Understanding Immuno-Oncology

Patients with Advanced Cancers Continue to Search for Improved Survival

• Surgery, radiation and cytotoxic/targeted therapies have been the mainstay of treatment in most advanced cancers1

• 5-year survival, however, remains poor for many patients with advanced solid tumors2

– For several common cancers, 5-year survival rates continue to remain below 20% for patients with metastatic disease2

– 5-year survival rates for patients with metastatic lung, colorectal, kidney and renal pelvis cancers, and melanoma are 3.9%, 12.5%, 12.3% and 16.0%, respectively2

• There is a need for new therapeutic(s) and modalities for advanced cancer that offer improvements in quality, long-term survival3

1. DeVita VT, Rosenberg SA. N Engl J Med. 2012:366:2207-2214. 2. Surveillance, Epidemiology and End Results (SEER) Program. http://seer.cancer.gov. 3. Rosenberg SA. Sci Transl Med. 2012;4:(127ps8):1.

Patients with Advanced Cancers Continue to Search for Improved Survival

• Surgery, radiation and cytotoxic/targeted therapies have been the mainstay of treatment in most advanced cancers1

• Global mortality, however, remains high for many patients with advanced solid tumors2

• There is a need for new therapeutic(s) and modalities for advanced cancer that offer improvements in quality, long-term survival3

1. DeVita VT, Rosenberg SA. . N Engl J Med. 2012:366:2207-2214. 2. Globalcan2008(IARC)(29.4.2013). globalcan.iarc.fr. 3. Rosenberg SA. Sci Transl Med. 2012; 4:(127ps8):1.

Recently Approved Therapies Have Provided Some Improvement in Median Overall Survival

Regorafenib, mCRC1

Approved 2012Application for approval in EU

Pertuzumab + trastuzumab + docetaxel, mBC2

Approved 2012 US, 2013 EU

Abiraterone acetate, mCRPC3

US & EU Approved 2011

1. Grothery A, Van Coffem E, Sobrero A, et al. Lancet. 2013; 381:303-12.2. Baselga J, Cortes J, Kim S-B, et al. N Engl J Med. 2012;366:109-119.3. De Bono JS, Logothetis CJ, Molina A, et al. N Engl J Med. 2011;364:1995-2005.

How Can We Measure Clinical Benefit?1-3

Long-term Survival*

Mean and Median OS

PFS

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*Long-term survival as measured by landmarks such as 1 yr, 2yr, 5 yr, etc1. Cancer Drug Approval Endpoints. www.fda.gov/About/CentersOfficeofMedicalProductsandtobacco/CDER/ucm117709.htm#lung 2. Workshop Summary on Endpoints for Approval of Cancer Drugs for Lung Cancer. www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/ DevelopmentResources/CancerDrugs/ucm094744.pdf. 3. Lee ME, Berstein D, Voest E, et al. Defining clinically meaningful outcomes: ASCO Recommendations to Raise the Bar for Clinical Trials [draft for public comment]. www.asco.org/sites/asco.org/files_asco_meaningful+outcomes_draft_for_comment_april_2013.pdf.

The Immune System Works to Protect Against Cancer

• The immune system surveys for and distinguishes tumor cells from normal tissue1

• Tumor cells recognized by the immune system as abnormal results in an immune response which, in most situations, destroys or controls the tumor2,3

• Multiple mechanisms participate in tumor recognition and control the response of the immune system to the tumor2

• Cancer cells can evade the immune system by escaping these pathways1,4

1. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. 2. Mellman I, Coukos G, Dranoff G. Nature. 2011;480:480-489. 3. Vivier E, et al. Science. 331:44-49. 4. Drake CG, Jaffee E, Pardoll DM. Adv Immunol. 2006;90:51-81.

The Science of Immuno-Oncology Is Driving the Development of Novel Immunotherapies That Directly Modulate the Immune System

Immune Hallmarks of Cancer1

• Ability to evade immunerecognition

• Ability to thrive in a chronically inflamed microenvironment

• Ability to suppress immune activity

• Increased understanding of how cancer evades the immune system is the foundation forImmuno-Oncology (I-O)2

• I-O incorporates the understanding of the mechanisms tumors use to escape the immune system and how these can be modulated to promote tumor destruction and/or growth3-4

• The focus in I-O is on understanding the pathways and mechanisms involved in tumor immune evasion and bringing therapies forward for investigation5,6

1. Cavallo F, Giovanni CD, Nanni P, et al. Cancer Immunol Immunother. 2011:60:319-326. 2. Finn OJ. Ann Oncol. 2012;23 Suppl 8:viii6-9. 3. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. 4. Mellman I, Coukos G, Dranoff G. Nature.2011;480:480-489. 5. BMS Press Release, May 29, 2012 Bristol-Myers Squibb Announces Global Collaboration with Leading Academic Institutions to Advance Science of Immuno-Oncology http://news.bms.com. 6. BMS. In the Pipeline. http://bms.com/research/pipeline/Pages/default.aspx. Accessed February 2013.

Immuno-Oncology Is an Emerging Therapeutic Modality1

• Immuno-Oncology treatment is different from other treatment modalities because it uses the natural capability of the patient’s own immune system to fight cancer2

• Immuno-Oncology treatment works with the body’s immune system to fight cancer rather than working directly on the tumor2

Surgery Radiation

Cytotoxic& Targeted Therapies

Immuno-therapy

1. DeVita VT, Rosenberg SA. N Eng J Med. 2012:366:2207-2214. 2. Borghaei H, Smith MR, Campbell KS. Eur J Pharmacol. 2009;625:41-54.

Durable Long-term Survival Has Been Demonstrated In Melanoma: An I-O TherapyYERVOY (ipilimumab), an I-O therapy that targets the immune system, is the first and only mMeltherapy proven in a phase 3 study to deliver a durable long-term survival benefit at 1 & 2 years in previously treated patients, with some alive up to 4.5 years1,2

1.YERVOY Prescribing Information. 2. Hodi FS, O’Day SJ, McDermott DF, et al. N Engl J Med 2010; 363:711-723.3. Data on File, Bristol-Myers-Squibb Company, Princeton, NJ.

• In clinical trials, most adverse events associated with YERVOY were immune related and were managed using YERVOY-specific treatment guidelines3

• The following are the most frequently reported adverse events associated with YERVOY (≥10%, all grades) in a clinical study with YERVOY monotherapy during the induction phase: diarrhea (27%), rash (26%), pruritus (26%), fatigue (24%), nausea (23%), vomiting (12%), decreased appetite (11%), abdominal pain (11%)3

Preliminary Studies Support Further Research Across Multiple Tumor Types1

Med. OS(months)

% Survival1 yr 2 yr

NSCLC 9.6 42 14(95% CI); (7.8, 12.4) (33,51); (4, 24);

pts at risk 43 50

100

80

60

40

20

03 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Died/treated88/129

100

80

60

40

20

00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Died/treated60/107

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Died/treated15/34

0

100

80

60

40

20

Med. OS(months)

% Survival1 yr 2 yr

Melanoma 16.8 62 43(95% CI); (12.5,31.6) (53,72); (32,53);

pts at risk 57 26

Med. OS(months)

% Survival1 yr 2 yr

RCC >22 70 50(95% CI); (13.6, NE) (55,86); (31,70);

pts at risk 23 8

1. Topalian SL. Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: survival and long-term safety in a phase I trial [oral slide presentation]. Presented at: ASCO Annual 2013 Meeting; May 31-June 4, 2013; Chicago, IL.http://meetinglibrary.asco.org/content/83737. Accessed June 24, 2013

OVE

RALL SURV

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 (%)

MONTHS SINCE TREATMENT INITIATION

For patients treated with Nivolumab

10

Immuno-Oncology Is an Emerging Therapeutic Modality1

• Immuno-Oncology treatment is different from other treatment modalities because it uses the natural capability of the patient’s own immune system to fight cancer2

• Immuno-Oncology treatment works with the body’s immune system to fight cancer rather than working directly on the tumor2

Surgery Radiation

Cytotoxic& Targeted Therapies

Immuno-therapy

1. DeVita VT, Rosenberg SA. N Eng J Med. 2012:366:2207-2214. 2. Borghaei H, Smith MR, Campbell KS. Eur J Pharmacol. 2009;625:41-54.