Download N Engl J Med

The Nurse View: Practice Pearls
in the Use of Immune Checkpoint
Inhibitors in Advanced NSCLC
Moderator
Kristen Kreamer, MSN, CRNP,
AOCNP
Nurse Practitioner
Fox Chase Cancer Center
Philadelphia, Pennsylvania
Panelist
Beth Eaby-Sandy, MSN, CRNP, OCN
Nurse Practitioner
Abramson Cancer Center
University of Pennsylvania
Philadelphia, Pennsylvania
This program will include a discussion of off-label
treatment not approved by the FDA for use in the
US, and data that were presented in abstract form.
These data should be considered preliminary until
published in a peer-reviewed journal.
Checkpoint Inhibitors Approved
in NSCLC
First-Line
• Pembrolizumab[a]
Second-Line
• Nivolumab[b]
• Pembrolizumab[a]
• Atezolizumab[c]
a. Keytruda® 2016.
b. Opdivo ® 2016.
c. Tecentriq® 2016.
Immunotherapy vs Chemotherapy
• Adverse events are different
Immunotherapy
•
•
•
•
•
•
•
Fatigue
Nausea
Decreased appetite
Asthenia
Diarrhea
Hypothyroidism
Rash
Chemotherapy
• Fatigue
• Nausea
• Bone marrow
suppression
• Nephrotoxicity
• Hearing loss
• Toxicities are managed differently
Kreamer KM. J Adv Pract Oncol. 2014;5:418-431; Brahmer J, et al. N Engl J Med.
2015;373:123-135; Borghaei H, et al. N Engl J Med. 2015;373:1627-1639; Herbst RS, et al.
Lancet. 2016;387:1540-1550.
Overview of Immune Regulation
Immune system
surveys for tumors
Downregulation of
immune system
Chen L, Flies DB. Nat Rev Immunol. 2013;13:227-242.
Kreamer KM. J Adv Pract Oncol. 2014;5:418-431.
Immunotherapy
prevents
downregulation
Basics of Immunotherapy
Tumor
PD-1
PD-L1
Activated
T cell
Resting
T cell
No Inhibition
Anti-PD-1/
of killing
PD-L1
PD-1
PD-L1
Tumor
antigen
CD28
Inhibition
of killing
Dendritic
cell
TCR
MHC
B7
Jiang T, Zhou C. Transl Lung Cancer Res. 2015;4:253-264.
Kreamer KM. J Adv Pract Oncol. 2014;5:418-431.
© Medscape, LLC
LYMPH
NODE
CheckMate Trial Design
CheckMate 026[c]
CheckMate 017/057[a,b]
• Second-line in advanced
NSCLC
• PD-L1 expression not
required for enrollment
• Nivolumab vs docetaxel
• Primary endpoint: OS
• First-line in advanced NSCLC
• PD-L1 expression of ≥5%
required for enrollment
• Nivolumab vs investigators
choice chemotherapy
• Primary endpoint: PFS
a. Brahmer J, et al. N Engl J Med. 2015;373:123-135.
b. Borghaei H, et al. N Engl J Med. 2015;373:1627-1639.
c. Socinski M, et al. ESMO 2016. Abstract LBA7.
Outcomes With Nivolumab
mOS, mo
mPFS, mo
ORR, %
AEs of Any
Grade, %
2-year
Survival,
%*[d]
CheckMate 017 (squamous, second line)[a]
Nivo (n = 131)
9.2
3.5
20
58
23
Doce (n = 129)
6.0
2.8
9
86
8
CheckMate 057 (nonsquamous, second line)[b]
Nivo (n = 287)
12.2
2.3
19
69
29
Doce (n = 268)
9.4
4.2
12
88
16
CheckMate 026 (≥5% PD-L1 expression, first line)[c]
Nivo (n = 211)
14.4
4.2
26.1
71.2
Not reported
Chemo (n = 212)
13.2
5.9
33.5
92.4
Not reported
*n = 135 for nivo and 137 for doce in CheckMate 017; 292 for nivo and 290 for doce in
CheckMate 057.
a. Brahmer J, et al. N Engl J Med. 2015;373:123-135; b. Borghaei H, et al. N Engl J Med.
2015;373:1627-1639; c. Socinski M, et al. ESMO abstract LBA7. 2016; d. Borghaei H, et al.
J Clin Oncol. 2016;34. [ASCO® 2016, abstract 9025].
KEYNOTE Trial Design
KEYNOTE-001[a]
• First and second-line in
advanced NSCLC
• PD-L1 expression of ≥1%
required for enrollment
• Pembrolizumab 2 mg/kg
or 10 mg/kg
• Primary endpoints:
safety, side-effect profile,
antitumor activity
KEYNOTE-010[b]
• Second-line in advanced
NSCLC
• PD-L1 expression of ≥1%
required for enrollment
• Pembrolizumab 2 mg/kg,
10 mg/kg, or docetaxel
• Primary endpoints: OS, PFS
a. Garon EB, et al. N Engl J Med. 2015;372:2018-2028.
b. Herbst RS, et al. Lancet. 2016;387:1540-1550.
Outcomes With Pembrolizumab
ORR, % mPFS, mo mOS, mo
AEs Any
Grade, %
2-Year
Survival, %[c]
KEYNOTE-001 (≥1% PD-L1 expression)[a]
Treatment Naive
(n = 101)
24.8
6.0
16.2
44.5
Previously
Treated (n = 394)
18
3.0
9.3
31.3*
KEYNOTE-010 (≥50% PD-L1 expression, second line)[b]
Pembro, 2 mg/kg
(n = 344)
30
5.0
14.9
63**
Doce (n = 343)
8
4.1
8.2
81
PD-L1 expression must be confirmed as ≥50%
for first-line and ≥1% for second-line before
treatment with pembrolizumab
*n = 449.
**n = 339.
a. Garon EB, et al. N Engl J Med. 2015;372:2018-2028; b. Herbst RS, et al. Lancet.
2016;387:1540-1550; c. Hui R, et al. J Clin Oncol. 2016;34(suppl). [ASCO® abstract 9026.]
KEYNOTE-024 Trial Design
• First-line for advanced NSCLC
• Pembrolizumab vs platinum-based chemotherapy
regimens
• PD-L1 expression of ≥50%
• Primary endpoint: PFS
Reck M, et al. N Engl J Med. 2016. [Epub ahead of print.]
Outcomes With First-Line
Pembrolizumab
Pembrolizumab
n = 154
Chemotherapy
n = 151
PFS, mo
10.3
6.0
6-month OS, %
80.2
72.4
mOS, mo
NR
NR
ORR, %
44.8
27.8
mDOR, mo
NR
6.3
AEs any grade, %
73.4
90.0*
Outcome
*n = 150.
Reck M, et al. N Engl J Med. 2016. [Epub ahead of print.]
OAK Trial Design
• Second-line for NSCLC
• Atezolizumab vs docetaxel
• Primary endpoint: OS
Barlesi F, et al. ESMO 2016. Abstract LBA44.
Outcomes With Atezolizumab
Atezolizumab
n = 425
Docetaxel
n = 425
mOS, mo
13.8
9.6
mPFS, mo
2.8
4.0
ORR, %
14
13
64
86
Outcome
mDOR, mo
AEs Any Grade, %
OS benefit was independent of histology, PD-L1
expression levels, presence of CNS metastases,
and smoking status
Barlesi F, et al. ESMO 2016. Abstract LBA44.
Most Common TRAEs With
Immunotherapy
Endocrine
Gastrointestinal
• Hypothyroidism
• Hyperthyroidism
• Nausea
• Diarrhea
• Decreased appetite
Muscular
Skin
• Fatigue
• Asthenia
• Rash
• Dermatitis
Brahmer J, et al. N Engl J Med. 2015;373:123-135; Borghaei H, et al. N Engl J Med. 2015;373:1627-1639; Herbst RS, et
al. Lancet. 2016;387:1540-1550; Reck M, et al. N Engl J Med. 2016. [Epub ahead of print]; Barlesi F, et al. ESMO 2016.
Abstract LBA44.
Management of AEs
• Rash or dermatitis
– Usually mild, but can be exacerbated
– Treat with topical corticosteroids
• Nausea
– Treat with 5-HTP antagonist
– Typically no vomiting or weight loss
• Fatigue
Immunotherapy is
not recommended in
patients with
autoimmune
disorders or who are
post-transplant
– Can be limiting, but is not typically
as intense as with chemotherapy
Friedman CF, et al. JAMA Oncol. 2016:e1-e8; Eigentler TK, et al. Cancer Treat Rev.
2016;45:7-18; O’Kane GM, et al. Oncologist. 2016. [Epub ahead of print]; Opdivo® 2016;
Keytruda® 2015; Tecentriq® 2016.
Grading of AEs
• There is no grading scale for immune-mediated
toxicities
• Toxicities may be included in CTCAE, but
management of immune-mediated toxicity
is different
• CTCAE
–
–
–
–
–
HHS website.
Organized by system organ class
Defines grade based on symptoms
Provides management guidance
Currently on version 4.0
Used in clinical trials more than in daily practice
Management of irAEs Based on Grade
Grade 1
• Continue therapy
• Provide supportive care
Grade 3
• Withhold therapy
• Start or increase dose of
corticosteroids
Grade 2
• Withhold therapy
• Start corticosteroids at
lower doses
Grade 4
• Discontinue therapy
• Start or increase dose of
corticosteroids
Taper steroids slowly—over at least 1 month
Friedman CF, et al. JAMA Oncol. 2016:e1-e8; Eigentler TK, et al. Cancer Treat Rev.
2016;45:7-18; O’Kane GM, et al. Oncologist. 2016. [Epub ahead of print].
Management of Diarrhea/Colitis
• Diarrhea
– Manage diarrhea with medications and
electrolyte supplements
– Have patients be alert that this could be a
precursor to colitis
• Colitis
– Hold therapy and start steroids for grade 2 colitis
that persists >5 days or recurs and for grade 3 to 4
– Progresses quickly
– Consider GI consult or lower-GI endoscopy
Friedman CF, et al. JAMA Oncol. 2016;2:1346-1353; Eigentler TK, et al. Cancer Treat Rev.
2016. [Epub ahead of print]; O’Kane GM, et al. Oncologist. 2016. [Epub ahead of print].
Management of Pneumonitis
• Presents with shortness of breath and cough
• Need to differentiate between cancer symptoms, COPD
symptoms, infection, and pneumonitis
• Consider pulmonary and infectious disease consults
• Consider bronchoscopy for severe presentation
• Hold therapy and administer steroids for grades 2 to 4
• Follow-up
– Grade 1: reassess every 1 to 3 weeks, resume treatment
when stable
– Grade 2: reassess every 1 to 3 days, taper steroids over
1 month before resuming
– Slowly taper steroids
Friedman CF, et al. JAMA Oncol. 2016;2:1346-1353; Eigentler TK, et al. Cancer Treat Rev.
2016. [Epub ahead of print]; O’Kane GM, et al. Oncologist. 2016. [Epub ahead of print].
Management of Steroid-Refractory irAEs
• Consider addition of mycophenolate mofitil
or infliximab
• Typically done in an inpatient setting
Friedman CF, et al. JAMA Oncol. 2016;2:1346-1353; Eigentler TK, et al. Cancer Treat Rev.
2016. [Epub ahead of print]; O’Kane GM, et al. Oncologist. 2016. [Epub ahead of print].
Restarting Immunotherapy
• Consider on a case-by-base basis taking maximum
grade of AE experienced into consideration
• May be able to restart immunotherapy once
patients is tapered off of steroids and AE has
resolved to grade 1 or 0
• Assess response prior to AE to aid decision
to restart
Friedman CF, et al. JAMA Oncol. 2016;2:1346-1353; Eigentler TK, et al. Cancer Treat Rev.
2016. [Epub ahead of print]; O’Kane GM, et al. Oncologist. 2016. [Epub ahead of print].
Management of Hypothyroidism
• Monitor with TSH
• Manage with hormone replacement
• Consider endocrinology consult
• Continue immunotherapy
• Inform patients that hormone replacement
will be lifelong
Friedman CF, et al. JAMA Oncol. 2016;2:1346-1353; Eigentler TK, et al. Cancer Treat Rev.
2016. [Epub ahead of print]; O’Kane GM, et al. Oncologist. 2016. [Epub ahead of print].
Importance of Patient Education
• Patients should be aware of differences between checkpoint
inhibitors and chemotherapy
• Patients should also be aware of timing of symptoms
– Typically peak between 6 to 12 weeks
– Still a concern even late in course in therapy
• Patients should know who to call to report an AE
– Stress the need to call immediately as AEs can be life-threatening and to
not be afraid of calling due to change of holding anti-cancer therapy
• Educational materials such as wallet cards are available for
both approved checkpoint inhibitors
– Use patient consent forms as alternative
Fecher LA, et al. Oncologist. 2013;18:733-743; Friedman CF, et al. JAMA Oncol. 2016;2:13461353; Eigentler TK, et al. Cancer Treat Rev. 2016. [Epub ahead of print]; O’Kane GM, et al.
Oncologist. 2016. [Epub ahead of print].
The Future of Immunotherapy
• There is ongoing research examining antibodies
targeting other checkpoint molecules both in
the first and second line setting as well as
combination therapies
• Continue to monitor AEs closely with new approvals
• New interventions may be developed for
managing AEs
Key Takeaways
• Checkpoint inhibitors are a new option for
lung cancer treatment
• While superior to chemotherapy in some
situations, checkpoint inhibitors are not a
replacement for chemotherapy
• AEs are different with checkpoint inhibitors—be
on the watch for them, involve patients, and
treat appropriately
Abbreviations
5-HTP = 5-hydroxytryptophan
AE = adverse event
CD38 = cluster of differentiation 38
CNS = central nervous system
COPD = chronic obstructive pulmonary disease
CTCAE = Common Terminology Criteria for Adverse Events
doce = docetaxel
GI = gastrointestinal
irAE = immune-related adverse event
mDOR = median duration of response
mOS = median overall survival
mPFS = median progression-free survival
nivo = nivolumab
NSCLC = non-small cell lung cancer
ORR = overall response rate
OS = overall survival
PD-1 = programmed death-1
Abbreviations (cont)
PD-L1 = programmed death-ligand 1
pembro = pembrolizumab
PFS = progression-free survival
SCLC = small cell lung cancer
TCR= antigen (t cell) receptor
TRAE= treatment-related adverse event
TSH = thyroid-stimulating hormone