Immunotherapy update

1. Adil Daud M.B.B.S
Professor of Medicine and Dermatology
Director, Melanoma Program
University of California, San Francisco
PD-1 agents in Melanoma

2. Disclosures
Research Funding-- GSK, Novartis, Pfizer, Genentech,
Bristol-Myers, Merck, OncoSec, Roche
Advisory Boards-- OncoSec, Novartis, Genentech, Merck,
Pfizer, Amgen
Speaker-- None
Stock Ownership-- OncoSec

6. HD IL-2 Therapy: Durable Responses
Atkins MB, et al. J Clin Oncol. 1999;17:2105-2116. McDermott DF, et al. Expert Opin Biol Ther. 2004;4:455-468.
Metastatic Melanoma (N = 270) Metastatic RCC (N = 255)
• HD IL-2 produces durable responses in 6% to 10% of patients with advanced melanoma or RCC
 Few relapses in patients responding for over 2.5 years (likely cured)
 FDA approval in 1992 (RCC) and 1997 (melanoma)
1.0
0.8
0.6
0.4
0.2
0.0
ProbabilityofContinuingResponse
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Duration of Response (Mos)
CR (n = 17)
PR (n = 26)
CR + PR (n = 43)
1.0
0.8
0.6
0.4
0.2
0.0
ProbabilityofContinuingResponse
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Duration of Response (Mos)
CR
PR
All
140 150 160 170 180

7. Ipilimumab + gp100 (A)
Ipilimumab alone (B)
gp100 alone (C)
1 2 3 4
Yrs
Comparison HR P Value
Arms A vs C 0.68 .0004
Arms B vs C 0.66 .0026
Hodi FS, et al. N Engl J Med. 2010;363:711-723.
Ipilimumab, gp100, or Both in Advanced
Melanoma (MDX010-20): Survival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
ProportionAlive
OS, %
Ipi + gp100
(n = 403)
Ipi + Placebo
(n = 137)
gp100 + Placebo
(n = 136)
Year 1 44 46 25
Year 2 22 24 14
0

8. TUMOR
Dendritic cell
perforin
granzyme
cytokines
Activated T cell
T cell
clonal expansion
Resting T cell
LYMPH
NODE
TCR CD28
MHC
B7
Tumor antigen
Tumor cell
Interferons
Anti–PD-1
Anti–PD-L1Adaptive Resistance to T Cell Killing

9. Topalianetal,NEJM

10. Hamid et al, NEJM 2013

11. A Pooled Analysis Of 655 Patients With Advanced
Melanoma Enrolled In KEYNOTE-001: Long-term Efficacy
Of Pembrolizumab (MK-3475)
Adil Daud,1 Anthony M. Joshua,2 Antoni Ribas,3 Caroline Robert,4
F. Stephen Hodi,5 Jedd Wolchok,6 Wen-Jen Hwu,7 Jeffrey S. Weber,8
Tara C. Gangadhar,9 Richard Joseph,10 Roxana Dronca,11 Amita Patnaik,12 Hassane
Zarour,13 Richard Kefford,14,15 Jill A. Lindia,16 Xiaoyun Nicole Li,16 Scot Ebbinghaus,16 S.
Peter Kang,16 Omid Hamid17
1University of California, San Francisco, CA; 2Princess Margaret Hospital, Toronto, Ontario; 3University of California,
Los Angeles, CA; 4Gustave-Roussy and Paris-Sud University, Villejuif, France; 5Dana-Farber Cancer Institute, Boston, MA; 6Memorial
Sloan-Kettering Cancer Center, New York, NY; 7MD Anderson Cancer Center, Houston, TX;
8H. Lee Moffitt Cancer Center, Tampa, FL; 9Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA; 10Mayo Clinic,
Jacksonville, FL; 11Mayo Clinic, Rochester, MN; 12South Texas Accelerated Research Therapeutics,
San Antonio, TX; 13University of Pittsburgh, Pittsburgh, PA; 14Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma
Institute Australia, Sydney, Australia; 15Macquarie University, Sydney, Australia;
16Merck & Co., Inc., Kenilworth, NJ; 17The Angeles Clinic and Research Institute, Los Angeles, CA

12. Efficacy in Total Population
(As of October 18, 2014; Median Follow-Up: 21 months)
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaseline,%
IPI-T
IPI-N
aAssessed in patients with measurable disease per central RECIST v1.1 at baseline.
N = 581a
CR, % (95% CI) 8 (6-11)
ORR, % (95% CI) 33 (30-37)
Response Duration
WithoutProgression,%
0 3 6 9 12 15 18 21 24 27 30
0
10
20
30
40
50
60
70
80
90
100
Time, months
204 190 162 138 91 67 50 22 17 5 0
n at risk
Median Change:
–36%
71%

13. Survival in Total Population
Analysis cut-off date: October 18, 2014.
PFS
• Median (95% CI):
4.4 months (3.1-5.5)
• Rate at 12 months: 35%
0 3 6 9 12 15 18 21 24 27 30 33 36
0
10
20
30
40
50
60
70
80
90
100
Time, months
Progression-FreeSurvival,%
655 343 264 226 201 134 99 72 35 29 11 0
n at risk
0
OS
• Median (95% CI):
22.8 months (19.8-28.7)
• Rate at 12 months: 66%
• Rate at 24 months: 49%
0 3 6 9 12 15 18 21 24 27 30 33 36
0
10
20
30
40
50
60
70
80
90
100
Time, months
OverallSurvival,%
655 584 510 461 416 318 231174 93 66 29 3
n at risk
0

14. Efficacy as First-Line Therapya
aExcludes patients with ocular melanoma.
Analysis cut-off date: October 18, 2014.
Duration of Response in First Line
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaseline,%
2 mg/kg Q3W
10 mg/kg Q3W
10 mg/kg Q2W
• Median: Not reached
• Range: 2.7+ to 27.5+ months
• Patients without progression: 86%
0 3 6 9 12 15 18 21 24 27 30
0
10
20
30
40
50
60
70
80
90
100
Time, months
65 62 53 43 32 22 18 7 4 1 0
n at risk
WithoutProgression,%
Median Change:
–54%
80%

15. 34%
ORR in Subgroups (RECIST v1.1, Central Review)
<Median
≥Median
BRAF inhib
Immunotherapy
Chemotherapy
≥3
2
1
0
M1c
M1b
M1a
Overall
Wild type
Mutant
Baseline
tumor size
Previous
therapy
No. lines
previous
therapy
M stage
BRAF
status
Yes
No
Elevated
Normal
1
0
≥65
<65
Female
Male
10 Q2W
10 Q3W
2 Q3W
Overall
IPI-T
IPI-N
Brain
metastases
LDH level
ECOG PS
Sex
IPI
exposure
Age
Dose/
schedule
Analysis cut-off date: April 18, 2014.
360
84
272
28
63
263
79
105
105
71
127
101
59
180
180
N
143
166
51
218
142
220
140
256
104
215
140
31
327
N
165
195
360
34%

16. AEs of Interest Based on Immune Etiology
Adverse Event, n (%) Any Grade Grade 3-4
Hypothyroidism 49 (7.5) 1 (0.2)
Hyperthyroidism 15 (2.3) 2 (0.3)
Pneumonitisa 18 (2.7) 2 (0.3)
Colitisb 11 (1.7) 7 (1.1)
Uveitisc 6 (0.9) 0 (0.0)
Hepatitisd 4 (0.6) 2 (0.3)
Nephritise 3 (0.5) 2 (0.3)
aIncludes interstitial lung disease of grade 1-2. bIncludes colitis microscopic and enterocolitis.
cIncludes iridocyclitis and iritis. dIncludes autoimmune hepatitis. eIncludes renal failure.
Analysis cut-off date: April 18, 2014.
• Some reported skin rashes may have been immune-mediated
• Other immune-mediated events observed in >2 patients: thyroiditis (n = 6); hypophysitis, hypopituitarism,
pruritus, and rash (n = 3 each); autoimmune thyroiditis, myositis, and rash generalized (n = 2 each)
Daud et al ASCO 2015

17. CA209-067: Study Design
17
Randomized, double-blind, phase III study
to compare NIVO + IPI or NIVO alone to IPI alone
Unresectable or
Metatastic Melanoma
• Previously untreated
• 945 patients
Treat until
progression**
or
unacceptable
toxicity
NIVO 3 mg/kg Q2W +
IPI-matched placebo
NIVO 1 mg/kg +
IPI 3 mg/kg Q3W
for 4 doses then
NIVO 3 mg/kg Q2W
IPI 3 mg/kg Q3W
for 4 doses +
NIVO-matched placebo
Randomize
1:1:1
Stratify by:
• PD-L1
expression*
• BRAF status
• AJCC M stage
*Verified PD-L1 assay with 5% expression level was used for the stratification
of patients; validated PD-L1 assay was used for efficacy analyses.
**Patients could have been treated beyond progression under protocol-defined circumstances.
N=314
N=316
N=315

18. Tumor Burden Change From Baseline
NIVO + IPI
Median change: -51.9%
NIVO
Median change: -34.5%
IPI
Median change: +5.9%
Confirmed responder
30% reduction in tumor burden by RECIST
v1.1
18
Baselinereductionfrom
baselineintargetlesions(%)
Baselinereductionfrom
baselineintargetlesions(%)
Baselinereductionfrom
baselineintargetlesions(%)

19. PFS (Intent-to-Treat)
NIVO + IPI
(N=314)
NIVO
(N=316)
IPI (N=315)
Median PFS, months
(95% CI)
11.5
(8.9–16.7)
6.9
(4.3–9.5)
2.9
(2.8–3.4)
HR (99.5% CI)
vs. IPI
0.42
(0.31–0.57)*
0.57
(0.43–0.76)*
--
HR (95% CI)
vs. NIVO
0.74
(0.60–0.92)**
-- --
*Stratified log-rank P<0.00001 vs. IPI
**Exploratory endpoint
19
No. at Risk
314NIVO + IPI 173 151 65 11 1219 0
316NIVO 147 124 50 9 1177 0
315IPI 77 54 24 4 0137 0
0 6 9 12 15 183 21
NIVO
NIVO + IPI
IPI
Months
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Proportionaliveandprogression-free

20. No. at Risk
IPI –202 82 44 31 12 1
NIVO 208 108 88 74 31 5 2
NIVO + IPI 210 142 112 96 42 9 2
0 3 6 9 12 15 17
Months
1.0
0.8
0.6
0.4
0.2
0.0
0 3 6 9 12 15 17
No. at Risk
IPI 075 40 22 17 9 2
NIVO 80 57 51 43 16 4 0
NIVO + IPI 68 53 44 39 16 1 0
Months
NIVO + IPI
NIVO
IPI
NIVO + IPI
NIVO
IPI
PFS by PD-L1 Expression Level (5%)
PD-L1 ≥5%* PD-L1 <5%*
*Per validated PD-L1 immunohistochemical assay based on PD-L1 staining of tumor cells in a section of at least 100 evaluable tumor cells.
Proportionaliveandprogression-free
Proportionaliveandprogression-free
1.0
0.8
0.6
0.4
0.2
0.0
mPFS HR
NIVO + IPI 14.0 0.40
NIVO 14.0 0.40
IPI 3.9 --
mPFS HR
NIVO + IPI 11.2 0.42
NIVO 5.3 0.60
IPI 2.8 --
20

21. ORR by PD-L1 Expression Level (5%)
NIVO + IPI NIVO IPI
PD-L1 (≥5%)
ORR, %
(95% CI)
72.1
(59.9, 82.3)
57.5
(45.9, 68.5)
21.3
(12.7, 32.3)
PD-L1 (<5%)
ORR, %
(95% CI)
54.8
(47.8, 61.6)
41.3
(34.6, 48.4)
17.8
(12.8, 23.8)
Pre-treatment tumor specimens were centrally assessed by PD-L1 immunohistochemistry (using a validated
BMS/Dako assay).
• NIVO + IPI resulted in a numerically higher ORR vs. NIVO alone regardless of
PD-L1 expression
21
-13.16-13.16

22. Safety Summary
Patients Reporting Event, %
NIVO + IPI (N=313) NIVO (N=313) IPI (N=311)
Any Grade
Grade
3–4 Any Grade
Grade
3–4
Any Grade
Grade
3–4
Treatment-related adverse event (AE) 95.5 55.0 82.1 16.3 86.2 27.3
Treatment-related AE leading to
discontinuation
36.4 29.4 7.7 5.1 14.8 13.2
Treatment-related death* 0 0.3 0.3
*One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest).
22
• 67.5% of patients (81/120) who discontinued the NIVO + IPI combination due to treatment-related AEs
developed a response

23. 7/10/15
Pre-Ipi/Nivo
8/20/15
s/p 2-Ipi/Nivo

24. CTLA-4
PD-1 Control (CD45+CD3-) TILs (CD45+CD3+CD8+)
Ipilimumab +Nivolumab responder

25. AN OPEN-LABEL, RANDOMIZED, PHASE 2 STUDY OF
NIVOLUMAB GIVEN SEQUENTIALLY WITH
IPILIMUMAB IN PATIENTS WITH ADVANCED
MELANOMA (CHECKMATE 064)
F. Stephen Hodi,1 Geoff Gibney,2 Ryan Sullivan,3 Jeffrey A. Sosman,4
Craig L. Slingluff, Jr,5 Donald P. Lawrence,3 Theodore F. Logan,6 Lynn M. Schuchter,7 Suresh
Nair,8 Leslie Fecher,6,9 Elizabeth Buchbinder,1 Mary Ruisi,10 George Kong,11 Christine Horak,10
Jeffrey S. Weber12
1Dana-Farber Cancer Institute, Boston, MA, USA; 2Georgetown Lombardi Comprehensive Cancer Center, Washington,
D.C., USA; 3Massachusetts General Hospital, Boston, MA, USA; 4Vanderbilt-Ingram Cancer Center, Nashville, TN, USA;
5University of Virginia School of Medicine, Charlottesville, VA, USA; 6Indiana University Simon Cancer Center,
Indianapolis, IN, USA; 7University of Pennsylvania, Philadelphia, PA, USA; 8Lehigh Valley Health Network, Allentown, PA,
USA; 9University of Michigan, Ann Arbor, MI, USA; 10Bristol-Myers Squibb, Princeton, NJ, USA; 11Bristol-Myers Squibb,
Wallingford, CT, USA; 12H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
Abstract Number 23LBA
25

26. CheckMate 064: Study Design
26
NIVO 3 mg/kg
Q2W x 6
Cohort A
N= ~70
Cohort B
N= ~70
IPI 3 mg/kg
Q3W x 4
NIVO 3 mg/kg
Q2W x 6
IPI 3 mg/kg
Q3W x 4
NIVO 3 mg/kg
Q2W
Randomize
TA = Tumor Assessment; = Biopsy Timepoint; PD = Progressive Disease
Induction Period 1 Induction Period 2 Continuation Period
1Week # 25
TA
13
TA
Until PD, unacceptable toxicity,
or withdrawal of consent
Randomized, open-label, phase 2 study evaluating the safety and efficacy of
two immune checkpoint inhibitors given sequentially with planned switch
TA
Database lock; May 22, 2015
2W
3W

27. 50%
7%
52%
38%
43%
24%
28%
22%
0%
10%
20%
30%
40%
50%
60%
Induction
Periods 1 and 2
Induction
Period 1
Induction
Period 2
NIVO Continuation
Period
A: NIVOIPI (N=68)
B: IPINIVO (N=70)
There were no study drug-related deaths in either cohort
Treatment-related grade 3-4 AEs leading to discontinuation Cohort A: 24%, Cohort B: 27%
27
Treatment-related Grade 3-4 AEs
* 95% CI: 37.6%–62.4%
** 95% CI: 31.1%–55.3%
ⱡAEs are counted only once for both induction periods
*
**
ⱡ
Primary
Endpoint

28. Efficacy Summary
28
Week 13 Week 25
A: NIVOIPI
(N=68)
B: IPINIVO
(N=70)
A: NIVOIPI
(N=68)
B: IPINIVO
(N=70)
Confirmed ORR, % (95% CI) -- --
41.2
(29.4–53.8)
20.0
(11.4–31.3)
Complete response, % 0 0 0 0
Unconfirmed ORR, % (95% CI)* 35.3 10.0
47.7
(35.1–60.5)**
22.6
(12.9–35.0)
Progression rate, % (95% CI)
38.2
(26.7–50.8)
61.4
(49.0–72.8)
38.2
(26.7–50.8)
60.0
(47.6–71.5)
*Statistical design required that Week 25 response be confirmed with a Week 33 scan; a confirmatory scan was not
required for Week 13 assessment.
**Includes 1 unconfirmed complete and 2 unconfirmed partial responses
(total of 31 objective responses [47.7%]).

29. Tumor Burden Change From
Baseline at Week 13
29
Confirmed responder
30% reduction in tumor burden
by RECIST v1.1
ReductionfromBaselinein
TargetLesion(%)atWeek13
Patients
75
50
100
0
-25
-50
-75
-100
25
B: IPINIVOA: NIVOIPI
Median change: -27% Median change: +10%

30. ReductionfromBaselinein
TargetLesion(%)atWeek25
Patients
Median change: -50%
(from -27% at week 13)
Median change: -17%
(from +10% at week 13)
75
50
100
0
-25
-50
-75
-100
25
B: IPINIVOA: NIVOIPI
30
Tumor Burden Change From
Baseline at Week 25
Confirmed responder
30% reduction in tumor burden
by RECIST v1.1

31. Patient With Melanoma Treated in KEYNOTE-001
Week 12Baseline Week 24 Week 52
Case courtesy of C. Robert, Gustave Roussy, Villejuif, France.

32. Early Pseudoprogression (irRC, Central Review)
Circles represent times of radiologic assessment. Open circles represent the time at which the 25% threshold for pseudoprogression was crossed.
Analysis cutoff: October 2014
Observed in 15 of 327 (4.6%)
patients followed by imaging for
≥28 weeks
0 12 24 36 48 60 72 84 96 108 120
-100
0
100
200
300
Time, weeks
ChangeFromBaseline,%

33. Association of Overall Survival With
Tumor Response (n = 594)
Analysis cutoff: October 2014
0 3 6 9 12 15 18 21 24 27 30 33 36
0
10
20
30
40
50
60
70
80
90
100
Time, months
OverallSurvival,%
205 205 205 204 199 159 118 93 53 40 21 2 0
122 122 112 104 98 73 55 43 18 10 4 0 0
15 15 15 14 14 13 7 5 3 2 1 0 0
75 75 65 55 47 36 26 18 10 7 1 1 0
177 167 113 84 58 37 25 15 9 7 2 0 0
CR or PR per RECIST v1.1
PD per RECIST v1.1,
CR or PR per irRC
SD per RECIST v1.1
PD per RECIST v1.1,
SD per irRC
PD per both

35. Keynote 001: Kaplan-Meier Estimate of PFS
(Central Review, RECIST 1.1)
Analysis cut-off date: April 18, 2014.
Population Median, mo 95% CI Rate, 6 mo
IPI-N 5.5 3.4-9.0 48%
IPI-T 5.1 3.2-5.6 42%
Overall 5.4 3.8-5.6 45%
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22 24
190 172 100 87 84 74 65 56 50 25 22 19 9
n at risk
Progression-FreeSurvival,%
Time, months
IPI naive
IPI treated 221 189 113 88 83 73 51 31 31 14 13 12 4
IPI naive
IPI treated

36. 36Taube et al, Clinical Cancer Research, March 2014

37. Sznol M , et al. Clin Cancer Res 2013;19:1021-1034.
*Implications for combination therapy with other checkpoint
inhibitors, chemotherapy, targeted therapy, and vaccines
PD-L1 Expression and Inflammation:
Implications for Mechanisms and
Therapy

38. Response Based on Tumor PD-L1 Expression: RECIST v1.1
PD-L1 and Radiologically Evaluable Patients (n = 113),a Independent Central Review
PD-L1 positivity defined as staining in ≥1% of tumor cells.
Analysis cutoff date: 18 October 2013.
aEvaluable patients were those patients in the training set with evaluable tumor PD-L1 expression who had measurable disease at baseline per central review.
b1-sided P values calculated by logistic regression, adjusting for dose/schedule. 38
40
58
49
65
13
37
0
10
20
30
40
50
60
70
80
Overall Response Rate Disease Control Rate
Rate,%
Unselected PD-L1+ PD-L1–
P = 0.0007b
P = 0.0070b
Daud et al AACR 2014

39. PD-L1 Expression and Relationship With Response
• Among first 411 patients enrolled,
67% evaluable for PD-L1 status
• Correlation between PD-L1 expression and ORR (P
< 0.0001)
APS, Allred proportion score.
Analysis cut-off date: October 18, 2014.
PD-L1 Positive
1-10% Staining
APS = 2
PD-L1 Negative
0% Staining
APS = 0
PD-L1 Positive
10-33% Staining
APS = 3
PD-L1 Positive
66-100% Staining
APS = 5
0
10
20
30
40
50
60
70
80
90
100
ORR,%(95%CI)
ORR, RECIST v1.1
APS 0
n = 28
APS 1
n = 24
APS 2
n = 72
APS 3
n = 54
APS 4
n = 32
APS 5
n = 34
PositiveNegative

40. Nature, 2014, Stratton and co-workers, Welcome CG Project

41. Science, 2015

43. Anti-PD1 clinical activity according to site of metastases
Conclusion: The Liver+/Lung- group showed a significantly lower ORR and PFS
(32%, 2.96) when compared to other groups. ORR and PFS remained significant
when adjusting for ocular melanoma.
Progressionfreesurvival
Follow-uptime(months)
AllLung (n=103) AllLiver(n=61)
Liver-/Lung+(n=75) Liver-/Lung-(n=64)
Liver+/Lung-(n=33)Liver+/Lung+(n=28)
Changeintargetlesionsfrombaseline(%)
B.A.
Liver+/Lung- vs.
Liver-/Lung+ 0.001
Liver-/Lung- 0.017
Liver+/Lung+ 0.478
Liver-/Lung+ vs.
Liver-/Lung- 0.177
Liver+/Lung+ 0.002
Liver+/Lung- 0.001
Pairwise Comparisons (p-value)
Liver-/Lung+ 23.01 mo
Liver-/Lung- 16.21 mo
Total Cohort 13.40 mo
Liver+/Lung+ 5.73 mo
Liver+/Lung- 2.96 mo

44. Immune response stratified by site of metastases
Conclusion: The liver group was associated with the “T-cell poor” phenotype, showing
reduced percentages of tumor infiltrating CD8+ and PD-1+ expressing T-cells.
B.
A.
(p<0.0001) (p<0.0017) (p<0.01)

45. Functional capacity of tumor-infiltrating CD8+ T-cells according to liver involvement
Conclusion:The liver group showed reduced numbers of the pembrolizumab target cell,
phenotypically defined as CTLA-4highPD-1+CD8+ T-cellsand functionally defined as lacking
stimulatedinterleukin-2 and TNF-alpha

48. Liver Non-Liver
0
10
20
30
40
50
60
70
%CTLA4+PD1hicells
***p=0.0007

52. P53
23 copies
P53
1 copy
Humans: Are we the Volkswagens of the animal world?

53. Acknowledgements
• Immunology Program
– Mike Rosenblum
– Roberto Sanchez
– Larry Fong
– Max Krummel
• Melanoma Program
– Alain Algazi
– Kim Loo
– Katy Tsai
– Adi Nosrati
– Neharika Khurana
– Martin McMahon
– Boris Bastian
• Genentech
– Ed Cha
• Merck
– Scot Ebbinghaus
– S Peter Kang
• BMS
– Alan Korman
– Jason Simon
• OncoSec Inc
– Rob Pierce
– Punit Dhillon
• UCLA
– Paul Tumeh
• Angeles Clinic
– Omid Hamid