CANCER RENAL

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▪ 26 Sept 2015
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2. CheckMate 025:
A randomized, open-
label, phase III study of
nivolumab versus
everolimus in advanced
renal cell carcinoma
Padmanee Sharma, Bernard Escudier, David F. McDermott, Saby George,
Hans J. Hammers, Sandhya Srinivas, Scott S. Tykodi, Jeffrey A. Sosman,
Giuseppe Procopio, Elizabeth R. Plimack, Daniel Castellano, Howard Gurney,
Frede Donskov, Petri Bono, John Wagstaff, Thomas C. Gauler, Takeshi Ueda,
Li-An Xu, Ian M. Waxman, Robert J. Motzer,
on behalf of the CheckMate 025 investigators

3. ▪ Consultant
▪ Amgen
▪ AstraZeneca/MedImmune
▪ Bristol-Myers Squibb
▪ GlaxoSmithKline
▪ Consultant and founder with stock
▪ Jounce Therapeutics
3
Disclosures

4. ▪ No phase III clinical trial has demonstrated an OS benefit
versus standard therapy in previously treated patients with
mRCC to date; this highlights a significant unmet need
▪ Nivolumab, a PD-1 immune checkpoint inhibitor,
demonstrated encouraging OS and acceptable safety in a
phase II study in previously treated patients with mRCC1
▪ This phase III study compared nivolumab versus
everolimus in patients with mRCC after prior anti-
angiogenic treatment (NCT01668784)
4
Introduction
1. Motzer RJ. J Clin Oncol 2015.

5. 5
Study design
Previously treated
mRCC
Stratification factors
Region
MSKCC risk group
Number of prior anti-
angiogenic therapies
Nivolumab
3 mg/kg intravenously
every two weeks
Everolimus
10 mg orally
once daily
Randomize1:1
• Patients were treated until progression or intolerable toxicity occurred
• Treatment beyond progression was permitted if drug was tolerated and
clinical benefit was noted
MSKCC, Memorial Sloan-Kettering Cancer Center.

6. ▪ Advanced or metastatic clear-cell RCC
▪ One or two prior anti-angiogenic therapies
▪ Measurable disease (RECIST v1.1)
▪ Karnofsky performance status (KPS) ≥70%
▪ Progression on or after most recent therapy and
within 6 months of enrollment
Key eligibility criteria
6

7. ▪ Primary endpoint
▪ Overall survival (OS)
▪ Secondary endpoints included
▪ Objective response rate (ORR)
▪ Progression-free survival (PFS)
▪ Adverse events
▪ Quality of life (QoL)
▪ OS by PD-L1 expression
Study endpoints
7

8. ▪ Safety
▪ Assessed at each clinic visit
▪ Tumor measurements
▪ CT or MRI: every 8 weeks through 12 months, then every 12 weeks
until progression or treatment discontinuation
▪ Quality of life
▪ Assessed using the FKSI-DRS questionnaire
▪ Tumor PD-L1 expression
▪ Assessed in sections with ≥100 evaluable tumor cells
Study assessments
FKSI-DRS, functional assessment of cancer therapy - kidney symptom index - disease-related symptoms. 8

9. ▪ Planned interim analysis occurred after 398 of the 569
deaths (70%) required for the final analysis
▪ O’Brien–Fleming alpha spending function applied a nominal
significance level of 0.0148 for the interim analysis
▪ Stratified log-rank test used as primary analysis; survival
curves estimated by Kaplan–Meier methods
▪ Data Monitoring Committee (DMC) assessment of
interim study results occurred on July 17, 2015
▪ Statistical boundary for declaring OS superiority of
nivolumab was crossed; DMC concluded that the study met
its primary endpoint
▪ Study was stopped early based on DMC assessment
Statistical analysis for primary endpoint
9

10. Characteristic
Nivolumab
N = 410
Everolimus
N = 411
Median age (range), years 62 (23–88) 62 (18–86)
Sex, %
Female
Male
23
77
26
74
MSKCC risk group, %
Favorable
Intermediate
Poor
35
49
16
36
49
15
Number of prior anti-angiogenic
regimens in advanced setting, %
1
2
72
28
72
28
Region, %
US/Canada
Western Europe
Rest of the world
42
34
23
42
34
24
10
Demographics and baseline characteristics

11. 11
Overall survival
Median OS, months (95% CI)
Nivolumab 25.0 (21.8–NE)
Everolimus 19.6 (17.6–23.1)
HR (98.5% CI): 0.73 (0.57–0.93)
P = 0.0018
0 3 6 129 15
Months
18 21 24 27 30 33
No. of patients at risk
Nivolumab 410 389 359 337 305 275 213 139 73 29 3 0
411 366 324 287 265 241 187 115 61 20 2 0Everolimus
0.0
0.3
0.1
0.2
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OverallSurvival(Probability)
Nivolumab
Everolimus
Minimum follow-up was 14 months.
NE, not estimable.

12. Overall survival by subgroup analyses
Subgroup
Nivolumab
n/N
Everolimus
n/N
MSKCC risk group
Favorable 45/145 52/148
Intermediate 101/201 116/203
Poor 37/64 47/60
Prior anti-angiogenic regimens
1 128/294 158/297
2 55/116 57/114
Region
US/Canada 66/174 87/172
Western Europe 78/140 84/141
Rest of the world 39/96 44/98
Age, years
<65 111/257 118/240
≥65 to <75 53/119 77/131
≥75 19/34 20/40
Sex
Female 48/95 56/107
Male 135/315 159/304
12Nivolumab
0.25 0.5 0.75 1.5 2.251
Everolimus
Favors
Analyses based on interactive voice response system data.

13. Overall survival by PD-L1 expression
PD-L1 <1% (n = 76%)
Median OS, months (95% CI)
Nivolumab 21.8 (16.5–28.1)
Everolimus 18.8 (11.9–19.9)
No. of patients at risk
Nivolumab 94 86 79 73 66 58 45 31 18 4 1 0
Everolimus 87 77 68 59 52 47 40 19 9 4 1 0
0.0
0 3 6 129 15
Months
18 21 24 27 30 33
0.3
0.1
0.2
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OverallSurvival(Probability)
Nivolumab
Everolimus
PD-L1 ≥1% (n = 24%)
13
Median OS, months (95% CI)
Nivolumab 27.4 (21.4–NE)
Everolimus 21.2 (17.7–26.2)
276 265 245 233 210 189 145 94 48 22 2 0
299 267 238 214 200 182 137 92 51 16 1 0
Nivolumab
0 3 6 129 15
Months
18 21 24 27 30 33
0.3
0.1
0.2
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
Everolimus
HR (95% CI): 0.79 (0.53–1.17) HR (95% CI): 0.77 (0.60–0.97)

14. 14
Antitumor activity
Nivolumab
N = 410
Everolimus
N = 411
Objective response rate, % 25 5
Odds ratio (95% CI)
P value
5.98 (3.68–9.72)
<0.0001
Best overall response, %
Complete response
Partial response
Stable disease
Progressive disease
Not evaluated
1
24
34
35
6
1
5
55
28
12
Median time to response,
months (range)
3.5 (1.4–24.8) 3.7 (1.5–11.2)
Median duration of response,
months (range)*
12.0 (0–27.6) 12.0 (0–22.2)
Ongoing response, n/N (%) 49/103 (48) 10/22 (45)
*For patients without progression or death, duration of response is defined as the time from the first response
(CR/PR) date to the date of censoring.

15. 15
Response characteristics
0 16 32 6448 80
Time (Weeks)
96 112 128
Responders
Ongoing response
First response
Off treatment
Nivolumab
Everolimus
On treatment

16. Progression-free survival
No. of patients at risk
Nivolumab 410 230 145 116 81 66 48 29 11 4 0
Everolimus 411 227 129 97 61 47 25 16 3 0 0
0 3 6 129 15
Months
18 21 24 27 30
0.0
0.3
0.1
0.2
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Progression-FreeSurvival(Probability)
Nivolumab
Everolimus
Median PFS, months (95% CI)
Nivolumab 4.6 (3.7–5.4)
Everolimus 4.4 (3.7–5.5)
HR (95% CI): 0.88 (0.75–1.03)
P = 0.1135
 In a post-hoc analysis of patients who had not progressed or died at 6
months, median PFS was 15.6 months for nivolumab vs 11.7 months for
everolimus (HR (95% CI): 0.64 (0.47–0.88)) 16

17. 17
Safety Summary
Nivolumab
N = 406
Everolimus
N = 397
Any Grade Grade 3-4 Any Grade Grade 3-4
Treatment-related AEs, % 79 19 88 37
Treatment-related AEs
leading to discontinuation, %
8 5 13 7
Treatment-related deaths, n 0 2a
a Septic shock (1), bowel ischemia (1).
 44% of patients in the nivolumab arm and 46% of patients in the
everolimus arm were treated beyond progression

18. 18
Treatment-related AEs in ≥10% of patients
Nivolumab
N = 406
Everolimus
N = 397
Any grade Grade 3 Grade 4a Any grade Grade 3 Grade 4b
Treatment-related AEs, % 79 18 1 88 33 4
Fatigue 33 2 0 34 3 0
Nausea 14 <1 0 17 1 0
Pruritus 14 0 0 10 0 0
Diarrhea 12 1 0 21 1 0
Decreased appetite 12 <1 0 21 1 0
Rash 10 <1 0 20 1 0
Cough 9 0 0 19 0 0
Anemia 8 2 0 24 8 <1
Dyspnea 7 1 0 13 <1 0
Edema peripheral 4 0 0 14 <1 0
Pneumonitis 4 1 <1 15 3 0
Mucosal inflammation 3 0 0 19 3 0
Dysgeusia 3 0 0 13 0 0
Hyperglycemia 2 1 <1 12 3 <1
Stomatitis 2 0 0 29 4 0
Hypertriglyceridemia 1 0 0 16 4 1
Epistaxis 1 0 0 10 0 0
a Grade 4 AEs not listed in table: increased blood creatinine (1), acute kidney injury (1), anaphylactic reaction (1).
b Grade 4 AEs not listed in table: increased blood triglycerides (2), acute kidney injury (1), sepsis (1), chronic
obstructive pulmonary disorder (1), increased blood cholesterol (1), neutropenia (1), pneumonia (1).

19. 19
Change from baseline in quality of life
scores on FKSI-DRS
Questionnaire completion rate: ≥80% during the first year of follow-up.
MeanChangeFromBaseline
Nivolumab
Everolimus
40 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
Week
-6
0
-4
-2
2
4
6
No. of patients at risk
Nivolumab 362 334 302 267 236 208 186 164 159 144 132 119 112 97 90 89 81 72 63 59 53 44 43 31 30 26 20
Everolimus 344 316 270 219 191 157 143 122 102 97 87 74 73 63 58 49 44 35 30 28 24 21 15 12 12 9 9
WorseBetter
▪ Mean change from baseline in the nivolumab group increased over time
and differed significantly from the everolimus group at each assessment
through week 76 (P<0.05)

20. ▪ CheckMate 025 met its primary endpoint, demonstrating
superior OS with nivolumab versus everolimus
▪ This is the only phase III trial to demonstrate a survival
advantage in previously-treated patients with mRCC versus
standard therapy
▪ Survival benefit with nivolumab was consistent across
subgroups and irrespective of PD-L1 expression
▪ Nivolumab was associated with a greater number of
objective responses
20
Conclusions (1)

21. ▪ Nivolumab was associated with fewer grade 3 and 4
treatment-related AEs and fewer treatment-related AEs
leading to discontinuation than everolimus
▪ FKSI-DRS results demonstrate a consistent improvement
in QoL with nivolumab versus everolimus
▪ The superior survival and favorable safety profile in this
phase III trial provide evidence for nivolumab as a
potential new treatment option for previously treated
patients with mRCC
21
Conclusions (2)

22. ▪ The patients and their families
▪ Research colleagues and clinical teams
▪ Support for this work from Bristol-Myers Squibb and Ono
Pharmaceutical Co., Ltd
▪ Jennifer McCarthy, CheckMate 025 protocol manager
▪ Justin Doan for involvement with QoL interpretation
▪ Dako for development of the PD-L1 immunohistochemistry
assay
▪ Writing and editorial assistance was provided by Jennifer
Granit and Maria Soushko, of PPSI, funded by Bristol-
Myers Squibb
22
Acknowledgments

23. 23
CheckMate 025 investigators
Argentina
E. Korbenfeld (Buenos Aires); F.S. Palazzo (Tucuman), G. Recondo (Buenos
Aires), M. Chacon (Buenos Aires), M.E. Richardet (Cordoba), M. Susana
(Buenos Aires)
Australia
D. Pook (Victoria), G. Toner (Victoria), H. Gurney (New South Wales), I. Davis
(Victoria), K.B. Pittman (South Australia)
Austria
A. Kavina (Vienna), M. Schmidinger (Vienna), W. Loidl (Linz)
Belgium
D. Schallier (Brussels), J-P. Machiels (Brussels), P. Schoffski (Leuven), S. Rottey
(Gent)
Brazil
C. Dzik (Sao Paulo), F. Schutz (Sao Paulo), F.A. Franke (Rio Grande Do Sul)
Canada
C.K. Kollmannsberger (Vancouver, BC), D. Heng (Calgary, AB), J. Knox
(Toronto, ON), L. Wood (Halfax, NS), N. Basappa (Edmonton, AB), P. Zalewski
(Oshawa, ON), S. Ghedira (Moncton, NB), W. Miller (Montreal, QC)
Czech Republic
B. Melichar (Olomouc), E. Kubala (Hradec Kralove), J. Prausova (Prague)
Denmark
F. Donskov (Aarhus), N.V. Jensen (Odense), P. Geertsen (Herlev)
Finland
P. Bono (Helsinki), K Peltola (Helsinki)
France
A. Ravaud (Bordeaux), B. Escudier (Villejuif Cedex), C. Chevreau (Toulouse
Cedex 9); F. Rolland (Saint Herblain Cedex), G. Gravis (Marseille Cedex 9),
J-M. Tourani (Poitiers), L. Geoffrois (Vandoeuvre Les Nancy), S. Oudard (Paris)
Germany
A. Heidenreich (Aachen), F. Imkamp (Hannover), J. Bedke (Tuebingen), J. Meiler
(Essen), M. Retz (Munich), P. Goebell (Erlangen), S. Pahernik (Heidelberg)
Greece
A. Bamias (Athens), K. Papazsis (Thessaloniki)
Ireland
J.A. McCaffrey (Dublin), R. McDermott (Dublin)
Israel
A. Neumann (Haifa), R. Berger (Ramat-gan), V. Neiman (Petah Tikva)
Italy
A. Santoro (Rozzano), C. Sternberg (Roma), F. Roila (Terni), G. Procopio (Milano),
M. Maio (Siena), S. Bracarda (Arezzo), U. De Giorgi (Meldola)
Japan
F. Hongo (Kyoto), G. Kimura (Tokyo), H. Kanayama (Tokushima), H. Kitamura (Hokai-
do), H. Kume (Tokyo), H. Uemura (Osaka), J. Yonese (Tokyo), K. Tanabe (Tokyo),
K. Tatsugami (Fukuoka), M. Eto (Kumamoto), M. Oya (Tokyo), M. Saito (Akita),
M. Uemura (Osaka), M. Yao (Kangawa), N. Shinohara (Hokkaido), R. Yamaguchi (Tokyo),
S. Fukasawa (Chiba), T. Kato (Yamagata), T. Sugiyama (Shizuoka), W. Obara (Iwate)
Norway
D. Heinrich (Lorenskog), O. Straume (Bergen)
Poland
C. Szcylik (Warszawa), G. Slomian (Energetykow), J. Wojcik-Tomaszewska (Gdansk),
P. Tomczak (Poznan), R. Zdrojowy (Wroclaw)
Romania
C. Volovat (Iasi), D. Lungulescu (Craiova), I. Sinescu (Bucharest)
Russian Federation
E. Poddubskaya (Moscow), P. Karlov (St. Petersburg), V. Matveev (Moscow)
Spain
C. Suarez (Barcelona), D. Castellano (Madrid), J. Puente (Madrid), J.A. Arranz
(Madrid), J.L. Perez Gracia (Navarra), X. Garcia Del Muro (Barcelona)
Sweden
A. Jellvert (Gothenberg), U. Harmenberg (Solna)
United Kingdom
J. Wagstaff (Carmarthenshire), M. Gore (London), P. Nathan (London), T. Eisen
(Cambridgeshire)
United States
A. Alva (Ann Arbor, MI), A. Amin (Charlotte, NC), B. Carthon (Atlanta, GA),
D. McDermott (Boston, MA), D. Quinn (Los Angeles, CA), D. Vaena (Iowa City, IA),
E. Lam (Aurora, CO), E. Plimack (Philadelphia, PA), F. Millard (La Jolla, CA),
F. Quddus (Greenville, SC), H. Beltran (New York, NY), H. Drabkin (Charleston, SC),
H-J. Hammers (Baltimore, MD), J. Brugarolas (Dallas, TX), J. Clark (Maywood, IL),
J. Hainsworth (Nashville, TN), J. Sarantopoulos (San Antonio, TX), J. Sosman
(Nashville, TN), J.T. Beck (Fayetteville, AR), L. Fong (San Francisco, CA), M. Fishman
(Tampa, FL), M. Harrison (Durham, NC), N. Dawson (Washington, DC), P. Sharma
(Houston, TX), R. Figlin (Los Angeles, CA), R. Motzer (New York, NY), S. George
(Buffalo, NY), S. Srinivas (Stanford, CA), S. Tykodi (Seattle, WA), T. Kuzel (Chicago,
IL), T. Logan (Indianapolis, IN), T. Olencki (Columbus, OH), U. Vaishampayan (Detroit,
MI), W. Voelzke (Richmond, VA)

24. 24