Background

Gastric/Gastroesophageal Junction Cancer• Gastric cancer is the fifth most common cancer worldwide by incidence and the third leading cause of cancer

mortality1

• Gastroesophageal junction (GEJ) cancer is often treated in a similar manner as gastric cancer due to biological similarity2

• The combination of platinum compounds (eg, oxaliplatin) and fluoropyrimidine is a standard of care for first-line metastatic gastric/GEJ cancers3-5

– Median overall survival (OS) with this combination ranges from 8 to 11 months in the United States and Europe and 12 to 14 months in Asian countries6-9

• New treatment options are needed to improve survival in patients with metastatic gastric/GEJ cancer

Targeting Immune Checkpoints in Gastric/Gastroesophageal Junction Cancer• Programmed death-1 (PD-1) is an immune checkpoint receptor that regulates T-cell activation through binding of

the ligands PD-L1 and PD-L210

• PD-L1 or PD-L2 expression has been reported in 22% to 40% of gastric cancers and is associated with depth of muscle invasion, tumor size, lymph node metastasis, and survival11,12

– Therefore, targeting PD-1 may improve survival in gastric/GEJ cancer

• Nivolumab is a fully human IgG4 monoclonal antibody that targets PD-113,14

• The monoclonal antibody ipilimumab, another immune checkpoint inhibitor, upregulates antitumor immunity by blocking cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), a negative regulator of T-cell activation15-17

• Combination treatment with nivolumab and ipilimumab may increase antitumor effects by enhancing T-cell function through distinct mechanisms (Figure 1)

Figure 1. Nivolumab and Ipilimumab Mechanism of Action

LYMPH NODE TUMOR MICROENVIRONMENT

Anti-CTLA-4 (ipilimumab) Anti-PD-1 (nivolumab)

Dendriticcell T cell T cell Tumor cell

TCR

MHC

B7

B7

anti-CTLA-4

CTLA-4

CD28

TCR

MHC

anti-PD-1

anti-PD-1

PD-L1

PD-L2

PD-1

PD-1

MHC, major histocompatibility complex; TCR, T-cell receptor.

Study Rationale• With a median OS of 8 to 14 months, there is an unment need for new first-line treatment options to improve

survival in patients with advanced or metastatic gastric/GEJ cancer

• Immune checkpoint inhibitors have demonstrated clinical activity in multiple advanced solid tumor types, with increased tolerability compared with standard chemotherapies18-22

• In an ongoing phase 1/2 study in patients with gastric/GEJ/esophageal cancer refractory to ≥ 2 chemotherapy regimens with or without PD-L1–expressing (PD-L1+) tumors, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg demonstrated a manageable safety profile and preliminary antitumor activity23

– Among all patients, the ORR was 26%, median OS was 6.9 months, and OS rate at 12 months was 34%

– In patients with PD-L1+ tumors, an ORR of 44% was observed

• Based on the activity in heavily pretreated patients, we hypothesized that nivolumab plus ipilimumab would improve outcomes in patients with previously untreated advanced or metastatic gastric/GEJ cancer compared with chemotherapy standard of care

• CheckMate 649 (NCT02872116) is a phase 3 study of nivolumab plus ipilimumab vs oxaliplatin plus fluoropyrimidine as first-line therapy in patients with advanced or metastatic gastric/GEJ cancer

Study Objective • To compare OS with nivolumab plus ipilimumab vs that with chemotherapy standard of care (oxaliplatin plus

fluoropyrimidine) in patients with previously untreated advanced or metastatic gastric/GEJ cancer with PD-L1+ tumors (PD-L1 ≥ 1% expression)

Study Design• CheckMate 649 is a randomized, multicenter, open-label, phase 3 study (Figure 2)

• An estimated 1266 patients will be randomized to receive nivolumab plus ipilimumab or 1 of 2 chemotherapy regimens (oxaliplatin plus capecitabine [XELOX] or oxaliplatin plus leucovorin plus fluorouracil [FOLFOX])

Figure 2. CheckMate 649 Study Design

Randomized

• ≥ 18 years old

• Inoperable advanced/metastatic gastric/GEJ cancer

• No prior systemic treatment, including HER2 inhibitors, as primary therapy for advanced or metastatic disease

• Available tumor tissue from ≤ 6 months prior to study treatment

Screening Treatment

Post-treatmentfollow-up

XELOX or FOLFOX

Nivolumab + ipilimumab (4 doses), then nivolumab monotherapy

Enrollment Criteria • Key enrollment criteria are below (Table 1)

Table 1. Key Inclusion and Exclusion Criteria

Inclusion criteria Exclusion criteria

Men and women ≥ 18 years old Presence of untreated known CNS metastasesInoperable advanced or metastatic gastric/GEJ cancer and histologically confirmed predominant adenocarcinoma

Active known or suspected autoimmune disease

No prior systemic treatment, including HER2 inhibitors, as primary therapy for advanced or metastatic disease

Presence of grade > 1 peripheral neuropathy

No neoadjuvant or adjuvant treatment (chemotherapy and/or radiotherapy) within the past 6 months

Known HER2+ status

ECOG performance status of 0 or 1 History of a positive test for HIV or known AIDS

Must agree to provide a tumor tissue sample for determination of PD-L1 status

Positive test for hepatitis B or C indicating acute or chronic infection

Study Endpoints and Assessments• Study endpoints are below (Figure 3)

Figure 3. Study Endpoints

• OS in all randomized patients• PFS in patients with PD-L1+ tumors and all randomized patients• TTSD assessed via the GaCS questionnaire in patients with PD-L1+ tumors and all randomized patients

Primary

Endpoint

Secondary

Endpoints

• OS in patients with PD-L1+ tumors

• OS, PFS, and TTSD will be evaluated ≈ 35 months after the �rst patient is randomized

GaCS, Gastric Cancer Subscale; TTSD, time to symptom deterioration.

Study Sites• Enrollment is planned for 95 study sites in 20 countries (Figure 4)

Figure 4. Planned Study Sites

USA 4

Canada 7

Argentina 5Brazil 5Chile 5Peru 3

Australia 5

Japan 10Taiwan 3Republic of Korea 2

France 8Germany 7Italy 6Israel 5Greece 4Hungary 4Poland 4Spain 4Romania 3Portugal 1

Study Dates• Study start: October 2016

• Estimated primary completion: July 2019 (final data collection date for primary endpoint)

• Estimated study completion: October 2020

References1. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence

worldwide in 2012. http://globocan.iarc.fr. Accessed December 8, 2016.

2. Cancer Genome Atlas Research Network. Nature. 2014;513:202-209.

3. NCCN Clinical Practice Guidelines in Oncology. Gastric Cancer. Version 3.2016. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed December 8, 2016.

4. Waddell T et al. Ann Oncol. 2013;24(suppl 6):vi57-vi63.

5. Japanese Gastric Cancer Association. Gastric Cancer. 2016 Jun 24. [Epub ahead of print].

6. Ohtsu A et al. J Clin Oncol. 2011;29:3968-3976.

7. Cunningham D et al. N Engl J Med. 2008;358:36-46.

8. Yamada Y et al. Ann Oncol. 2015;26:141-148.

9. Al-Batran SE et al. J Clin Oncol. 2008;26:1435-1442.

10. Zou W et al. Sci Transl Med. 2016;8:328rv4.

11. Wu C et al. Acta Histochem. 2006;108:19-24.

12. Ohigashi Y et al. Clin Cancer Res. 2005;11:2947-2953.

13. Opdivo (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2016.

14. Opdivo (nivolumab) [summary of product characteristics]. Uxbridge, UK: Bristol-Myers Squibb Pharma EEIG; 2016.

15. Grosso JF, Jure-Kunkel MN. Cancer Immun. 2013;13:5.

16. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2015.

17. Yervoy (ipilimumab) [summary of product characteristics]. Uxbridge, UK: Bristol-Myers Squibb Pharma EEIG; 2016.

18. Hodi FS et al. N Engl J Med. 2010;363:711-723.

19. Ferris RL et al. N Engl J Med. 2016;375:1856-1867.

20. Robert C et al. N Engl J Med. 2015;372:320-330.

21. Borghaei H et al. N Engl J Med. 2015;373:1627-1639.

22. Motzer RJ et al. N Engl J Med. 2015;373:1803-1813.

23. Janjigian Y et al. J Clin Oncol. 2016;34(suppl) [abstract 4010].

Acknowledgments• The patients and families who made this trial possible

• The clinical study teams who participated in this trial

• Bristol-Myers Squibb, Inc. (Princeton, NJ), and Ono Pharmaceutical Company, Limited (Osaka, Japan)

• This study is supported by Bristol-Myers Squibb, Inc.

• All authors contributed to and approved the presentation; writing and editorial assistance was provided by Jonathan Morgan of Chrysalis Medical Communications, Inc., funded by Bristol-Myers Squibb, Inc.

CheckMate 649: a Randomized, Multicenter, Open-Label, Phase 3 Study of Nivolumab Plus Ipilimumab vs Oxaliplatin Plus Fluoropyrimidine in Patients With Previously Untreated Advanced or Metastatic Gastric or

Gastroesophageal Junction CancerYelena Y. Janjigian,1 Antoine Adenis,2 Jean-Sébastien Aucoin,3 Carlo Barone,4 Narikazu Boku,5 Ian Chau,6 James M. Cleary,7 Kynan Feeney,8 Fabio Andre Franke,9 Markus Moehler,10 Enrique Roca,11 Michael Schenker,12 Mingshun Li,13 Jaffer A. Ajani14

1Memorial Sloan Kettering Cancer Center, New York, NY; 2Centre Oscar Lambret, Lille, Nord, France; 3Centre Intégré Universitaire de Santé et de Services Sociaux de la Mauricie-et-du-Centre-du-Québec, QC, Canada; 4Fondazione Policlinico Universitario A. Gemelli, Rome, Italy; 5National Cancer Center Hospital, Tokyo, Japan; 6Royal Marsden Hospital, London and Surrey, United Kingdom; 7Dana-Farber Cancer Institute, Boston, MA; 8University of Notre Dame, Fremantle, and Edith Cowan University, Joondalup, WA, Australia; 9Cacon, Hospital De Caridade De Ijui, Ijui, Brazil; 10University Medical Center Mainz, Mainz, Germany; 11Hospital de Gastroenterología “Dr. C. B.

Udaondo,” Buenos Aires, Argentina; 12Sf. Nectarie Oncology Center, Craiova, Romania; 13Bristol-Myers Squibb, Princeton, NJ; 14The University of Texas MD Anderson Cancer Center, Houston, Texas

Presented at the 2017 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO-GI); January 19–21, 2017; San Francisco, CA

TPS213

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