The Current Status of Immune Checkpoint Inhibitors:

Arvin Yang, MD PhD

Oncology Global Clinical Research

Bristol-Myers Squibb

Immune Checkpoint Inhibitors Conference,

March 25, 2015 Boston, MA

A Global Overview of the Field

Agenda

● Discuss how checkpoint antibodies have changed the way we

think about and treat cancer

● Identify the critical issues facing the development of cancer

immunotherapies

● Discuss the importance of collaboration between industry,

academia, regulators, payers and advocacy groups to

advance cancer immunotherapies

How Immunotherapy and Checkpoint Inhibitors have

Revolutionized Cancer Treatment

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Estimated Survival Rate 1 Year 2 Year 3 Year*

Ipilimumab + DTIC

n=250 47.3 28.5 20.8

Placebo + DTIC

n=252 36.3 17.9 12.2

*3-year survival was a post-hoc analysis

Ipilimumab + DTIC

Placebo + DTIC

Pro

po

rtio

n A

live

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Years

0 1 2 3 4

Yervoy Improves Overall Survival in Advanced Melanoma

Robert C NEJM 2011

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Yervoy Treatments Results in Durable Long-Term Overall Survival in Pooled Analysis of Patients with Advanced Melanoma

5

Patients at Risk

Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0

Pro

po

rtio

n a

live

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months 0 12 24 36 48 60 72 84 96 108 120

Median OS: 11.4 mo (95% CI 10.7–12.1 mo)

3-year Survival Rate: 22% (95% CI 20–24%)

Ipilimumab

CENSORED

N = 1861 Patients Across 12 Studies

Schadendorf et al; European Cancer Congress 2013; Amsterdam

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Nivolumab Improves Overall Survival Compared to Dacarbazine in Previously Untreated Advanced Melanoma

HR 0.42 (99.79% CI, 0.25–0.73; P < 0.0001)

(Boundary for statistical significance 0.0021)

Robert et al. NEJM 2014 NR=not reached. Based on 5 August 2014 database lock

Patients who died, n/N

Median OS mo (95% CI)

Nivolumab 50/210 NR

Dacarbazine 96/208 10.8 (9.3–12.1)

Nivolumab

(N=210)

Dacarbazine

(N=208)

Months

100

90

80

70

60

0

50

40

30

20

10

Patients at

Risk

Nivolumab

Dacarbazine 210

208

185

177

150

123

105

82

45

22 8

3

0

0

0 3 6 9 12 15 18

Pa

tie

nts

Su

rviv

ing

(%

)

1-yr OS 73%

1-yr OS 42%

Follow-up since randomization: 5.2–16.7 months

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Aspirational Goal with Combination

7

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0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Patients at Risk

Cohort 2 (Nivo 1 + Ipi 3) 17 17 17 16 16 14 14 14 13 7 4 3 3 3 0 0 0 Concurrent Cohorts 1–3 53 52 49 47 45 42 37 30 25 16 11 7 5 5 1 1 0

Month

OS

(%

)

Concurrent Cohorts 1–3

Censored

0

10

20

30

40

50

60

70

80

90

100

1-yr OS 85%

2-yr OS 79%

Cohort 2 (Nivo 1 + Ipi 3)

1-yr OS 94% 2-yr OS 88%

Cohort 2 dose is similar to the dose/schedule used in phase 3 clinical studies

Phase 1 Nivolumab + Ipilimumab 1 & 2-Year Overall Survival Rates in Patients with Advanced Melanoma

Kluger et al. ESMO 2014 based on June 2014 database lock

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Ipilimumab improves Recurrence-free Survival in Melanoma

Ipilimumab Placebo

Events/patients 234/475 294/476

HR (95% CI)* 0.75 (0.64–0.90)

Log-rank P value* 0.0013

2-Year RFS rate (%) 51.5 43.8

3-Year RFS rate (%)** 46.5 34.8

Ipilimumab 10 mg/kg

Placebo

Patients at Risk

O N

Ipilimumab

Placebo

Pa

tie

nts

Ali

ve

Wit

ho

ut

Re

lap

se

(%

)

100

90

80

70

60

50

40

30

20

10

0 0 12 24 36 48 60

Months

475

476

276

260

205

193

67

62

5

4

0

0

Median: 17.1 mo

Median: 26.1 mo

*Stratified by stage.

**Data are not yet mature.

9

234

294

What is Beyond Melanoma?

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Overall Survival with Nivolumab in Advanced, Pretreated Squamous Cell Lung Cancer

117 93 68 51 28 0 5 Nivolumab 3mg/kg

0 3 6 9 12 18 15

Number of Patients at Risk

1-year OS = 41%

100

90

80

70

60

0

50

40

30

20

10

Median OS = 8.2 months

Overall Survival (Months)

Overa

ll S

urv

ival

(%)

Median OS, months (95% CI) 8.2 (6, 11)

1-year OS rate, % (95% CI) 41 (32, 50)

Number of events 72/117

Median follow-up for survival: 8 months (range, 0–17 months)

Ramalingam CMSTO 2014

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Broad activity demonstrated with checkpoint blockade

BMS Phase 3 Studies as an Example

Melanoma RCC Lung Other

Untreated

Previously

Treated

Adjuvant

OPDIVO*

OPDIVO* OPDIVO*

OPDIVO* OPDIVO*

Head & Neck

OPDIVO* Glioblastoma

OPDIVO* + YERVOY YERVOY

Sq NSCLC

YERVOY SCLC

YERVOY Prostate

YERVOY

OPDIVO* + YERVOY

OPDIVO*

YERVOY

Additional BMS Studies

Hodgkin Lymphoma

Breast Cancer

Bladder Cancer

Gastric Cancer

Pancreatic Cancer

Hepatocellular Carcinoma

Colon Cancer

Non-Hodgkin Lymphoma

OPDIVO

What Do We Still Need to Address?

Critical Issues Facing the Development of Cancer Immunotherapies

● Combination conundrum

– What are the appropriate endpoints?

● Understanding and finding biomarkers of response?

– Is PDL1 a relevant biomarker?

• Enrichment and response rate are not associated with survival

• PDL1 positive and negative patients benefit

• Temporal heterogeneity

The Future of Immunotherapy: Combinations and Collaboration

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Aspirational Goal with Combination

1

6

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Immuno-Oncology: Research & Preclinical Focus

17

What is the Appropriate Endpoint?

Patients at Risk

Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0

Pro

po

rtio

n a

live

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months 0 12 24 36 48 60 72 84 96 108 120

Ipilimumab

CENSORED

Schadendorf et al; European Cancer Congress 2013; Amsterdam

• Overall Survival

• Progression Free Survival

• Durable Response

Nivolumab treatment in both PD-L1 Positive and Negative Melanoma patients improves Overall Survival

Robert et al. NEJM 2014 NR=not reached. Based on 5 August 2014 database lock

II-ON: Industry-Academia Collaboration

Facilitate translation

of cancer research

findings into clinical

trials… clinical practice

Work to further

advance innovation

in drug discovery

and development

20

An Example: Extending Leadership through Partnerships