Download Nivolumab (BMS-936558) in Patients With Advanced Solid Tumors

Nivolumab (BMS-936558) in Patients With
Advanced Solid Tumors:
Clinical Activity, Safety, and Molecular Markers
David M Feltquate, MD PhD
Executive Director,
Global Clinical Research – Oncology
Bristol-Myers Squibb
Princeton NJ
Principal Investigators Participating on the Study
Dr. S.J. Antonia, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
Dr. J.R. Brahmer, Sidney Kimmel Comprehensive Cancer Center at
John Hopkins, Baltimore, MD
Dr. R.D. Carvajal, Memorial Sloan-Kettering Cancer Center, New York, NY
Dr. F.S. Hodi, Dana-Farber Cancer Institute, Boston, MA
Dr. D.P. Lawrence, Massachusetts General Hospital Cancer Center, Boston, MA
Dr. P. Leming, The Christ Hospital, Cincinnati, OH
Dr. D. McDermott, Beth Israel Deaconess Medical Center, Boston, MA
Dr. D. Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ
Dr. J.D. Powderly, Carolina BioOncology Institute, Huntersville, NC
Dr. D.C. Smith, University of Michigan, Ann Arbor, MI
Dr. J. Sosman, Vanderbilt University Medical Center, Nashville, TN
Dr. D.R. Spigel, Sarah Cannon Research Institute/Tennessee Oncology, PLC, Nashville, TN
Dr. M. Sznol, Yale Cancer Center, New Haven, CT
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Conflicts of Interest
• Employee of Bristol-Myers Squibb
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Role of PD-1 in suppressing anti-tumor immunity2,3
MHC +
tumor
antigen
Tumor cell
Death
PD-L1
Activated
T cell
anti-PD-1
PD-L2
anti-PD-1
Cytokines,
cytolytic molecules
MHC = major histocompatibility complex; PD = programmed death;
PD-L1 = PD ligand 1; TCR = T cell receptor
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Nivolumab
Nivolumab: Anti-programmed death-1 (PD-1) antibody
• Nivolumab (BMS-936558/MDX-1106) is a fully human IgG4 antihuman PD-1 blocking antibody
– Exhibits high affinity for PD-1 and blocks binding to both known ligands:
PD ligand 1 (PD-L1) (B7-H1, broadly expressed) and PD-L2 (B7-DC, selective
for antigen-presenting cells)
• Favorable safety profile and evidence of clinical activity in
patients with treatment-refractory solid tumors evaluated in
CA209-001, a Phase 1 single ascending dose study (Brahmer, JCO
2010)
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CA209-003: Phase 1 multi-dose escalation study
Primary objective
• Assess safety and tolerability of Nivolumab
Secondary/exploratory objective
• Assess anti-tumor activity, pharmacodynamics, and molecular
markers
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CA209-003 Phase 1 study design
8-week treatment cycle
Day
1
15
29
43
a
a
a
a
57
Rapid PD or
clinical deterioration
Off study
Unacceptable
toxicity
Follow-up
Every 8 weeks
× 6 (48 weeks)
CR/PR/SD or PD
but clinically stable
Treat to confirmed CR,
worsening PD,
Unacceptable toxicity,
or 12 cycles (96 weeks)
Scans
Eligibility: advanced MEL, RCC, NSCLC, CRC, or CRPC with PD after 1 to 5 systemic therapies
aDose
administered IV every 2 weeks
CR = complete response; CRC = colorectal cancer; CRPC = castration-resistant prostate cancer;
IV = intravenous; MEL = melanoma; NSCLC = non-small cell lung cancer; PD = progressive disease;
PR = partial response; RCC = renal cell cancer; SD = stable disease
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CA209-003: Cohort Schematic
Original Design
Dose Expansion (1, 3, and 10 mg/kg)
Melanoma (N=16/dose)
Dose Escalation (1, 3, and 10 mg/kg)
Melanoma, NSCLC, RCC, CRC, CRPC
Dose Expansion (10 mg/kg)
NSCLC, RCC, CRC, CRPC (N=16/dose)
Additional Cohorts
Dose Expansion (0.1, 0.3, and 1) mg/kg)
Melanoma (N=16/dose)
~48 patients
Dose Expansion (1, 3, and 10 mg/kg)
Non-Squamous NSCLC (N=16/dose)
~48 patients
Dose Expansion (1, 3, and 10 mg/kg)
Squamous NSCLC (N=16/dose)
~48 patients
Dose Expansion (1 mg/kg)
RCC (N=16/dose)
~16 patients
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Results
• Analysis as of July 2012 (N=304)
– NSCLC (127), MEL (107), RCC (34), CRC (19), and CRPC (17)
– Median age = 63 years
– ECOG performance status = 0 (43%) or 1 (53%)
• Dose cohorts
– Maximum tolerated dose not reached (1, 3, 10 mg/kg)
– Expansion cohorts enrolled at 10 mg/kg in all histologies
– Cohorts added for MEL (0.1, 0.3, 1, 3 mg/kg), SQ-NSCLC (1, 3, 10
mg/kg), NSQ-NSCLC (1, 3, 10 mg/kg), and RCC (1 mg/kg)
• Majority of patients were heavily pretreated
– 47% received at least 3 prior regimens
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Drug-related AEs occurring in ≥5%
AE
All Grades, n (%)
Grade 3–4, n (%)
Any event
220 (72)
45 (15)
Fatigue
78 (26)
5 (2)
Rash
41 (14)
0
Diarrhea
36 (12)
3 (1)
Pruritus
31 (10)
1 (0.3)
Nausea
24 (8)
1 (0.3)
Appetite 
24 (8)
0
Hemoglobin 
18 (6)
1 (0.3)
Pyrexia
16 (5)
0
AE = adverse event
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Select Treatment-Related AEs in >1%
N = 304
Any Select AE
All Grades (%)
Grade 3/4 (%)
122 (41%)
18 (6%)
36 (12%)
28 (9%)
8 (3%)
6 (2%)
5 (2%)
4 (1%)
1(< 1%)
-
33 (11%)
3 (1%)
9 (3%)
4 (1%)
3 (1%)
-
11 (4%)
8 (3%)
2 (1%)
2 (1%)
1 (< 1%)
1 (< 1%)
9 (3%)
7 (2%)
3 (1%)
1 (< 1%)
1 (< 1%)
1 (< 1%)
Skin
Rash
Pruritis
Vitiligo
Rash Pruritic
Urticaria
Macular rash
GI
Diarrhea
Pulmonary
Pneumonitis
Allergic Rhinitis
Liver
ALT Increased
AST Increased
Hepatitis
Endocrine
TSH increased
Hypothyroidism
Hyperthyroidism
There were 3 (1%) deaths in patients with pneumonitis (2 NSCLC, 1 CRC);
Select AEs in ≤1% of patients included colitis, hepatitis, hypophysitis, and thyroiditis
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Clinical Activity of Nivolumab
% (CI90)
Dose Level (mg/kg Q2W)
0.1
0.3
1
3
10
Objective Response Rate (# responses)
Melanoma
N = 106
35 (n = 6)
N = 17
28 (n = 5)
N = 18
32 (n = 11)
N = 34
41 (n = 7)
N = 17
20 (n = 4)
N = 20
NSCLC* - SQ
N=48
--
--
0
N = 13
27 (n = 4)
N = 15
25 (n = 5)
N = 20
NSCLC* NSQ
N=73
--
--
5 (n = 1)
N = 18
28 (n = 5)
N = 18
14 (n = 5)
N = 37
RCC
N=34
--
--
28 (n = 5)
N = 18
--
31 (n = 5)
N = 16
Response evaluation by standard RECIST
8 patients had a persistent reduction in baseline target lesions in the presence of new
lesions but were not classified as responders for the ORR calculation.
*1 mg/kg - 1 pt with PR and unknown histology
Efficacy population; cutoff July 1, 2011
BMS Highly Confidential
- Forand
Internal
Planning Only
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Response kinetics in MEL
96 weeksa
Change in Target Lesions from Baseline (%)
100
Melanoma 1 mg/kg
90
80
70
60
50
40
30
20
10
First occurrence
of new lesion
On study
Off study
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
Weeks Since Treatment Initiation
a96
weeks represents the protocol-specified maximum duration of active therapy
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Partial regression of metastatic RCC
Case studies
• 57-year-old male patient
• Developed progressive disease following radical surgery and treatment with sunitinib,
temsirolimus, sorafenib, and pazopanib
Pretreatment
6 Months
RCC = renal cell cancer
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Non-classic response patterns can be observed
Subject with previously treated NSCLC
Topalian SL et al. N Engl J Med. 2012. 366:2443-2454
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Correlation of PD-L1 expression in pretreatment
tumor biopsies with clinical outcomes
17/17
Proportion of Patients
1
CR/PR
0.8
NR
16a/25
0.6
0.4
P=0.006b
9/25
0.2
0/17
0
PD-L1 (+)
PD-L1 (–)
*Normal structure for
comparison
42 patients include 18 MEL, 10 NSCLC, 7 CRC, 5 RCC, and 2 CRPC
a2 patients still under evaluation; bAnalysis not pre-planned and based on subset of patients
CR = complete response; CRC = colorectal cancer; CRPC = castration-resistant prostate cancer;
MEL = melanoma; NR = nonresponder; NSCLC = non-small cell lung cancer; PR = partial response;
RCC = renal cell cancer
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Conclusions
• Nivolumab can be administered safely in an outpatient setting to
heavily pretreated patients with durable clinical benefit in NSCLC, MEL,
and RCC
• These findings support the importance of the PD-1 pathway in cancer
therapy across multiple histologies
• Preliminary data correlating PD-L1 expression in pretreatment tumor
biopsies with clinical outcomes will be further explored
• Phase 3 trials (5) of Nivolumab in patients with NSCLC, MEL, and RCC
have begun
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Phase 3 Study (CA209-057/NCT01673867)
Phase 3 Trial
Stage IIIB/IV non-squamous NSCLC
N=574
Primary Endpoints
• OS
Secondary Endpoints
• PFS
• ORR
Docetaxel
75 mg/m2 IV
Q3W
Nivolumab
3 mg/kg IV
Q2W
• QoL
Key Eligibility Criteria
• ≥ 18 years of age
• Stage IIIB/IV non-squamous NSCLC
Treat until progression or
unacceptable toxicity or
withdrawal of consent
• Prior Pt-containing chemotherapy (2nd-line) required:
additional TKI therapy allowed (3rd-line)
• Patient may have received continuous or switch maintenance
with pemetrexed, erlotinib or bevacizumab post Pt-containing
chemotherapy
• ECOG PS ≤ 1
Overall Survival (OS)
Start Date: November 2012
Estimated Study Completion Date: November 2014
Estimated Primary Completion Date: November 2014
Status: Recruiting
Study Director: BMS
• Formalin fixed, paraffin-embedded (FFPE) tumor tissue block or
unstained slides of tumor sample (archival or recent) must be
available for biomarker evaluation
• No prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, antiCD137 or anti-CTLA-4 or other antibody targeting
T-cell co-stimulation or checkpoint pathways
ECOG PS, Eastern Cooperative Oncology Group Performance Status; ORR, Objective response rate;
OS, Overall survival; PFS, Progression-free survival; Pt, Platinum;
QoL, Quality
of life; TKI, Tyrosine kinase inhibitor
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Acknowledgments
• The patients and their families
• The study sites enrolling patients to the trial
• Funding for the study from Bristol-Myers Squibb and ONO
Pharmaceuticals Company Limited
• Research grants from the National Institutes of Health and the
Melanoma Research Alliance
• Writing and editing assistance by StemScientific; funded by BristolMyers Squibb
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