8 weeks thereafter for the first year and then every 12 weeks until
progression or treatment discontinuation, whichever occurred later.
The major efficacy outcome measure was overall survival (OS). The trial demonstrated
a statistically significant improvement in OS for patients randomized to OPDIVO as
compared with everolimus at the prespecified interim analysis when 398 events
were observed (70% of the planned number of events for final analysis) (Table 18 and
Figure 10). OS benefit was observed regardless of PD-L1 expression level.
Other endpoints include confirmed objective response rates, which are also presented
in Table 20.
OPDIVO® (nivolumab)
Table 20:
OPDIVO® (nivolumab)
Efficacy Results - Trial 5
Table 21:
OPDIVO
(n=410)
Trial 7 and Trial 8
(n=95)
Objective Response Rate, n (%)a
(95% CI)
Overall Survival
Deaths (%)
Median survival in months (95% CI)
183 (45)
215 (52)
25.0 (21.7, NE)
19.6 (17.6, 23.1)
Hazard ratio (95% CI)a
Efficacy in cHL after Autologous HSCT and Brentuximab Vedotin
Everolimus
(n=411)
Complete Remission Rate
(95% CI)
0.73 (0.60, 0.89)
p-valueb,c
62 (65%)
(55, 75)
7 (7%)
(3, 15)
Partial Remission Rate
(95% CI)
0.0018
Confirmed Objective Response
Rate (95% CI)
21.5% (17.6, 25.8)
3.9% (2.2, 6.2)
Median duration of response in
months (95% CI)
23.0 (12.0, NE)
13.7 (8.3, 21.9)
Median time to onset of confirmed
response in months (min, max)
3.0 (1.4, 13.0)
3.7 (1.5, 11.2)
55 (58%)
(47, 68)
Median Duration of Response (months)
(95% CI)
Range
8.7
(6.8, NE)
0.0+, 23.1+
Median Time to Response (months)
Range
2.1
0.7, 5.7
a Per 2007 revised International Working Group criteria.
a Based on a stratified proportional hazards model.
b Based on a stratified log-rank test.
c
14.5
p-value is compared with .0148 of the allocated alpha for this interim analysis.
Figure 10:
Trial 9 was a randomized (2:1), active-controlled, open-label study enrolling patients
with metastatic or recurrent SCCHN who had experienced disease progression
during or within 6 months of receiving platinum-based therapy administered in
either the adjuvant, neo-adjuvant, primary (unresectable locally advanced) or
metastatic setting. The trial excluded patients with autoimmune disease, medical
conditions requiring immunosuppression, recurrent or metastatic carcinoma of the
nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland
or non-squamous histologies (e.g., mucosal melanoma), or untreated brain metastasis.
Patients with treated brain metastases were eligible if neurologically stable. Patients
were randomized to receive OPDIVO administered intravenously (IV) at 3 mg/kg every
2 weeks or investigator’s choice of:
Overall Survival - Trial 5
1.0
0.9
0.8
Probability of Survival
Recurrent or Metastatic Squamous Cell Carcinoma of the Head and
Neck (SCCHN)
0.7
0.6
0.5
•
cetuximab 400 mg/m2 loading dose IV followed by 250 mg/m2 weekly,
0.4
•
methotrexate 40 to 60 mg/m2 IV weekly, or
•
docetaxel 30 to 40 mg/m2 IV weekly.
0.3
0.2
Randomization was stratified by prior cetuximab treatment (yes/no). The first tumor
assessments were conducted 9 weeks after randomization and continued every
6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy
outcome measures were PFS and ORR.
OPDIVO
Everolimus
0.1
0.0
0
3
Number at Risk
OPDIVO
410 389
Everolimus
411 366
14.4
6
9
12
15
18
21
Overall Survival (Months)
24
27
30
33
359
337
305
275
213
139
73
29
3
0
324
287
265
241
187
115
61
20
2
0
Classical Hodgkin Lymphoma
Two studies evaluated the efficacy of OPDIVO as a single agent in patients with cHL
after failure of autologous HSCT and post-transplantation brentuximab vedotin.
Trial 7 was a single-arm, open-label, multicenter, multicohort study in cHL. Trial 8
was an open-label, multicenter, dose escalation study that included cHL. Both studies
included patients regardless of their tumor PD-L1 status and excluded patients with
ECOG performance status of 2 or greater, autoimmune disease, symptomatic interstitial
lung disease, hepatic transaminases more than 3 times ULN, creatinine clearance less
than 40 mL/min, prior allogeneic HSCT, or chest irradiation within 24 weeks. In addition,
both studies required an adjusted diffusion capacity of the lungs for carbon monoxide
(DLCO) of over 60% in patients with prior pulmonary toxicity.
In Trial 9, total of 361 patients were randomized; 240 patients to OPDIVO and 121 patients
to investigator’s choice (45% received docetaxel, 43% received methotrexate, and
12% received cetuximab). The median age was 60 years (range: 28 to 83) with
31% ≥65 years of age, 83% were White, 12% Asian, and 4% were Black, and 83%
male. Baseline ECOG performance status was 0 (20%) or 1 (78%), 76% were former/
current smokers, 90% had Stage IV disease, 45% of patients received only one prior line
of systemic therapy, the remaining 55% received two or more prior lines of systemic
therapy, and 25% had HPVp16-positive tumors, 24% had HPV p16-negative tumors,
and 51% had unknown status.
The trial demonstrated a statistically significant improvement in OS for patients
randomized to OPDIVO as compared with investigator’s choice at a pre-specified
interim analysis (78% of the planned number of events for final analysis). The survival
results are displayed in Table 22 and Figure 11. There were no statistically significant
differences between the two arms for PFS (HR=0.89; 95% CI: 0.70, 1.13) or ORR
(13.3% [95% CI: 9.3, 18.3] vs 5.8% [95% CI: 2.4, 11.6] for nivolumab and investigator’s
choice, respectively).
Table 22:
Patients received 3 mg/kg of OPDIVO administered intravenously over 60 minutes every
2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity.
A cycle consisted of one dose. Dose reduction was not permitted.
Efficacy was evaluated by objective response rate (ORR) as determined by an
independent radiographic review committee (IRRC). Additional outcome measures
included duration of response. Efficacy was evaluated in 95 patients in Trials 7 and 8
combined who had received brentuximab vedotin after failure of autologous HSCT. The
median age was 37 years (range: 18 to 72). The majority were male (64%) and white
(87%). Patients had received a median of 5 prior systemic regimens (range: 3 to 15).
Results are shown in Table 21. Patients received a median of 17 doses of OPDIVO (range:
3 to 48), with a median duration of therapy of 8.3 months (range: 1.9 to 24 months).
Overall Survival in Trial 9
OPDIVO
(n=240)
Investigator’s Choice
(n=121)
Deaths (%)
133 (55%)
85 (70%)
Median (months)
(95% CI)
7.5
(5.5, 9.1)
5.1
(4.0, 6.0)
Overall Survival
Hazard ratio (95% CI)a
p-valueb,c
0.70 (0.53, 0.92)
0.0101
a Based on stratified proportional hazards model.
b Based on stratified log-rank test.
c
p-value is compared with 0.0227 of the allocated alpha for this interim analysis.
OPDIVO® (nivolumab)
Figure 11:
OPDIVO® (nivolumab)
Overall Survival - Trial 9
Table 23:
Efficacy Results in Trial 10
All Patients
1.0
Probability of Survival
0.8
0.7
Complete Response Rate
0.6
Partial Response Rate
N=270
N=146
N=124
22 (15.1%)
(9.7, 21.9)
31 (25.0%)
(17.7, 33.6)
7 (2.6%)
1 (0.7%)
6 (4.8%)
46 (17.0%)
21 (14.4%)
25 (20.2%)
7.6
(3.7,12.0+)
NE
(1.9+, 12.0+)
Median Duration of Responsea (months)
10.3
(range)
(1.9+, 12.0+)
0.5
0.4
PD-L1 ≥ 1%
53 (19.6%)
(15.1, 24.9)
0.9
Confirmed Objective Response Rate, n (%)
(95% CI)
PD-L1 < 1%
a Estimated from the Kaplan-Meier Curve
0.3
0.2
OPDIVO
0.1
Inv Choice
16
HOW SUPPLIED/STORAGE AND HANDLING
OPDIVO®
(nivolumab) is available as follows:
0.0
0
Number at Risk
OPDIVO
240
INV Choice
121
3
6
9
12
Overall Survival (Months)
15
18
167
109
52
24
7
0
87
42
17
5
1
0
14.6
The median age was 66 years (range 38 to 90), 78% were male, 86% of patients
were white. Twenty-seven percent had non-bladder urothelial carcinoma and 84% had
visceral metastases. Thirty-four percent of patients had disease progression following
prior platinum-containing neoadjuvant or adjuvant therapy. Twenty-nine percent of
patients had received ≥2 prior systemic regimens in the metastatic setting. Thirty-six
percent of patients received prior cisplatin only, 23% received prior carboplatin only,
and 7% were treated with both cisplatin and carboplatin in the metastatic setting.
Forty-six percent of patients had an ECOG performance status of 1. Eighteen percent
of patients had a hemoglobin <10 g/dL, and twenty-eight percent of patients had liver
metastases at baseline. Patients were included regardless of their PD-L1 status.
Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx
assay at a central laboratory and the results were used to define subgroups
for pre-specified analyses. Of the 270 patients, 46% were defined as having
PD-L1 expression of ≥1% (defined as ≥1% of tumor cells expressing PD-L1).
The remaining 54% of patients, were classified as having PD-L1 expression of
<1% (defined as <1% of tumor cells expressing PD-L1). Confirmed ORR in all patients
and the two PD-L1 subgroups are summarized in Table 23. Median time to response was
1.9 months (range; 1.6-7.2). In 77 patients who received prior systemic therapy only
in the neoadjuvant or adjuvant setting, the ORR was 23.4% (95% CI: 14.5%, 34.4%).
40 mg/4 mL single-dose vial
0003-3772-11
100 mg/10 mL single-dose vial
0003-3774-12
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients of the risk of immune-mediated adverse reactions that may require
corticosteroid treatment and withholding or discontinuation of OPDIVO, including:
•
Pneumonitis: Advise patients to contact their healthcare provider immediately
for any new or worsening cough, chest pain, or shortness of breath [see
Warnings and Precautions (5.1)].
•
Colitis: Advise patients to contact their healthcare provider immediately for
diarrhea or severe abdominal pain [see Warnings and Precautions (5.2)].
•
Hepatitis: Advise patients to contact their healthcare provider immediately for
jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy,
or easy bruising or bleeding [see Warnings and Precautions (5.3)].
•
Endocrinopathies: Advise patients to contact their healthcare provider
immediately for signs or symptoms of hypophysitis, adrenal insufficiency,
hypothyroidism, hyperthyroidism, and diabetes mellitus [see Warnings and
Precautions (5.4)].
•
Nephritis and Renal Dysfunction: Advise patients to contact their healthcare
provider immediately for signs or symptoms of nephritis including decreased
urine output, blood in urine, swelling in ankles, loss of appetite, and any other
symptoms of renal dysfunction [see Warnings and Precautions (5.5)].
•
Skin Adverse Reactions: Advise patients to contact their healthcare provider
immediately for rash [see Warnings and Precautions (5.6)].
•
Encephalitis: Advise patients to contact their healthcare provider immediately for
neurological signs or symptoms of encephalitis [see Warnings and Precautions
(5.7)].
•
Infusion Reactions: Advise patients of the potential risk of infusion reaction [see
Warnings and Precautions (5.9)].
•
Complications of allogeneic HSCT after OPDIVO: Advise patients of potential risk
of post-transplant complications [see Warnings and Precautions (5.10)].
•
Females of Reproductive Potential: Advise females of reproductive potential of
the potential risk to a fetus and to inform their healthcare provider of a known
or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific
Populations (8.1)]. Advise females of reproductive potential to use effective
contraception during treatment with OPDIVO and for at least 5 months following
the last dose of OPDIVO [see Use in Specific Populations (8.3)].
•
Lactation: Advise women not to breastfeed while taking OPDIVO [see Use in
Specific Populations (8.2)].
Urothelial Carcinoma
In Trial 10, 270 patients with locally advanced or metastatic urothelial carcinoma who
had disease progression during or following platinum-containing chemotherapy or who
had disease progression within 12 months of treatment with a platinum-containing
neoadjuvant or adjuvant chemotherapy regimen were treated with OPDIVO. Patients
were excluded for active brain or leptomeningeal metastases, active autoimmune
disease, medical conditions requiring systemic immunosuppression, and ECOG
performance status >1. Patients received an intravenous infusion of 3 mg/kg of OPDIVO
every 2 weeks until unacceptable toxicity or either radiographic or clinical progression.
Tumor response assessments were conducted every 8 weeks for the first 48 weeks
and every 12 weeks thereafter. Major efficacy outcome measures included confirmed
objective response rate (ORR) as assessed by independent radiographic review
committee (IRRC) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and
duration of response (DOR).
NDC
Store OPDIVO under refrigeration at 2°C to 8°C (36°F to 46°F). Protect OPDIVO from
light by storing in the original package until time of use. Do not freeze or shake.
17
Archival tumor specimens were retrospectively evaluated for PD-L1 expression using
the PD-L1 IHC 28-8 pharmDx assay. Across the study population, 28% (101/361) of
patients had non-quantifiable results. Among the 260 patients with quantifiable results,
43% (111/260) had PD-L1 negative SCCHN, defined as <1% of tumor cells expressing
PD-L1, and 57% (149/260) had PD-L1 positive SCCHN, defined as ≥1% of tumor cells
expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratio for
survival was 0.89 (95% CI: 0.54, 1.45) with median survivals of 5.7 and 5.8 months for
the nivolumab and chemotherapy arms, respectively, in the PD-L1 negative subgroup.
The HR for survival was 0.55 (95% CI: 0.36, 0.83) with median survivals of 8.7 and
4.6 months for the nivolumab and chemotherapy arms, respectively, in the PD-L1
positive SCCHN subgroup.
Carton Contents
Manufactured by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
U.S. License No. 1713
OPDIVO® (nivolumab)
MEDICATION GUIDE
OPDIVO® (op-DEE-voh)
(nivolumab)
Injection
Read this Medication Guide before you start receiving OPDIVO and before each infusion. There may be new information. If
your healthcare provider prescribes OPDIVO in combination with ipilimumab (YERVOY®), also read the Medication Guide
that comes with ipilimumab. This Medication Guide does not take the place of talking with your healthcare provider about
your medical condition or your treatment.
What is the most important information I should know about OPDIVO?
OPDIVO is a medicine that may treat your melanoma, lung cancer, kidney cancer, blood cancer, head and neck cancer, or
bladder cancer by working with your immune system. OPDIVO can cause your immune system to attack normal organs and
tissues in many areas of your body and can affect the way they work. These problems can sometimes become serious or
life-threatening and can lead to death. These problems may happen anytime during treatment or even after your treatment
has ended. Some of these problems may happen more often when OPDIVO is used in combination with ipilimumab.
Call or see your healthcare provider right away if you develop any symptoms of the following problems or these
symptoms get worse:
Lung problems (pneumonitis). Symptoms of pneumonitis may include:
Ɣ
new or worsening cough
Ɣ
chest pain
Ɣ
shortness of breath
Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and symptoms of colitis may
include:
Ɣ
Ɣ
Ɣ
diarrhea (loose stools) or more bowel movements than usual
blood in your stools or dark, tarry, sticky stools
severe stomach-area (abdomen) pain or tenderness
Liver problems (hepatitis). Signs and symptoms of hepatitis may include:
Ɣ
yellowing of your skin or the whites of your eyes
Ɣ
dark urine (tea colored)
Ɣ
severe nausea or vomiting
Ɣ
bleeding or bruising more easily than normal
Ɣ
pain on the right side of your stomach area (abdomen)
Ɣ
feeling less hungry than usual
Ɣ
drowsiness
Hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas). Signs and symptoms that
your hormone glands are not working properly may include:
Ɣ
headaches that will not go away or unusual headaches
Ɣ
hair loss
Ɣ
extreme tiredness
Ɣ
feeling cold
Ɣ
weight gain or weight loss
Ɣ
constipation
Ɣ
dizziness or fainting
Ɣ
voice gets deeper
Ɣ
changes in mood or behavior, such as decreased sex
drive, irritability, or forgetfulness
Ɣ
excessive thirst or lots of urine
Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include:
Ɣ
Ɣ
decrease in the amount of urine
blood in your urine
Ɣ
Ɣ
swelling in your ankles
loss of appetite
Ɣ
Ɣ
skin blistering
ulcers in mouth or other mucous membranes
Skin Problems. Signs of these problems may include:
Ɣ
Ɣ
rash
itching
OPDIVO® (nivolumab)
,QÀDPPDWLRQRIWKHEUDLQHQFHSKDOLWLVSigns and symptoms of encephalitis may include:
Ɣ
headache
Ɣ
fever
Ɣ
tiredness or weakness
Ɣ
confusion
Ɣ
memory problems
Ɣ
Ɣ
sleepiness
seeing or hearing things that are not really there
(hallucinations)
seizures
stiff neck
Ɣ
severe muscle weakness
Ɣ
Ɣ
Problems in other organs. Signs of these problems may include:
Ɣ
Ɣ
changes in eyesight
severe or persistent muscle or joint pains
Getting medical treatment right away may keep these problems from becoming more serious.
Your healthcare provider will check you for these problems during treatment with OPDIVO. Your healthcare provider may
treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or
completely stop treatment with OPDIVO, if you have severe side effects.
What is OPDIVO?
OPDIVO is a prescription medicine used to treat:
Ɣ
a type of skin cancer called melanoma that has spread or cannot be removed by surgery (advanced
melanoma). You may receive OPDIVO alone or in combination with ipilimumab.
Ɣ
a type of advanced stage lung cancer (called non-small cell lung cancer)
OPDIVO may be used when your lung cancer:
ż has spread or grown, and
ż you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
If your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for tumors
with these abnormal genes, and it did not work or is no longer working.
kidney cancer (renal cell carcinoma)
ż OPDIVO may be used when your cancer has spread or grown after treatment with other cancer medications.
a type of blood cancer that affects white blood cells known as lymphocytes (called classical Hodgkin
lymphoma)
OPDIVO may be used if:
ż your cancer has come back or spread after a type of stem cell transplant that uses your own stem cells
(autologous), and
ż you used the drug brentuximab vedotin (Adcetris®) after your stem cell transplant.
head and neck cancer
OPDIVO may be used when your head and neck cancer:
ż has come back or spread, and
ż you have tried chemotherapy that contains platinum and it did not work or is no longer working.
bladder cancer (urothelial carcinoma)
OPDIVO may be used when your bladder cancer:
ż has spread or grown, and
ż you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
Ɣ
Ɣ
Ɣ
Ɣ
It is not known if OPDIVO is safe and effective in children less than 18 years of age.
What should I tell my healthcare provider before receiving OPDIVO?
Before you receive OPDIVO, tell your healthcare provider if you:
Ɣ
have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
Ɣ
have had an organ transplant
OPDIVO® (nivolumab)
Ɣ
have lung or breathing problems
Ɣ
have liver problems
Ɣ
have any other medical conditions
Ɣ
are pregnant or plan to become pregnant. OPDIVO can harm your unborn baby.
ż
ż
Ɣ
Females who are able to become pregnant should use an effective method of birth control during and for at least
5 months after the last dose of OPDIVO. Talk to your healthcare provider about birth control methods that you can
use during this time.
Tell your healthcare provider right away if you become pregnant during treatment with OPDIVO.
are breastfeeding or plan to breastfeed. It is not known if OPDIVO passes into your breast milk. Do not breastfeed
during treatment with OPDIVO.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show your healthcare providers and pharmacist when
you get a new medicine.
How will I receive OPDIVO?
Ɣ
Your healthcare provider will give you OPDIVO into your vein through an intravenous (IV) line over 60 minutes.
Ɣ
OPDIVO is usually given every 2 weeks.
Ɣ
When used in combination with ipilimumab, OPDIVO is usually given every 3 weeks, for a total of 4 doses. Ipilimumab
will be given on the same day. After that, OPDIVO will be given alone every 2 weeks.
Ɣ
Your healthcare provider will decide how many treatments you need.
Ɣ
Your healthcare provider will do blood tests to check you for side effects.
Ɣ
If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.
What are the possible side effects of OPDIVO?
OPDIVO can cause serious side effects, including:
Ɣ
See “What is the most important information I should know about OPDIVO?”
Ɣ
Severe infusion reactions. Tell your doctor or nurse right away if you get these symptoms during an infusion of
OPDIVO:
Ɣ
ż
chills or shaking
ż
dizziness
ż
itching or rash
ż
fever
ż
ÀXVKLQJ
ż
feeling like passing out
ż
GLI¿FXOW\EUHDWKLQJ
Complications of stem cell transplant that uses donor stem cells (allogeneic) after treatment with OPDIVO.
These complications can be severe and can lead to death. Your healthcare provider will monitor you for signs of
complications if you have an allogeneic stem cell transplant.
The most common side effects of OPDIVO when used alone include:
Ɣ
feeling tired
Ɣ
rash
Ɣ
pain in muscles, bones, and joints
Ɣ
itchy skin
Ɣ
diarrhea
Ɣ
nausea
Ɣ
cough
Ɣ
shortness of breath
Ɣ
constipation
Ɣ
decreased appetite
Ɣ
back pain
Ɣ
upper respiratory tract infection
Ɣ
fever
Ɣ
weakness
OPDIVO® (nivolumab)
The most common side effects of OPDIVO when used in combination with ipilimumab include:
Ɣ
Ɣ
Ɣ
Ɣ
feeling tired
diarrhea
fever
shortness of breath
Ɣ
Ɣ
Ɣ
rash
nausea
vomiting
These are not all the possible side effects of OPDIVO. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of OPDIVO.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more
information about OPDIVO, talk with your healthcare provider. You can ask your healthcare provider for information about
OPDIVO that is written for health professionals.
What are the ingredients in OPDIVO?
Active ingredient: nivolumab
Inactive ingredients: mannitol, pentetic acid, polysorbate 80, sodium chloride, sodium citrate dihydrate, and Water for
Injection. May contain hydrochloric acid and/or sodium hydroxide.
OPDIVO® and YERVOY® are trademarks of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their
respective owners.
Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713
For more information, call 1-855-673-4861 or go to www.OPDIVO.com.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
1363787A3
Revised: February 2017
1506US1700258-01-01
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use YERVOY safely
and effectively. See full prescribing information for YERVOY.
YERVOY® (ipilimumab) injection, for intravenous use
Initial U.S. Approval: 2011
• Adjuvant melanoma:
ż 10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses,
followed by 10 mg/kg every 12 weeks for up to 3 years or until documented
disease recurrence or unacceptable toxicity. (2.2)
• Permanently discontinue for severe adverse reactions. (2.3)
-------------------------DOSAGE FORMS AND STRENGTHS ------------------------
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
See full prescribing information for complete boxed warning.
YERVOY can result in severe and fatal immune-mediated adverse reactions.
These immune-mediated reactions may involve any organ system; however,
the most common severe immune-mediated adverse reactions are
enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis),
neuropathy, and endocrinopathy. The majority of these immune-mediated
reactions initially manifested during treatment; however, a minority occurred
weeks to months after discontinuation of YERVOY.
Permanently discontinue YERVOY and initiate systemic high-dose
corticosteroid therapy for severe immune-mediated reactions. (2.3)
Assess patients for signs and symptoms of enterocolitis, dermatitis,
neuropathy, and endocrinopathy and evaluate clinical chemistries including
liver function tests, adrenocorticotropic hormone (ACTH) level, and thyroid
function tests at baseline and before each dose. (5.1, 5.2, 5.3, 5.4, 5.5)
-----------------------------RECENT MAJOR CHANGES ---------------------------Indications and Usage (1.2)
Dosage and Administration (2.1, 2.2, 2.3)
Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7)
10/2015
10/2015
10/2015
----------------------------- INDICATIONS AND USAGE -----------------------------
• Injection: 50 mg/10 mL (5 mg/mL) (3)
• Injection: 200 mg/40 mL (5 mg/mL) (3)
------------------------------- CONTRAINDICATIONS ------------------------------None. (4)
-------------------------- WARNINGS AND PRECAUTIONS -------------------------Immune-mediated adverse reactions: Permanently discontinue for severe reactions.
Withhold dose for moderate immune-mediated adverse reactions until return to
baseline, improvement to mild severity, or complete resolution, and patient is receiving
less than 7.5 mg prednisone or equivalent per day. Administer systemic high-dose
corticosteroids for severe, persistent, or recurring immune-mediated reactions. (5.1,
5.2, 5.3, 5.4, 5.5)
• Immune-mediated hepatitis: Evaluate liver function tests before each dose of
YERVOY (ipilimumab). (5.2)
• Immune-mediated endocrinopathies: Monitor clinical chemistries, ACTH level,
and thyroid function tests prior to each dose. Evaluate at each visit for signs and
symptoms of endocrinopathy. Institute hormone replacement therapy as needed.
(5.5)
• Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and
use of effective contraception. (5.7)
------------------------------- ADVERSE REACTIONS ------------------------------Most common adverse reactions (≥5%) are fatigue, diarrhea, pruritus, rash, and colitis.
Additional common adverse reactions at the 10 mg/kg dose (≥5%) include nausea,
vomiting, headache, weight loss, pyrexia, decreased appetite, and insomnia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at
1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody
indicated for:
• Treatment of unresectable or metastatic melanoma. (1.1)
• Adjuvant treatment of patients with cutaneous melanoma with pathologic
involvement of regional lymph nodes of more than 1 mm who have undergone
complete resection, including total lymphadenectomy. (1.2)
-------------------------- USE IN SPECIFIC POPULATIONS --------------------------
-------------------------- DOSAGE AND ADMINISTRATION --------------------------
• Lactation: Discontinue nursing during treatment with YERVOY. (8.2)
• Unresectable or metastatic melanoma:
ż 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total
of 4 doses. (2.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 10/2015
FULL PRESCRIBING INFORMATION: CONTENTS *
7
DRUG INTERACTIONS
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
8
USE IN SPECIFIC POPULATIONS
1
INDICATIONS AND USAGE
1.1
1.2
2
DOSAGE AND ADMINISTRATION
2.1
2.2
2.3
2.4
Recommended Dosing for Unresectable or Metastatic Melanoma
Recommended Dosing for Adjuvant Treatment of Melanoma
Recommended Dose Modifications
Preparation and Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
5.2
5.3
5.4
5.5
5.6
5.7
6
8.1
8.2
8.3
8.4
8.5
8.6
8.7
Unresectable or Metastatic Melanoma
Adjuvant Treatment of Melanoma
Immune-Mediated Enterocolitis
Immune-Mediated Hepatitis
Immune-Mediated Dermatitis
Immune-Mediated Neuropathies
Immune-Mediated Endocrinopathies
Other Immune-Mediated Adverse Reactions, Including Ocular
Manifestations
Embryo-fetal Toxicity
ADVERSE REACTIONS
6.1
6.2
6.3
Clinical Trials Experience
Postmarketing Experience
Immunogenicity
Pregnancy
Lactation
Females and Males of Reproductive Potential
Pediatric Use
Geriatric Use
Renal Impairment
Hepatic Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
12.3
13
NONCLINICAL TOXICOLOGY
13.1
14
Mechanism of Action
Pharmacokinetics
Carcinogenesis, Mutagenesis, Impairment of Fertility
CLINICAL STUDIES
14.1
14.2
Unresectable or Metastatic Melanoma
Adjuvant Treatment of Melanoma
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not listed.
YERVOY® (ipilimumab)
FULL PRESCRIBING INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse reactions.
These immune-mediated reactions may involve any organ system; however, the
most common severe immune-mediated adverse reactions are enterocolitis,
hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and
endocrinopathy. The majority of these immune-mediated reactions initially
manifested during treatment; however, a minority occurred weeks to months
after discontinuation of YERVOY.
Permanently discontinue YERVOY and initiate systemic high-dose
corticosteroid therapy for severe immune-mediated reactions [see Dosage and
Administration (2.3)].
Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy,
and endocrinopathy, and evaluate clinical chemistries including liver function
tests, adrenocorticotropic hormone (ACTH) level, and thyroid function tests, at
baseline and before each dose [see Warnings and Precautions (5.1, 5.2, 5.3,
5.4, 5.5)].
1
INDICATIONS AND USAGE
1.1
Unresectable or Metastatic Melanoma
2.4
Preparation and Administration
• Do not shake product.
• Inspect parenteral drug products visually for particulate matter and discoloration prior
to administration. Discard vial if solution is cloudy, there is pronounced discoloration
(solution may have pale-yellow color), or there is foreign particulate matter other than
translucent-to-white, amorphous particles.
Preparation of Solution
• Allow the vials to stand at room temperature for approximately 5 minutes prior to
preparation of infusion.
• Withdraw the required volume of YERVOY and transfer into an intravenous bag.
• Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP
to prepare a diluted solution with a final concentration ranging from 1 mg/mL to
2 mg/mL. Mix diluted solution by gentle inversion.
• Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C,
36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F).
• Discard partially used vials or empty vials of YERVOY.
YERVOY is indicated for the treatment of unresectable or metastatic melanoma [see
Clinical Studies (14.1)].
Administration Instructions
• Do not mix YERVOY with, or administer as an infusion with, other medicinal products.
1.2
• Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose
Injection, USP after each dose.
Adjuvant Treatment of Melanoma
YERVOY is indicated for the adjuvant treatment of patients with cutaneous melanoma
with pathologic involvement of regional lymph nodes of more than 1 mm who
have undergone complete resection, including total lymphadenectomy [see Clinical
Studies (14.2)].
• Administer diluted solution over 90 minutes through an intravenous line containing a
sterile, non-pyrogenic, low-protein-binding in-line filter.
3
DOSAGE FORMS AND STRENGTHS
2
DOSAGE AND ADMINISTRATION
Injection: 50 mg/10 mL (5 mg/mL)
2.1
Recommended Dosing for Unresectable or Metastatic Melanoma
Injection: 200 mg/40 mL (5 mg/mL)
The recommended dose of YERVOY is 3 mg/kg administered intravenously over
90 minutes every 3 weeks for a maximum of 4 doses. In the event of toxicity, doses may
be delayed, but all treatment must be administered within 16 weeks of the first dose
[see Clinical Studies (14.1)].
4
None.
5
2.2
Recommended Dosing for Adjuvant Treatment of Melanoma
The recommended dose of YERVOY is 10 mg/kg administered intravenously over
90 minutes every 3 weeks for 4 doses followed by 10 mg/kg every 12 weeks for up
to 3 years [see Clinical Studies (14.2)]. In the event of toxicity, doses are omitted, not
delayed.
2.3
Recommended Dose Modifications
Table 1:
Target/Organ
System
Endocrine
Recommended Treatment Modifications for Immune-Mediated
Adverse Reactions of YERVOY
Adverse Reaction (CTCAE v3)
Symptomatic endocrinopathy
Treatment Modification
Withhold YERVOY
Resume YERVOY in patients with
complete or partial resolution of
adverse reactions (Grade 0 to 1)
and who are receiving less than
7.5 mg prednisone or equivalent
per day.
• Symptomatic reactions lasting
6 weeks or longer
• Inability to reduce corticosteroid
dose to 7.5 mg prednisone or
equivalent per day
Permanently discontinue YERVOY
Ophthalmologic Grade 2 through 4 reactions
• not improving to Grade 1 within
2 weeks while receiving topical
therapy or
• requiring systemic treatment
Permanently discontinue YERVOY
All Other
Withhold YERVOY
Resume YERVOY in patients with
complete or partial resolution of
adverse reactions (Grade 0 to 1)
and who are receiving less than
7.5 mg prednisone or equivalent
per day.
Grade 2
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
YERVOY can result in severe and fatal immune-mediated reactions [see Boxed Warning].
5.1
Immune-Mediated Enterocolitis
Immune-mediated enterocolitis, including fatal cases, can occur with YERVOY.
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal
pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as
peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and
consider endoscopic evaluation for persistent or severe symptoms.
Permanently discontinue YERVOY in patients with severe enterocolitis and initiate
systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon
improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over
at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence
or worsening symptoms of enterocolitis in some patients. Consider adding anti-TNF or
other immunosuppressant agents for management of immune-mediated enterocolitis
unresponsive to systemic corticosteroids within 3 to 5 days or recurring after symptom
improvement.
Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment
and, if persistent for more than 1 week, initiate systemic corticosteroids at a dose of
0.5 mg/kg/day prednisone or equivalent [see Dosage and Administration (2.3)].
Metastatic Melanoma
• Grade 2 reactions lasting 6 weeks Permanently discontinue YERVOY
or longer
• Inability to reduce corticosteroid
dose to 7.5 mg prednisone or
equivalent per day
• Grade 3 or 4
In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal (diarrhea
of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3 to 5) immunemediated enterocolitis occurred in 34 YERVOY-treated patients (7%), and moderate
(diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool;
Grade 2) enterocolitis occurred in 28 YERVOY-treated patients (5%). Across all YERVOYtreated patients (n=511), 5 patients (1%) developed intestinal perforation, 4 patients
(0.8%) died as a result of complications, and 26 patients (5%) were hospitalized for
severe enterocolitis.
The median time to onset of Grade 3 to 5 enterocolitis was 1.7 months (range: 11 days to
3.1 months) and for Grade 2 enterocolitis was 1.4 months (range: 2 days to 4.3 months).
Twenty-nine patients (85%) with Grade 3 to 5 enterocolitis were treated with high-dose
(≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day
of prednisone or equivalent; the median duration of treatment was 16 days (ranging
up to 3.2 months) followed by corticosteroid taper. Of the 28 patients with moderate
enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated
with <40 mg prednisone or equivalent per day for a median duration of 1.2 months,
and 25% were treated with high-dose corticosteroids for a median duration of 10 days
prior to corticosteroid taper. Infliximab was administered to 5 (8%) of the 62 patients
with moderate, severe, or life-threatening immune-mediated enterocolitis following
inadequate response to corticosteroids.
YERVOY® (ipilimumab)
Of the 34 patients with Grade 3 to 5 enterocolitis, 74% experienced complete resolution,
3% experienced improvement to Grade 2 severity, and 24% did not improve. Among
the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11%
improved, and 11% did not improve.
Adjuvant Treatment of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 5 immune-mediated
enterocolitis occurred in 76 patients (16%) and Grade 2 enterocolitis occurred in 68
patients (14%). Seven patients (1.5%) developed intestinal perforation and 3 patients
(0.6%) died as a result of complications [see Adverse Reactions (6.1)].
The median time to onset for Grade 3 to 4 enterocolitis was 1.1 months (range: 1 day to
33.1 months) and for Grade 2 enterocolitis was 1.1 months (range: 1 day to 20.6 months).
Seventy-one patients (95%) with Grade 3 to 4 enterocolitis were treated with systemic
corticosteroids. The median duration of treatment was 4.7 months (ranging up to
52.3 months).
Of the 68 patients with moderate enterocolitis, 51 patients (75%) were treated with
systemic corticosteroids with a median duration of treatment of 3.5 months (ranging up
to 52.2 months). Non-corticosteroids immunosuppression, consisting almost exclusively
of infliximab, was used to treat 36% of patients with Grade 3 to 4 enterocolitis and 15%
of patients with a Grade 2 event.
Of the 75 patients with Grade 3 to 4 immune-mediated enterocolitis, 86% experienced
complete resolution, 3% experienced improvement to Grade 1, and 11% did not improve.
Among the 68 patients with Grade 2 enterocolitis, 94% experienced complete resolution,
3% experienced improvement to Grade 1, and 3% did not improve.
5.2
Immune-Mediated Hepatitis
Immune-mediated hepatitis, including fatal cases, can occur with YERVOY.
Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients
for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with
hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver
function test monitoring until resolution.
Permanently discontinue YERVOY in patients with Grade 3 to 4 hepatotoxicity and
administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or
equivalent. When liver function tests show sustained improvement or return to baseline,
initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical
development program for YERVOY, mycophenolate treatment has been administered in
patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold
YERVOY in patients with Grade 2 hepatotoxicity [see Dosage and Administration (2.3)].
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal
hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal
or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3 to 5)
occurred in 8 YERVOY-treated patients (2%), with fatal hepatic failure in 0.2% and
hospitalization in 0.4% of YERVOY-treated patients. An additional 13 patients (2.5%)
experienced moderate hepatotoxicity manifested by liver function test abnormalities
(AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit
of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times
the upper limit of normal; Grade 2). The underlying pathology was not ascertained in
all patients but in some instances included immune-mediated hepatitis. There were
insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical
course of this event.
Adjuvant Treatment of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 4 immune-mediated
hepatitis occurred in 51 patients (11%) and moderate Grade 2 immune-mediated
hepatitis occurred in 22 patients (5%). Liver biopsy performed in 6 patients with Grade 3
to 4 hepatitis showed evidence of toxic or autoimmune hepatitis. The median time to
onset for Grade 3 to 4 hepatitis was 2.0 months (range: 1 day to 4.2 months) and for
Grade 2 hepatitis was 1.4 months (range: 13 days to 6.5 months). Of the 51 patients
with Grade 3 to 4 immune-mediated hepatitis, 94% experienced complete resolution,
4% experienced improvement to Grade 1, and 2% did not improve. Of the 22 patients
with Grade 2 immune-mediated hepatitis, 91% experienced complete resolution and
9% did not improve.
Forty-six patients (90%) with Grade 3 to 4 hepatitis were treated with systemic
corticosteroids. The median duration of treatment was 4.4 months (ranging up to
56.1 months). Sixteen patients (73%) with moderate hepatitis were treated with
systemic corticosteroids. The median duration of treatment was 2.6 months (ranging
up to 41.4 months).
YERVOY® (ipilimumab)
Monitor patients for signs and symptoms of dermatitis, such as rash and pruritus. Unless
an alternate etiology has been identified, signs or symptoms of dermatitis should be
considered immune-mediated.
Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic
epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or
necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at
a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled,
corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY
dosing in patients with moderate to severe signs and symptoms [see Dosage and
Administration (2.3)].
For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically.
Administer topical or systemic corticosteroids if there is no improvement of symptoms
within 1 week.
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal immunemediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or
rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic
manifestations; Grade 3 to 5) occurred in 13 YERVOY-treated patients (2.5%). One patient
(0.2%) died as a result of toxic epidermal necrolysis and one additional patient required
hospitalization for severe dermatitis. There were 63 patients (12%) with moderate
(Grade 2) dermatitis.
The median time to onset of moderate, severe, or life-threatening immune-mediated
dermatitis was 22 days and ranged up to 4.0 months from the initiation of YERVOY.
Seven YERVOY-treated patients (54%) with severe dermatitis received high-dose
corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 3.4 months
followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to
resolution ranged up to 3.6 months.
Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic
corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of
15 days, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not
receive systemic or topical corticosteroids. Forty-four patients (70%) with moderate
dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1)
severity, and 12 (19%) had no reported improvement.
Adjuvant Treatment of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 4 immune-mediated
dermatitis occurred in 19 patients (4%). There were 99 patients (21%) with moderate
(Grade 2) dermatitis. The median time to onset for Grade 3 to 4 dermatitis was 14 days
(range: 5 days to 11.3 months) and for Grade 2 dermatitis was 11 days (range: 1 day to
16.6 months).
Sixteen patients (84%) with Grade 3 to 4 dermatitis were treated with systemic
corticosteroids for a median of 21 days (ranging up to 49.2 months) resulting in complete
resolution of dermatitis within a median time of 4.3 months (range up to 44.4 months).
Of the 3 patients (16%) not treated with systemic or topical corticosteroids, 2 (11%) had
complete resolution and 1 had improvement to Grade 1.
Of the 99 patients with Grade 2 dermatitis, 67 (68%) were treated with systemic
corticosteroids for a median of 2.6 months, 16 (16%) were treated with only topical
corticosteroids and 16 (16%) did not receive systemic or topical corticosteroids.
Seventy-seven patients (78%) had complete resolution, 15 (15%) improved to mild
(Grade 1) severity, and 7 (7%) did not improve.
5.4
Immune-Mediated Neuropathies
Immune-mediated neuropathies, including fatal cases, can occur with YERVOY.
Monitor for symptoms of motor or sensory neuropathy such as unilateral or
bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue
YERVOY in patients with severe neuropathy (interfering with daily activities) such
as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for
management of severe neuropathy. Consider initiation of systemic corticosteroids at a
dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold
YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities)
[see Dosage and Administration (2.3)].
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, 1 case of fatal Guillain-Barré syndrome
and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the
clinical development program of YERVOY, myasthenia gravis and additional cases of
Guillain-Barré syndrome have been reported.
Concurrent Administration with Vemurafenib
Adjuvant Treatment of Melanoma
In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant
increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY
(3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID).
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 5 immune-mediated
neuropathy occurred in 8 patients (2%); the sole fatality was due to complications of
Guillain-Barré syndrome [see Adverse Reactions (6.1)]. Moderate Grade 2 immunemediated neuropathy occurred in 1 patient (0.2%).
5.3
Immune-Mediated Dermatitis
Immune-mediated dermatitis, including fatal cases, can occur with YERVOY.
The time to onset across the 9 patients with Grade 2 to 5 immune-mediated neuropathy
ranged from 1.4 to 27.4 months. All 8 patients with Grade 3 to 5 neuropathy were
YERVOY® (ipilimumab)
YERVOY® (ipilimumab)
treated with systemic corticosteroids (range: 3 days to 38.3 months) and 3 also received
tacrolimus. Four of the 8 patients with Grade 3 to 5 immune-mediated neuropathy
experienced complete resolution, 1 improved to Grade 1, and 3 did not improve. The
single patient with Grade 2 immune-mediated neuropathy experienced complete
resolution without the use of corticosteroids.
5.5
Immune-Mediated Endocrinopathies
Immune-mediated endocrinopathies, including life-threatening cases, can occur with
YERVOY.
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency
(including adrenal crisis), and hyper- or hypothyroidism. Patients may present with
fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and
hypotension, or nonspecific symptoms which may resemble other causes such as brain
metastasis or underlying disease. Unless an alternate etiology has been identified, signs
or symptoms of endocrinopathies should be considered immune-mediated.
Monitor clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid
function tests at the start of treatment, before each dose, and as clinically indicated
based on symptoms. In a limited number of patients, hypophysitis was diagnosed by
imaging studies through enlargement of the pituitary gland.
Withhold YERVOY dosing in symptomatic patients and consider referral to an
endocrinologist. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of
prednisone or equivalent, and initiate appropriate hormone replacement therapy [see
Dosage and Administration (2.3)].
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, severe to life-threatening immunemediated endocrinopathies (requiring hospitalization, urgent medical intervention, or
interfering with activities of daily living; Grade 3 to 4) occurred in 9 YERVOY-treated
patients (1.8%). All 9 patients had hypopituitarism and some had additional concomitant
endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism.
Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate
endocrinopathy (requiring hormone replacement or medical intervention; Grade 2)
occurred in 12 patients (2.3%) and consisted of hypothyroidism, adrenal insufficiency,
hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome.
The median time to onset of moderate to severe immune-mediated endocrinopathy was
2.5 months and ranged up to 4.4 months after the initiation of YERVOY.
Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required
long-term hormone replacement therapy including, most commonly, adrenal hormones
(n=10) and thyroid hormones (n=13).
Adjuvant Treatment of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 4 immune-mediated
endocrinopathies occurred in 39 patients (8%) and Grade 2 immune-mediated
endocrinopathies in 93 patients (20%). Of the 39 patients with Grade 3 to 4 immunemediated endocrinopathies, 35 patients had hypopituitarism (associated with one
or more secondary endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and
hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary hypothyroidism. The
median time to onset of Grade 3 to 4 immune-mediated endocrinopathy was 2.2 months
(range: 2 days to 8 months). Twenty-seven of the 39 patients (69%) were hospitalized
for immune-mediated endocrinopathies, and 4 patients (10%) were reported to have
resolution.
Of the 93 patients with Grade 2 immune-mediated endocrinopathy, 74 had primary
hypopituitarism (associated with one or more secondary endocrinopathy, e.g., adrenal
insufficiency, hypogonadism, and hypothyroidism), 9 had primary hypothyroidism, 3 had
hyperthyroidism, 3 had thyroiditis with hypo- or hyperthyroidism, 2 had hypogonadism,
1 had both hyperthyroidism and hypopituitarism, and 1 subject developed Graves’
ophthalmopathy. The median time to onset of Grade 2 immune-mediated endocrinopathy
was 2.1 months (range: 9 days to 19.3 months), and 20% were reported to have
resolution.
One hundred twenty-four patients received systemic corticosteroids as
immunosuppression and/or adrenal hormone replacement for Grade 2 to 4 immunemediated endocrinopathy. Of these, 42 (34%) were able to discontinue corticosteroids.
Seventy-three patients received thyroid hormones for treatment of Grade 2 to 4 immunemediated hypothyroidism. Of these, 14 patients (19%) were able to discontinue thyroid
replacement therapy.
5.6
Other Immune-Mediated
Manifestations
Adverse
Reactions,
Including
Ocular
Permanently discontinue YERVOY for clinically significant or severe immune-mediated
adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day
prednisone or equivalent for severe immune-mediated adverse reactions.
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis.
Permanently discontinue YERVOY for immune-mediated ocular disease that is
unresponsive to local immunosuppressive therapy [see Dosage and Administration (2.3)].
Metastatic Melanoma
In Trial 1, the following clinically significant immune-mediated adverse reactions were
seen in less than 1% of YERVOY-treated patients: nephritis, pneumonitis, meningitis,
pericarditis, uveitis, iritis, and hemolytic anemia.
Adjuvant Treatment of Melanoma
In Trial 2, the following clinically significant immune-mediated adverse reactions were
seen in less than 1% of YERVOY-treated patients unless specified: eosinophilia (2.1%),
pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis, pericarditis, uveitis, and fatal
myocarditis [see Adverse Reactions (6.1)].
Other Clinical Experience
Across 21 dose-ranging trials administering YERVOY at doses of 0.1 to 20 mg/kg (n=2478),
the following likely immune-mediated adverse reactions were also reported with less
than 1% incidence: angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica,
conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema
multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis,
autoimmune central neuropathy (encephalitis), myositis, polymyositis, ocular myositis,
hemolytic anemia, and nephritis.
5.7
Embryo-fetal Toxicity
Based on its mechanism of action and data from animal studies, YERVOY can cause
fetal harm when administered to a pregnant woman. In animal reproduction studies,
administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis
through delivery resulted in higher incidences of abortion, stillbirth, premature delivery
(with corresponding lower birth weight), and higher incidences of infant mortality in a
dose-related manner. The effects of ipilimumab are likely to be greater during the second
and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment
with a YERVOY-containing regimen and for 3 months after the last dose of YERVOY [see
Use in Specific Populations (8.1, 8.3)].
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the
labeling.
• Immune-mediated enterocolitis [see Warnings and Precautions (5.1)].
• Immune-mediated hepatitis [see Warnings and Precautions (5.2)].
• Immune-mediated dermatitis [see Warnings and Precautions (5.3)].
• Immune-mediated neuropathies [see Warnings and Precautions (5.4)].
• Immune-mediated endocrinopathies [see Warnings and Precautions (5.5)].
• Other immune-mediated adverse reactions, including ocular manifestations [see
Warnings and Precautions (5.6)].
In patients receiving YERVOY 3 mg/kg for unresectable or metastatic melanoma in Trial 1,
15% of patients receiving monotherapy and 12% of patients treated in combination
with gp100 peptide vaccine experienced Grade 3 to 5 immune-mediated reactions.
In patients receiving YERVOY 10 mg/kg for adjuvant treatment of melanoma in Trial 2,
41% experienced Grade 3 to 5 immune-mediated reactions.
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse
reaction rates observed cannot be directly compared with rates in other clinical trials or
experience with therapeutics in the same class and may not reflect the rates observed
in clinical practice.
The data described below reflect exposure to YERVOY 3 mg/kg in Trial 1, a randomized
trial in patients with unresectable or metastatic melanoma and to YERVOY 10 mg/kg in
Trial 2, a randomized trial in patients with resected Stage IIIA (>1 mm nodal involvement),
IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma.
Clinically significant adverse reactions were evaluated in a total of 982 patients treated
in Trials 1 and 2 and in 21 dose-ranging trials (n=2478) administering YERVOY at doses
of 0.1 to 20 mg/kg [see Warnings and Precautions (5.6)].
Unresectable or Metastatic Melanoma
The safety of YERVOY was evaluated in Trial 1, a randomized, double-blind clinical trial
in which 643 previously treated patients with unresectable or metastatic melanoma
received YERVOY 3 mg/kg for 4 doses given by intravenous infusion as a single agent
(n=131), YERVOY with an investigational gp100 peptide vaccine (gp100) (n=380), or
gp100 peptide vaccine as a single agent (n=132) [see Clinical Studies (14.1)]. Patients in
the trial received a median of 4 doses (range: 1 to 4 doses).
Trial 1 excluded patients with active autoimmune disease or those receiving systemic
immunosuppression for organ transplantation.
The trial population characteristics were: median age 57 years (range: 19 to 90),
59% male, 94% white, and baseline ECOG performance status 0 (56%).
YERVOY was discontinued for adverse reactions in 10% of patients.
Table 2 presents selected adverse reactions from Trial 1, which occurred in at least 5%
of patients in the YERVOY-containing arms and with at least 5% increased incidence over
the control gp100 arm for all-grade events and at least 1% incidence over the control
group for Grade 3 to 5 events.
YERVOY® (ipilimumab)
Table 2:
YERVOY® (ipilimumab)
Table 4 presents selected adverse reactions from Trial 2 which occurred in at least 5%
of YERVOY-treated patients and with at least 5% increased incidence over the placebo
group for all-grade events.
Selected Adverse Reactions in Trial 1
Percentage (%) of Patientsa
YERVOY
3 mg/kg
n=131
System Organ Class/
Preferred Term
Any
Grade
Grade
3 to 5
YERVOY
3 mg/kg+gp100
n=380
Any
Grade
Grade
3 to 5
Table 4:
gp100
n=132
Any
Grade
Percentage (%) of Patientsa
Grade
3 to 5
General Disorders and
Administration-Site Conditions
Fatigue
41
7
34
5
31
3
Gastrointestinal Disorders
Diarrhea
32
5
37
4
20
1
Colitis
8
5
5
3
2
0
Pruritus
31
0
21
<1
11
0
Rash
29
2
25
2
8
0
Skin and Subcutaneous Tissue
Disorders
a Incidences
presented in this table are based on reports of adverse events regardless
of causality.
Table 3 presents the per-patient incidence of severe, life-threatening, or fatal immunemediated adverse reactions from Trial 1.
Table 3:
Severe to Fatal Immune-Mediated Adverse Reactions in Trial 1
Percentage (%) of Patients
YERVOY
3 mg/kg
n=131
YERVOY
3 mg/kg+gp100
n=380
Any Immune-Mediated Adverse Reaction
15
12
Enterocolitisa,b
7
7
Hepatotoxicitya
1
2
Dermatitisa
2
3
Neuropathya
1
<1
Endocrinopathy
4
1
Hypopituitarism
4
1
Adrenal insufficiency
0
1
Pneumonitis
0
<1
Meningitis
0
<1
Other
Nephritis
1
0
1
0
Pericarditisa,c
0
<1
a Including
fatal outcome. b Including intestinal perforation.
etiology not established.
c Underlying
Adjuvant Treatment of Melanoma
The safety of YERVOY was evaluated in Trial 2, a randomized (1:1), double-blind,
placebo-controlled trial in which 945 patients with resected Stage IIIA (>1 mm nodal
involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma received
YERVOY 10 mg/kg (n=471) or placebo (n=474) administered as an intravenous infusion
for 4 doses every 3 weeks followed by 10 mg/kg every 12 weeks beginning at Week 24
up to a maximum of 3 years [see Clinical Studies (14.2)]. In this trial, 36% of patients
received YERVOY for longer than 6 months and 26% of patients received YERVOY for
longer than 1 year. YERVOY-treated patients in the trial received a median of 4 doses
(range: 1 to 16).
Trial 2 excluded patients with prior systemic therapy for melanoma, autoimmune disease,
a condition requiring systemic immunosuppression, or a positive test for hepatitis B,
hepatitis C, or HIV.
The trial population characteristics were: median age 51 years (range: 18 to 84 years),
62% male, 99% white, and baseline ECOG performance status 0 (94%).
YERVOY was discontinued for adverse reactions in 52% of patients.
Placebo
YERVOY
10 mg/kg
n=471
n=474
Any
Grade
Grade
3 to 5
Any
Grade
Grade
3 to 5
50
45
2.1
2.3
20
15
0
0
Diarrhea
Nausea
Colitisb
Vomiting
Investigations
49
25
16
13
10
0.2
8
0.4
30
18
1.5
6
2.1
0
0.4
0.2
Weight Decreased
General Disorders and
Administration-Site Conditions
Fatigue
Pyrexia
Nervous System Disorders
32
0.2
9
0.4
46
18
2.3
1.1
38
4.9
1.5
0.2
33
0.8
18
0.2
14
0.2
3.4
0.2
10
0
4.4
0
System Organ Class/
Preferred Term
Skin and Subcutaneous Tissue
Disorders
Rash
Pruritus
Gastrointestinal Disorders
Headache
Metabolism and Nutrition
Disorders
Decreased Appetite
Psychiatric Disorders
Insomnia
a Incidences
presented in this table are based on reports of adverse events regardless
of causality.
b Includes 1 death.
Table 5 presents selected laboratory abnormalities from Trial 2 which occurred in at least
10% of YERVOY-treated patients at a higher incidence compared to placebo.
Table 5:
Eosinophiliac
Selected Adverse Reactions in Trial 2
Laboratory Abnormalities Worsening from Baseline Occurring in
≥10% of YERVOY-Treated Patients (Trial 2)a
Percentage of Patients with Worsening
Laboratory Test from Baselinea
YERVOY
Test
Chemistry
Increased ALT
Increased AST
Increased lipaseb
Increased amylaseb
Increased alkaline phosphatase
Increased bilirubin
Increased creatinine
Hematology
Decreased hemoglobin
Placebo
All
Grades
Grade
3 to 4
All
Grades
Grade
3 to 4
46
38
26
17
17
11
10
10
9
9
2.0
0.6
1.5
0.2
16
14
17
7
6
9
6
0
0.2
4.5
0.6
0.2
0
0
25
0.2
14
0
a Each
test incidence is based on the number of patients who had both baseline and at
least one on-study laboratory measurement available. Excluding lipase and amylase,
YERVOY group (range: 466 to 470 patients) and placebo group (range: 472 to 474
patients).
b For lipase and amylase, YERVOY group (range: 447 to 448 patients) and placebo group
(range: 462 to 464 patients).
Table 6 presents the per-patient incidence of severe, life-threatening, or fatal immunemediated adverse reactions from Trial 2.
YERVOY® (ipilimumab)
Table 6:
YERVOY® (ipilimumab)
Severe to Fatal Immune-Mediated Adverse Reactions in Trial 2
Percentage (%) of Patients
YERVOY
10 mg/kg
n=471
ipilimumab are likely to be greater during the second and third trimesters of pregnancy.
Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore,
ipilimumab has the potential to be transmitted from the mother to the developing fetus.
There is insufficient human data for YERVOY exposure in pregnant women. Advise
pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects
and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%,
respectively.
Any Immune-Mediated Adverse Reaction
41
Enterocolitisa,b
16
Hepatitis
11
Data
Dermatitis
4.0
Animal Data
Neuropathya
1.7
Endocrinopathy
8
Hypopituitarism
7
Primary hypothyroidism
0.2
Hyperthyroidism
0.6
Other
Myocarditisa
0.2
Meningitis
0.4
Pericarditisc
0.2
Pneumonitis
0.2
Uveitis
0.2
In a combined study of embryo-fetal and peri-postnatal development, pregnant
cynomolgus monkeys received ipilimumab every 3 weeks from the onset of
organogenesis in the first trimester through parturition. No treatment-related adverse
effects on reproduction were detected during the first two trimesters of pregnancy.
Beginning in the third trimester, administration of ipilimumab at doses resulting
in exposures approximately 2.6 to 7.2 times the human exposure at a dose of
3 mg/kg resulted in dose-related increases in abortion, stillbirth, premature delivery
(with corresponding lower birth weight), and an increased incidence of infant mortality. In
addition, developmental abnormalities were identified in the urogenital system of 2 infant
monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the AUC in humans at
the 3 mg/kg dose). One female infant monkey had unilateral renal agenesis of the left
kidney and ureter, and 1 male infant monkey had an imperforate urethra with associated
urinary obstruction and subcutaneous scrotal edema.
fatal outcome.
b Including intestinal perforation.
c Underlying etiology not established.
Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/−), the target for
ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/− heterozygous
offspring. Mated CTLA-4+/− heterozygous mice also produced offspring deficient in
CTLA-4 (homozygous negative, CTLA-4−/−). The CTLA-4−/− homozygous negative
offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative
disease by 2 weeks of age, and all died by 3 to 4 weeks of age with massive
lymphoproliferation and multiorgan tissue destruction.
Other Clinical Experience
8.2
Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the
following adverse reactions were also reported (incidence less than 1% unless otherwise
noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress
syndrome, renal failure, and infusion reaction.
Risk Summary
a Including
6.2
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of YERVOY.
Because these reactions are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal relationship
to drug exposure.
Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic
symptoms (DRESS syndrome)
It is not known whether YERVOY is secreted in human milk. In monkeys, ipilimumab was
present in milk. There are no data to assess the effects of YERVOY on milk production.
Advise women to discontinue nursing during treatment with YERVOY and for 3 months
following the final dose.
Data
In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than
those in humans at a 3 mg/kg dose, ipilimumab was present in milk at concentrations
of 0.1 mcg/mL and 0.4 mcg/mL, representing a ratio of up to 0.3% of the steady-state
serum concentration of the drug.
8.3
6.3
Females and Males of Reproductive Potential
Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity.
Eleven (1.1%) of 1024 evaluable patients with unresectable or metastatic melanoma
tested positive for treatment-emergent binding antibodies against ipilimumab (TE-ADAs)
in an electrochemiluminescent (ECL) based assay. This assay had substantial limitations
in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Seven (4.9%) of
144 patients receiving ipilimumab and 7 (4.5%) of 156 patients receiving placebo for
the adjuvant treatment of melanoma tested positive for TE-ADAs using an ECL assay
with improved drug tolerance. No patients tested positive for neutralizing antibodies.
No infusion-related reactions occurred in patients who tested positive for TE-ADAs.
Immunogenicity assay results are highly dependent on several factors including assay
sensitivity and specificity, assay methodology, sample handling, timing of sample
collection, concomitant medications, and underlying disease. For these reasons,
comparison of incidence of antibodies to ipilimumab with the incidences of antibodies to
other products may be misleading.
7
Lactation
Contraception
Based on its mechanism of action, YERVOY can cause fetal harm when administered to a
pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive
potential to use effective contraception during treatment with YERVOY and for 3 months
following the last dose of YERVOY.
8.4
Pediatric Use
Safety and effectiveness of YERVOY have not been established in pediatric patients.
8.5
Geriatric Use
Of the 511 patients treated with YERVOY in Trial 1, 28% were 65 years and over.
No overall differences in safety or efficacy were reported between the elderly patients
(65 years and over) and younger patients (less than 65 years).
Trial 2 did not include sufficient numbers of patients aged 65 years and older to
determine whether they respond differently from younger patients.
DRUG INTERACTIONS
No formal pharmacokinetic drug interaction studies have been conducted with YERVOY.
8.6
Renal Impairment
8
USE IN SPECIFIC POPULATIONS
No dose adjustment is needed for patients with renal impairment [see Clinical
Pharmacology (12.3)].
8.1
Pregnancy
8.7
Risk Summary
Based on data from animal studies and its mechanism of action, YERVOY can cause
fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].
In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys
from the onset of organogenesis through delivery resulted in higher incidences of
abortion, stillbirth, premature delivery (with corresponding lower birth weight), and
higher incidences of infant mortality in a dose-related manner [see Data]. The effects of
Hepatic Impairment
No dose adjustment is needed for patients with mild hepatic impairment (total bilirubin
[TB] >1.0 to 1.5 times the upper limit of normal [ULN] or AST >ULN). YERVOY has not
been studied in patients with moderate (TB >1.5 to 3.0 times ULN and any AST) or severe
(TB >3 times ULN and any AST) hepatic impairment [see Clinical Pharmacology (12.3)].
10
OVERDOSAGE
There is no information on overdosage with YERVOY.
YERVOY® (ipilimumab)
11
DESCRIPTION
YERVOY (ipilimumab) is a recombinant, human monoclonal antibody that binds to the
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa
immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is
produced in mammalian (Chinese hamster ovary) cell culture.
YERVOY is a sterile, preservative-free, clear to slightly opalescent, colorless to paleyellow solution for intravenous infusion, which may contain a small amount of visible
translucent-to-white, amorphous ipilimumab particulates. It is supplied in single-use
vials of 50 mg/10 mL and 200 mg/40 mL. Each milliliter contains 5 mg of ipilimumab and
the following inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg),
mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg),
tris hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a monoclonal antibody
that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86.
Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation,
including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition
of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to
a general increase in T cell responsiveness, including the anti-tumor immune response.
12.3
Pharmacokinetics
The pharmacokinetics (PK) of ipilimumab was studied in 785 patients with unresectable
or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every 3 weeks
for 4 doses. The PK of ipilimumab is linear in the dose range of 0.3 to 10 mg/kg. Following
administration of YERVOY every 3 weeks, the systemic accumulation was 1.5-fold or
less. Steady-state concentrations of ipilimumab were reached by the third dose; the
mean Cmin at steady state was 19.4 mcg/mL at 3 mg/kg and 58.1 mcg/mL at 10 mg/kg
every 3 weeks. The mean value (percent coefficient of variation) based on population PK
analysis for the terminal half-life (t1/2) was 15.4 days (34%) and for clearance (CL) was
16.8 mL/h (38%).
YERVOY® (ipilimumab)
peptide by deep subcutaneous injection every 3 weeks for 4 doses. Assessment of
tumor response was conducted at weeks 12 and 24, and every 3 months thereafter.
Patients with evidence of objective tumor response at 12 or 24 weeks had assessment
for confirmation of durability of response at 16 or 28 weeks, respectively.
The major efficacy outcome measure was overall survival (OS) in the YERVOY plus gp100
arm compared to that in the single-agent gp100 arm. Secondary efficacy outcome
measures were OS in the YERVOY plus gp100 arm compared to the YERVOY arm, OS in
the YERVOY arm compared to the gp100 arm, best overall response rate (BORR) at week
24 between each of the trial arms, and duration of response.
Of the randomized patients, 61%, 59%, and 54% in the YERVOY plus gp100, YERVOY, and
gp100 arms, respectively, were men. Twenty-nine percent were ≥65 years of age, the
median age was 57 years, 71% had M1c stage, 12% had a history of previously treated
brain metastasis, 98% had ECOG performance status of 0 and 1, 23% had received
aldesleukin, and 38% had elevated LDH level. Sixty-one percent of patients randomized
to either YERVOY-containing arm received all 4 planned doses. The median duration of
follow-up was 8.9 months.
The OS results are shown in Table 7 and Figure 1.
Table 7:
Overall Survival Results
Hazard Ratio (vs. gp100)
(95% CI)
p-value
Hazard Ratio (vs. YERVOY)
YERVOY
n=137
YERVOY+gp100
n=403
0.66
(0.51, 0.87)
p=0.0026a
0.68
(0.55, 0.85)
p=0.0004
1.04
(95% CI)
Median (months)
(95% CI)
a Not
gp100
n=136
(0.83, 1.30)
10
(8.5, 11.5)
10
(8.0, 13.8)
6
(5.5, 8.7)
adjusted for multiple comparisons.
Specific Populations
Renal Impairment: The effect of renal impairment on the CL of ipilimumab was evaluated
in patients with mild (GFR <90 and ≥60 mL/min/1.73 m2; n=349), moderate (GFR <60 and
≥30 mL/min/1.73 m2; n=82), or severe (GFR <30 and ≥15 mL/min/1.73 m2; n=4) renal
impairment compared to patients with normal renal function (GFR ≥90 mL/min/1.73 m2;
n=350) in population PK analyses. No clinically important differences in the CL of
ipilimumab were found between patients with renal impairment and patients with normal
renal function [see Use in Specific Populations (8.6)].
Hepatic Impairment: The effect of hepatic impairment on the CL of ipilimumab was
evaluated in patients with mild hepatic impairment (n=76) compared to patients
with normal hepatic function (n=708) in the population PK analyses, and no clinically
important differences in the CL of ipilimumab were found. YERVOY has not been studied
in patients with moderate or severe hepatic impairment [see Use in Specific Populations
(8.7)].
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of ipilimumab has not been evaluated in long-term animal
studies, and the genotoxic potential of ipilimumab has not been evaluated.
Fertility studies have not been performed with ipilimumab.
14
CLINICAL STUDIES
14.1
Unresectable or Metastatic Melanoma
The safety and efficacy of YERVOY were investigated in a randomized (3:1:1), double-blind,
double-dummy trial (Trial 1) that included 676 randomized patients with unresectable or
metastatic melanoma previously treated with one or more of the following: aldesleukin,
dacarbazine, temozolomide, fotemustine, or carboplatin. Of these 676 patients, 403 were
randomized to receive YERVOY at 3 mg/kg in combination with an investigational peptide
vaccine with incomplete Freund’s adjuvant (gp100), 137 were randomized to receive
YERVOY at 3 mg/kg, and 136 were randomized to receive gp100 as a single agent. The
trial enrolled only patients with HLA-A2*0201 genotype; this HLA genotype facilitates the
immune presentation of the investigational peptide vaccine. The trial excluded patients
with active autoimmune disease or those receiving systemic immunosuppression for
organ transplantation. YERVOY/placebo was administered at 3 mg/kg as an intravenous
infusion every 3 weeks for 4 doses. Gp100/placebo was administered at a dose of 2 mg
Figure 1:
PROPORTION ALIVE
The effects of various covariates on the PK of ipilimumab were assessed in population
PK analyses. The CL of ipilimumab increased with increasing body weight supporting the
recommended body weight (mg/kg) based dosing. The following factors had no clinically
important effect on the CL of ipilimumab: age (range: 23 to 88 years), sex, performance
status, renal impairment, mild hepatic impairment, previous cancer therapy, and baseline
lactate dehydrogenase (LDH) levels. The effect of race was not examined due to limited
data available in non-Caucasian ethnic groups.
Overall Survival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
4
20
24
28
32
36
40
44
SUBJECTS AT RISK
Ipi+
gp100 403 297 223 163 115 81
Ipi
137 106 79 56 38 30
gp100 136 93 58 32 23 17
54
24
16
42
18
7
33
13
5
24
13
5
17
8
3
7
5
1
Ipi+gp100
CENSORED
8
12
16
Ipi
CENSORED
48 52 56
MONTHS
6
2
0
4
1
0
0
0
0
gp100
CENSORED
The best overall response rate (BORR) as assessed by the investigator was 5.7% (95%
CI: 3.7%, 8.4%) in the YERVOY plus gp100 arm, 10.9% (95% CI: 6.3%, 17.4%) in the
YERVOY arm, and 1.5% (95% CI: 0.2%, 5.2%) in the gp100 arm. The median duration of
response was 11.5 months in the YERVOY plus gp100 arm and has not been reached in
the YERVOY or gp100 arm.
14.2
Adjuvant Treatment of Melanoma
The safety and efficacy of YERVOY for the adjuvant treatment of melanoma were
investigated in Trial 2, a randomized (1:1), double-blind, placebo-controlled trial in patients
with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit
metastases) histologically confirmed cutaneous melanoma. Patients were randomized
to receive YERVOY 10 mg/kg or placebo as an intravenous infusion every 3 weeks for
4 doses, followed by YERVOY 10 mg/kg or placebo every 12 weeks from Week 24 to
Week 156 (3 years) or until documented disease recurrence or unacceptable toxicity.
Enrollment required complete resection of melanoma with full lymphadenectomy within
12 weeks prior to randomization. Patients with prior therapy for melanoma, autoimmune
disease, and prior or concomitant use of immunosuppressive agents were ineligible.
Randomization was stratified by stage according to American Joint Committee on
Cancer (AJCC) 2002 classification (Stage IIIA >1 mm nodal involvement, Stage IIIB,
Stage IIIC with 1 to 3 involved lymph nodes, and Stage IIIC with ≥4 involved lymph
YERVOY® (ipilimumab)
YERVOY® (ipilimumab)
nodes) and by region (North America, Europe, and Australia). The major efficacy outcome
measures were recurrence-free survival (RFS) defined as the time between the date of
randomization and the date of first recurrence (local, regional, or distant metastasis) or
death, whichever occurs first and assessed by an independent review committee and
overall survival. Tumor assessment was conducted every 12 weeks for the first 3 years
then every 24 weeks until distant recurrence.
Among 951 patients enrolled, 475 were randomized to receive YERVOY and 476 to
placebo. Median age was 51 years old (range: 18 to 84), 62% were male, 99% were
white, 94% had ECOG performance status of 0. With regard to disease stage, 20% had
Stage IIIA with lymph nodes >1 mm, 44% had Stage IIIB, and 36% had Stage IIIC (with
no in-transit metastases). Other disease characteristics of the trial population were:
clinically palpable lymph nodes (58%), 2 or more positive lymph nodes (54%), and
ulcerated primary lesions (42%).
The RFS results are in Table 8 and Figure 2. Based on the observation of 282 deaths
at the time of the RFS analysis, the final analysis of overall survival has not occurred
(planned at the time of 491 deaths).
Table 8:
Number of Events, n (%)
Recurrence
Death
Median (months)
(95% CI)
Hazard Ratio
(95% CI)
p-value (stratified log-ranka)
a Stratified
Figure 2:
HOW SUPPLIED/STORAGE AND HANDLING
YERVOY is available as follows:
Carton Contents
YERVOY
N=475
Placebo
N=476
NDC 0003-2327-11
One 200 mg vial (5 mg/mL), single-use vial
NDC 0003-2328-22
Store YERVOY under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect
vials from light.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Immune-Mediated Adverse Reactions
234 (49%)
220
14
26
(19, 39)
294 (62%)
289
5
17
(13, 22)
Embryo-fetal Toxicity
Advise female patients that YERVOY can cause fetal harm. Advise females of reproductive
potential to use effective contraception during treatment with YERVOY and for 3 months
after the last dose. Advise female patients to contact their healthcare provider with a
known or suspected pregnancy. Advise females who may have been exposed to YERVOY
during pregnancy to contact Bristol-Myers Squibb at 1-800-721-5072 [see Warnings
and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)].
Lactation
0.75
(0.64, 0.90)
p<0.002
Advise women not to breastfeed during treatment with YERVOY and for 3 months after
the last dose [see Use in Specific Populations (8.2)].
by disease stage.
Manufactured by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
Recurrence-Free Survival
1.0
U.S. License No. 1713
0.9
PROPORTION RECURRENCE-FREE
0.8
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0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
Number of Subjects at Risk
Ipilimumab
475 338 276 233
Placebo
476 319 260 224
205
131
193
119
10 mg/kg Ipilimumab
NDC
One 50 mg vial (5 mg/mL), single-use vial
Inform patients of the potential risk of immune-mediated adverse reactions [see
Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6)].
Efficacy Results in Trial 2
Recurrence-Free Survival
16
30
36
MONTHS
42
48
54
60
67
23
5
3
0
62
19
4
2
0
Placebo
YERVOY® (ipilimumab)
MEDICATION GUIDE
YERVOY® (yur-voi)
(ipilimumab)
Read this Medication Guide before you start receiving YERVOY and before each infusion. There may be new information.
This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your
treatment.
What is the most important information I should know about YERVOY?
YERVOY can cause serious side effects in many parts of your body which can lead to death. These problems may happen
anytime during treatment with YERVOY or after you have completed treatment.
Call your healthcare provider right away if you develop any of these signs or symptoms or they get worse. Do not
try to treat symptoms yourself.
Intestinal problems (colitis) that can cause tears or holes (perforation) in the intestines. Signs and symptoms of
colitis may include:
Ɣ diarrhea (loose stools) or more bowel movements than usual
Ɣ
blood in your stools or dark, tarry, sticky stools
Ɣ
stomach pain (abdominal pain) or tenderness
Liver problems (hepatitis) that can lead to liver failure. Signs and symptoms of hepatitis may include:
Ɣ yellowing of your skin or the whites of your eyes
Ɣ
dark urine (tea colored)
Ɣ
nausea or vomiting
Ɣ
pain on the right side of your stomach
Ɣ
bleeding or bruise more easily than normal
Skin problems that can lead to severe skin reaction. Signs and symptoms of severe skin reactions may include:
Ɣ skin rash with or without itching
Ɣ
sores in your mouth
Ɣ
your skin blisters or peels
Nerve problems that can lead to paralysis. Symptoms of nerve problems may include:
Ɣ unusual weakness of legs, arms, or face
Ɣ
numbness or tingling in hands or feet
Hormone gland problems (especially the pituitary, adrenal, and thyroid glands). Signs and symptoms that your
glands are not working properly may include:
Ɣ persistent or unusual headaches
Ɣ
unusual sluggishness
Ɣ
feeling cold all the time
Ɣ
weight gain
Ɣ
changes in mood or behavior such as decreased sex drive, irritability, or forgetfulness
Ɣ
dizziness or fainting
Eye problems. Symptoms may include:
Ɣ blurry vision, double vision, or other vision problems
Ɣ
eye pain or redness
Getting medical treatment right away may keep the problem from becoming more serious.
Your healthcare provider will check you for these problems during treatment with YERVOY. Your healthcare provider may
treat you with corticosteroid medicines. Your healthcare provider may need to delay or completely stop treatment with
YERVOY if you have severe side effects.
YERVOY® (ipilimumab)
What is YERVOY?
YERVOY is a prescription medicine used to treat a kind of skin cancer called melanoma. YERVOY may be used:
Ɣ
when your melanoma has spread or cannot be removed by surgery.
Ɣ
to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by
surgery.
It is not known if YERVOY is safe and effective in children less than 18 years of age.
What should I tell my healthcare provider before receiving YERVOY?
Before you receive YERVOY, tell your healthcare provider about all your medical conditions, including if you:
Ɣ
have immune system problems (autoimmune disease), such as ulcerative colitis, Crohn’s disease, lupus, or sarcoidosis
Ɣ
have had an organ transplant
Ɣ
have liver problems
Ɣ
are pregnant or plan to become pregnant. YERVOY can harm your unborn baby.
ż
Ɣ
Females who are able to become pregnant should use effective birth control during treatment with YERVOY and
for 3 months after the last dose of YERVOY.
are breastfeeding or plan to breastfeed.
ż
ż
It is not known if YERVOY passes into your breast milk.
Do not breastfeed during treatment with YERVOY and for 3 months after the last dose of YERVOY.
Tell your healthcare provider about all the medicines you take, including all prescription and over-the-counter medicines,
vitamins, and herbal supplements.
Know the medicines you take. Keep a list to show your healthcare providers and pharmacists each time you get a
new medicine.
You should not start a new medicine before you talk with the healthcare provider who prescribes you YERVOY.
How will I receive YERVOY?
Ɣ
YERVOY is given to you into your vein through an intravenous (IV) line over 90 minutes.
Ɣ
Your healthcare provider will decide how many treatments you will need.
Ɣ
Your healthcare provider will do blood tests before starting and during treatment with YERVOY.
Ɣ
It is important for you to keep all appointments with your healthcare provider. Call your healthcare provider if you miss
an appointment. There may be special instructions for you.
What are the possible side effects of YERVOY?
YERVOY can cause serious side effects. See “What is the most important information I should know about
YERVOY?”
The most common side effects of YERVOY include:
Ɣ
Ɣ
Ɣ
Ɣ
Ɣ
Ɣ
tiredness
diarrhea
itching
rash
nausea
vomiting
Ɣ
Ɣ
Ɣ
Ɣ
Ɣ
headache
weight loss
fever
decreased appetite
GLI¿FXOW\IDOOLQJRUVWD\LQJDVOHHS
Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all of the
possible side effects of YERVOY. For more information, ask your healthcare provider.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
You may also report side effects to Bristol-Myers Squibb at 1-800-721-5072.
YERVOY® (ipilimumab)
General information about the safe and effective use of YERVOY.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
This Medication Guide summarizes the most important information about YERVOY. If you would like more information, talk
with your healthcare provider. You can ask your healthcare provider or pharmacist for information about YERVOY that is
written for healthcare professionals. For more information, call 1-800-321-1335.
What are the ingredients of YERVOY?
Active ingredient: ipilimumab
Inactive ingredients: diethylene triamine pentaacetic acid (DTPA), mannitol, polysorbate 80, sodium chloride,
tris hydrochloride, and Water for Injection, USP
Manufactured by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA
U.S. License No. 1713
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 10/2015
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1321744A1
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