Abstract 1416P
Background
In this exploratory analysis of the phase II KEYNOTE-059 (NCT02335411) and phase III KEYNOTE-061 (NCT02370498) studies of patients (pts) with previously treated advanced gastric cancer (GC) receiving pembrolizumab, we evaluated the genomic landscape of late-stage GC with a focus on comparing our results with previously reported data from TCGA of early-stage tumors in Caucasian pts. We also evaluated genomic features of advanced GC tumors in Caucasian and Asian pts.
Methods
In GC tumor samples from pts enrolled in KEYNOTE-059 and KEYNOTE-061, we analyzed DNA using whole exome sequencing (WES) to determine TCGA molecular subtypes (MSI, EBV, GS, CIN) and alterations in genes of interest in GC (TP53, KRAS, RHOA, CDH1, ARID1A, and PIK3CA mutations and EGFR, ERBB2, CD274, CCNE1, and CCND1 amplifications), DNA mutational signatures, and genomic scores (TMB, PD-L1 CPS). The prevalence of genomic features was evaluated based on clinical characteristics, PD-L1 CPS, and HER2 status.
Results
The prevalence of TCGA subtypes in our data set was comparable between Caucasian pts (N=243; MSI, 4.9%; EBV, 6.6%; GS, 37.0%; CIN, 51.4%) and Asian pts (N=142; MSI, 4.2%; EBV, 7.7%; GS, 34.5%; CIN, 53.5%); MSI-H and EBV subtypes had numerically lower prevalence than in TCGA (MSI-H, 22%; EBV, 9%). Within subtypes, the prevalence of molecular characteristics (Table) was consistent with TCGA: TMB ≥175 mut/exome was highest in MSI-H (100%/100% in Caucasian/Asian), CPS ≥1 in MSI-H and EBV (91.7%/66.7% and 93.8%/90.9), TP53 mutations in CIN (64.8%/61.8%), and CDH1 mutations in GS (8.9%/14.3%). Focal amplifications in EGFR and ERBB2 were enriched in CIN (17.6%/9.2% and 24.0%/14.5%). dMMR mutational signature was ubiquitous in MSI-H pts.
Conclusions
In this exploratory WES analysis of KEYNOTE-059 and KEYNOTE-061 in pts with advanced GC, no major molecular differences between Caucasian and Asian populations were observed. MSI-H and EBV subtypes in late-stage disease demonstrated lower prevalence than TCGA. Table: 1416P
| GS White | GS Asian | EBV White | EBV Asian | CIN White | CIN Asian | MSI-H White | MSI-H Asian | ||
| N | 90 | 49 | 16 | 11 | 125 | 76 | 12 | 6 | |
| Molecular scores | TMB ≥175 mut/exome, % | 8.9 | 6.1 | 6.3 | 18.2 | 19.2 | 10.5 | 100 | 100 |
| CPS ≥1, % | 66.7 | 53.1 | 93.8 | 90.9 | 76.0 | 50.0 | 91.7 | 66.7 | |
| GC-specific genes with frequent mutations | TP53, % | 32.2 | 36.7 | 31.3 | 9.1 | 64.8 | 61.8 | 33.3 | 16.7 |
| KRAS, % | 5.6 | 2.0 | 12.5 | 18.2 | 1.6 | 1.3 | 25.0 | 33.3 | |
| RHOA, % | 7.8 | 6.1 | 6.3 | 0 | 4.0 | 7.9 | 16.7 | 0 | |
| CDH1, % | 8.9 | 14.3 | 12.5 | 0 | 2.4 | 9.2 | 8.3 | 0 | |
| ARID1A, % | 8.9 | 12.2 | 18.8 | 45.5 | 8.8 | 5.3 | 58.3 | 50.0 | |
| PIK3CA, % | 5.6 | 10.2 | 25.0 | 27.3 | 4.0 | 5.3 | 8.3 | 16.7 | |
| GC-specific genes with frequent amplifications | EGFR, % | 3.3 | 4.1 | 6.3 | 0 | 17.6 | 9.2 | 8.3 | 0 |
| ERBB2, % | 1.1 | 6.1 | 6.3 | 0 | 24.0 | 14.5 | 0 | 0 | |
| CD274, % | 0 | 0 | 6.3 | 0 | 3.2 | 2.6 | 8.3 | 0 | |
| CCNE1, % | 7.8 | 12.2 | 12.5 | 18.2 | 17.6 | 21.1 | 0 | 0 | |
| CCND1, % | 1.1 | 0 | 0 | 0 | 5.6 | 5.3 | 8.3 | 0 |
Clinical trial identification
NCT02335411 (KEYNOTE-059) and NCT02370498 (KEYNOTE-061).
Editorial acknowledgement
Medical writing and/or editorial assistance was provided by Holly Cappelli, PhD, CMPP, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA).
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure
Y.Y. Janjigian: Financial Interests, Personal, Advisory Role, Advisory/consultancy: Bristol Myers Squibb, Merck Serono, RGENIX, Eli Lilly, Daiichi Sankyo, Pfizer, Bayer, Imugene, Merck, Zymeworks, Seattle Genetics, Basilea Pharmaceutica, AstraZeneca; Financial Interests, Personal, Stocks/Shares: RGENIX; Financial Interests, Institutional, Research Grant: NCI, Department of Defense, Cycle for Survival, Fred’s Team, RGENIX, Bayer, Genentech/Roche, Bristol-Myers Squibb, Eli Lilly, Merck. M. Cecchini: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Agios Pharmaceuticals, Eisai Inc; Financial Interests, Personal, Stocks/Shares: Parthenon Therapeutics; Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Genentech/Roche. K. Shitara: Financial Interests, Personal, Other, Honoraria: Novartis, AbbVie, Yakult; Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Astellas Pharma, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Taiho, MSD, Novartis , AbbVie ,Glaxo Smith Kline, Daiichi Sankyo. Amgen, Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Lilly, Ono Pharmaceutical, Dainippon Sumitomo Pharma, MSD, Daiichi Sankyo, Taiho Pharmaceutical, ChugaiPharm, Astellas Pharma, Medi Science, Eisai. P.C. Enzinger: Financial Interests, Personal, Other, Honoraria: ALX Oncology, Arcus Bioscience, Astellas, Astra-Zeneca, Blueprint Medicines, BMS, Celgene, Daiichi Sankyo, Five Prime, Ideaya, Istari, Legend, Lilly, Loxo, Merck, Ono, Taiho, Takeda, Turning Point Therapeutics, Xencor, Zymeworks; Financial Interests, Personal, Advisory Role, Advisory/Consultancy: ALX Oncology, Arcus Bioscience, Astellas, Astra-Zeneca, Blueprint Medicines, BMS, Celgene, Daiichi Sankyo, Five Prime, Ideaya, Istari, Legend, Lilly, Loxo, Merck, Ono, Taiho, Takeda, Turning Point Therapeutics, Xencor, Zymeworks. Z.A. Wainberg: Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Array; Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Amgen, AstraZeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Array; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Roche/Genentech, Array/Pfizer. D.V. Catenacci: Financial Interests, Personal, Other, Honoraria: Genentech/Roche, Seattle Genetics, Amgen, Eli Lilly, Five Prime, Merck, BMS, Ono, Taiho, Astellas, Gritstone, Pieris, Daiichi Sankyo, Zymeworks, QED, Basilea, Arcus, Foundation Medicine, Tempus, Guardant Health, Archer, Natera; Financial Interests, Personal, Advisory Board, Advisory/Consultancy: Genentech/Roche, Seattle Genetics, Amgen, Eli Lilly, Five Prime, Merck, BMS, Ono, Taiho, Astellas, Gritstone, Pieris, Daiichi Sankyo, Zymeworks, QED, Basilea, Arcus, Foundation Medicine, Tempus, Guardant Health, Archer, Natera; Financial Interests, Personal, Speaker’s Bureau, Speaker Bureau/Expert Testimony: Genentech/Roche, Eli Lilly, Merck, Daiichii, AstraZeneca, Tempus, Guardant Health. I. Chau: Financial Interests, Personal, Advisory Role, Advisory/consultancy: Eli-Lilly, Bristol Meyers Squibb, MSD, Bayer, Roche, Merck-Serono, Five Prime Therapeutics, Astra-Zeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astella; Financial Interests, Personal, Research Grant: Eli-Lilly, Janssen-Cilag. T. Satoh: Financial Interests, Personal, Other, Honoraria: Daiichi Sankyo, Ono pharmaceutical, BrystolMyers, Elli-Lilly, Chugai Pharmaceutical; Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Takara-bio; Financial Interests, Personal, Research Grant: Yakult-Honsha, Chugai Pharmaceutical, Ono Pharmaceutical; Financial Interests, Personal, Research Grant: Daiichi Sankyo, Ono pharmaceutical, Brystol Myers, Elli-Lilly, Chugai Pharmaceutical, Parexell, MSD, Yakult-Honsha, Taiho. J. Lee: Financial Interests, Personal, Advisory Role, Advisory/consultancy: Mirati, Seattle Genetics, Oncologie, AstraZeneca. A. Loboda: Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.; Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Other: Pending patents: WO 2020/167619: Angiogenesis and mMDSC gene expression based biomarker of tumor response to PD-1 antagonists. J. Kobie: Financial Interests, Personal, Stocks/Shares: Merck; Financial Interests, Personal, Full or part-time Employment: Merck. Y. Li: Financial Interests, Personal, Full or part-time Employment: Merck & Co. C. Shih: Financial Interests, Personal, Stocks/Shares: Merck & Co.; Financial Interests, Personal, Full or part-time Employment: Merck & Co. R. Cristescu: Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.; Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Other: Pending patent: Patent WO 2020/167619. Z.A. Cao: Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Bristol Myers Squibb; Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.