Standard 1L chemo options for advanced or metastatic HER2-negative GC/GEJC result in poor overall survival (OS; median < 1 year). CheckMate 649 is the largest randomized, global phase III study of programmed death (PD)-1 inhibitor-based therapies in 1L GC/GEJC/EAC. We report OS at a pre-specified interim analysis and progression-free survival (PFS) at final analysis from the NIVO + chemo vs chemo arms in patients (pts) whose tumors expressed PD-ligand 1 (L1) combined positive score (CPS) ≥ 5.
Adults with previously untreated, unresectable advanced, or metastatic GC/GEJC/EAC were enrolled, regardless of PD-L1 expression. Pts with known HER2-positive status were excluded. Pts were randomized to receive NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review, in pts whose tumors expressed PD-L1 CPS ≥ 5.
1581 pts were concurrently randomized in nivo+chemo and chemo arms, including 955 pts (60%) with PD-L1 CPS ≥ 5. With a minimum follow-up of 12 months (mo), NIVO + chemo showed a statistically significant improvement in OS and PFS vs chemo in pts whose tumors expressed PD-L1 CPS ≥ 5 (OS, HR 0.71 [98.4% CI 0.59–0.86;
Efficacy NIVO + chemo Chemo PD-L1 CPS ≥ 5 N = 473 N = 482 14.4 (13.1–16.2) 11.1 (10.0-12.1) HR (98.4% CI; 0.71 (0.59-0.86; 7.7 (7.0-9.2) 6.1 (5.6-6.9) HR (98.0% CI; 0.68 (0.56-0.81; 14.0 (12.6-15.0) 11.3 (10.6-12.3) HR (99.3% CI; 0.77 (0.64–0.92; 13.8 (12.6–14.6) 11.6 (10.9-12.5) HR (99.3% CI; 0.80 (0.68-0.94; Any grade 444 (95) 407 (88) Grade 3-4 277 (59) 203 (44) Leading to discontinuation 178 (38) 115 (25) Deaths 8 (2) 4 (<1)
NIVO is the first PD-1 inhibitor to demonstrate superior OS and PFS in combination with chemo vs chemo alone in previously untreated pts with advanced GC/GEJC/EAC, with a manageable safety profile. NIVO + chemo represents a potential new standard 1L treatment option for these pts.
NCT02872116.
Writing and editorial assistance was provided by Tanmayi Mankame, PhD, of Parexel International, funded by Bristol-Myers Squibb Company.
Bristol-Myers Squibb Company.
Bristol-Myers Squibb Company.
M. Moehler: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Adboards: Bristol Myers Squibb. K. Shitara: Advisory/Consultancy, Research grant/Funding (institution): Astellas Pharma; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly and Company; Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Takeda Pharmaceuticals; Advisory/Consultancy: Pfizer Inc; Advisory/Consultancy: Ono Pharmaceutical; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: AbbVie Inc; Honoraria (self): Yakult; Research grant/Funding (institution): Dainippon Sumitomo Pharma; Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): Chugai Pharma; Advisory/Consultancy, Research grant/Funding (institution): Merck Pharmaceutical; Research grant/Funding (institution): Medi Science; Advisory/Consultancy: GlaxoSmithKline. M. Garrido: Advisory/Consultancy, Research grant/Funding (institution): Bristol Myers Squibb; Advisory/Consultancy: MSD; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Roche. K. Yamaguchi: Advisory/Consultancy, Research grant/Funding (institution): Taiho; Advisory/Consultancy: Chugai; Research grant/Funding (institution): Sanofi; Advisory/Consultancy, Research grant/Funding (institution): Daiichi-Sankyo; Advisory/Consultancy: Lilly; Advisory/Consultancy, Research grant/Funding (institution): Ono; Advisory/Consultancy, Research grant/Funding (institution): Yakult Honsha; Advisory/Consultancy: Takeda; Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Merck Serono. M. Schenker: Research grant/Funding (self), fee for clinical research activity: Bristol Myers Squibb; Research grant/Funding (self), fee for clinical research activity: Roche; Research grant/Funding (self), fee for clinical research activity: Pfizer; Research grant/Funding (self), fee for clinical research activity: MSD; Research grant/Funding (self), fee for clinical research activity: Eli Lilly; Research grant/Funding (self), fee for clinical research activity: Novartis; Research grant/Funding (self), fee for clinical research activity: Astellas; Research grant/Funding (self), fee for clinical research activity: GSK; Research grant/Funding (self), fee for clinical research activity: AstraZeneca; Research grant/Funding (self), fee for clinical research activity: Merck Serono; Research grant/Funding (self), fee for clinical research activity: Regeneron. M. Tehfe: Advisory/Consultancy: Bristol Myers Squibb. V. Poulart: Full/Part-time employment: Bristol Myers Squibb. D. Cullen: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol Myers Squibb. M. Lei: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol Myers Squibb. K. Kondo: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol Myers Squibb. M. Li: Full/Part-time employment: Bristol Myers Squibb. J.A. Ajani: Advisory/Consultancy, Research grant/Funding (institution): Bristol Myers Squibb. Y.Y. Janjigian: Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Speaker Bureau/Expert testimony: ASCO; Advisory/Consultancy: Michael J. Hennessy Associates; Advisory/Consultancy: Paradigm Medical Communications, LLC; Advisory/Consultancy: Zymeworks Inc.; Advisory/Consultancy: Jounce Therapeutics; Advisory/Consultancy: Seattle Genetics; Shareholder/Stockholder/Stock options: Rgenix; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Daiichi Sankyo; Research grant/Funding (institution): Ono Pharma; Advisory/Consultancy, Research grant/Funding (institution): Merck & Co Inc.; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Imugene. All other authors have declared no conflicts of interest.
Nivolumab has a survival benefit for heavily pretreated patients with advanced or recurrent G/GEJ cancer. ATTRACTION-4 is a randomized, multicenter, phase 2/3 study to evaluate the efficacy and safety of nivolumab plus chemotherapy vs. chemotherapy as first-line treatment in patients with HER2-negative, advanced or recurrent G/GEJ cancer. Here we report the results of the double-blind phase III part.
Patients were randomized 1:1 to receive nivolumab plus chemotherapy (N+C, S-1 plus oxaliplatin or capecitabine plus oxaliplatin) or placebo plus chemotherapy (C). Nivolumab or placebo was intravenously administered every 3 weeks until disease progression or unacceptable toxicity. Tumor assessment was performed every 6 weeks through week 54, then repeated every 12 weeks. The co-primary endpoints were centrally-assessed PFS and OS, and it was prespecified that the primary objective is deemed to be achieved if at least one of the null hypotheses of the primary endpoints is rejected.
A total of 724 Asian patients were randomized to N+C (n=362) or C (n=362) between Mar 7, 2017, and May 10, 2018. At the interim analysis primary for PFS with the median follow-up period of 11.6 mo, PFS was significantly improved in N+C vs. C (HR 0.68; 98.51% CI 0.51-0.90; p=0.0007; median PFS, 10.5 vs. 8.3 mo), meeting the primary endpoint. At the final analysis primary for OS with the median follow-up period of 26.6 mo, there was no statistically significant difference (HR 0.90; 95% CI 0.75-1.08; p=0.257; median OS, 17.5 vs. 17.2 mo), while PFS was continuously longer in N+C than in C. ORR was higher in N+C than in C (57.5 vs. 47.8%; p=0.0088). The incidences of grade 3 to 5 treatment-related adverse events were 57.9% in N+C and 49.2% in C.
PFS was significantly improved in N+C vs. C, achieving the primary objective. The combination of nivolumab and chemotherapy, which demonstrated clinically meaningful efficacy in PFS and ORR with a manageable safety profile but not statistically significant improvement in OS, can be considered a new first-line treatment option in advanced or recurrent G/GEJ cancer.
NCT02746796; Study start date: March 2016.
Ono Pharmaceutical Co., Ltd.
Ono Pharmaceutical Co., Ltd. Bristol-Myers Squibb.
N. Boku: Honoraria (self): Ono; Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self), Research grant/Funding (institution): Taiho. M.H. Ryu: Honoraria (self), Advisory/Consultancy: Ono; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy: Taiho; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Daehwa. D-Y. Oh: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): Novartis; Advisory/Consultancy: Genentech; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Bayer; Advisory/Consultancy: Taiho; Advisory/Consultancy: Aslan; Advisory/Consultancy: Halozyme; Advisory/Consultancy: Zymeworks; Advisory/Consultancy: Celgene; Research grant/Funding (self): Array; Research grant/Funding (self): Eli Lilly; Advisory/Consultancy: Roche. H.C. Chung: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck-Serono; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Honoraria (self): Foundation Medicine; Advisory/Consultancy, Research grant/Funding (institution): Taiho; Advisory/Consultancy: Celltrion; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy: Gloria; Advisory/Consultancy, Research grant/Funding (institution): Beigene; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy: Zymework; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Ono pharmaceutical. K-W. Lee: Honoraria (self): BMS; Honoraria (self): Eli Lilly; Honoraria (self): Genexine; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Ono pharmaceutical; Research grant/Funding (institution): Green Cross Corp.; Research grant/Funding (institution): Aslan Pharmaceuticals; Research grant/Funding (institution): AstraZeneca/MedImmune; Research grant/Funding (institution): Five Prime Therapeutics; Research grant/Funding (institution): LSK BioPharma; Research grant/Funding (institution): Merck KGaA; Research grant/Funding (institution): Array BioPharma; Research grant/Funding (institution): Pharmacyclics; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): ALX Oncology; Research grant/Funding (institution): Zymeworks; Research grant/Funding (institution): BeiGene; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Taiho Pharmaceutical. K. Shitara: Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self): Yakult; Advisory/Consultancy, Research grant/Funding (institution): Astellas; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy: BMS; Advisory/Consultancy: Takeda; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Ono Pharmaceutical; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy, Research grant/Funding (institution): Taiho; Advisory/Consultancy: GSK; Research grant/Funding (institution): Sumitomo Dainippon Pharma; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Chugai; Research grant/Funding (institution): Medi Science. S. Sakuramoto: Research grant/Funding (institution): Ono pharmaceutical; Research grant/Funding (institution): Taiho; Research grant/Funding (institution): Kaken pharmaceutical; Research grant/Funding (institution): Chugai. K. Yamaguchi: Honoraria (institution), Speaker Bureau/Expert testimony: Daiichi Sankyo; Honoraria (institution), Speaker Bureau/Expert testimony: Taiho; Honoraria (institution), Speaker Bureau/Expert testimony: Chugai; Speaker Bureau/Expert testimony: BMS; Honoraria (institution), Speaker Bureau/Expert testimony: Ono Pharmaceutical; Speaker Bureau/Expert testimony: Takeda; Honoraria (institution), Speaker Bureau/Expert testimony: Eli Lilly; Honoraria (institution), Speaker Bureau/Expert testimony: Sanofi; Honoraria (institution): MSD oncology; Honoraria (institution): Sumitomo Dainippon Pharma; Honoraria (institution): Gilead Sciences; Honoraria (institution): Boehringer Ingelheim; Honoraria (institution): Eisai; Honoraria (institution): Yakult Honsya. K. Kato: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Ono Pharmaceutical; Advisory/Consultancy, Research grant/Funding (institution): Beigene; Advisory/Consultancy, Research grant/Funding (institution): MSD; Speaker Bureau/Expert testimony: Taiho; Speaker Bureau/Expert testimony: Eli Lilly; Speaker Bureau/Expert testimony, Research grant/Funding (institution): BMS; Research grant/Funding (institution): Shionogi; Research grant/Funding (institution): Merck Bio; Research grant/Funding (institution): Chugai. S. Kadowaki: Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self), Research grant/Funding (institution): Taiho; Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self): Yakult Honsya; Honoraria (self): Chugai; Honoraria (self): Bayer; Honoraria (self): Merck; Research grant/Funding (institution): MSD. J-S. Chen: Honoraria (self), Advisory/Consultancy: Ono Pharmaceutical; Honoraria (self): TTY Biopharma; Honoraria (self): MSD oncology; Honoraria (self): MedImmune; Honoraria (self): Merck KGaA; Honoraria (self): Roche; Honoraria (self): AstraZeneca. L-Y. Bai: Honoraria (self): AbbVie; Honoraria (self): Bayer; Honoraria (self): BMS; Honoraria (self): Johnson & Johnson; Honoraria (self): GSK; Honoraria (self): Eli Lilly; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Pfizer; Honoraria (self): PharmaEngine; Honoraria (self): Roche; Honoraria (self): SynCore Biotechnology; Honoraria (self): Takeda; Honoraria (self): TTY Biopharm. L-T. Chen: Honoraria (self): Ono Pharmaceutical; Honoraria (self): Eli Lilly; Honoraria (self): MSD; Honoraria (self), Advisory/Consultancy: PharmaEngine; Honoraria (self), Research grant/Funding (institution): TTY Biopharm; Honoraria (self), Research grant/Funding (institution): SyncorePharm; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Ipsen; Leadership role: National Institute of Cancer Research, Taiwan; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): Polaris; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): BMS; Licensing/Royalties: ENO-1 mAb from HuniLife; Full/Part-time employment: National Health Research Institutes, Taiwan; Officer/Board of Directors: SinoPharm Taiwan, Ltd. Y-K. Kang: Advisory/Consultancy: ALX Oncology; Advisory/Consultancy: BMS; Advisory/Consultancy: Amgen; Advisory/Consultancy: Daehwa; Advisory/Consultancy: Macrogenics; Advisory/Consultancy: Novartis; Advisory/Consultancy: Surface Oncology; Advisory/Consultancy: Zymeworks. All other authors have declared no conflicts of interest.
KEYNOTE-590 (NCT03189719) is a randomized, international, double-blind study of 1L pembrolizumab (pembro) + chemotherapy (chemo) vs chemo alone in patients (pts) with locally advanced/unresectable or metastatic adenocarcinoma or esophageal squamous cell carcinoma (ESCC) or Siewert type 1 esophagogastric junction adenocarcinoma (EGJ).
Eligible pts were randomized 1:1 to pembro 200 mg or placebo Q3W for up to 2 yr + chemo (cisplatin 80 mg/m2 Q3W [d1; 6 doses] + 5-FU 800 mg/m2 on d1-5 Q3W). Randomization was stratified by Asia vs Rest of World, adenocarcinoma vs ESCC, and ECOG PS 0 vs 1. Treatment continued until progression, unacceptable toxicity, or withdrawal, or 2 yr. No crossover was permitted. Primary end points were OS in pts with ESCC PD-L1 combined positive score (CPS) ≥10 tumors, and OS and PFS (RECIST v1.1 ; by investigator) in ESCC, PD-L1 CPS ≥10, and all pts. The secondary end point was ORR (RECIST v1.1; by investigator) in all pts. Data cutoff for interim OS/final PFS analysis was July 2, 2020.
At data cutoff, 749 pts (83% male, 73% ESCC) were randomized (373 pembro + chemo; 376 chemo). Median follow-up was 10.8 mo. Pembro + chemo vs chemo was superior for OS in pts with ESCC CPS ≥10 (median 13.9 vs 8.8 mo; HR 0.57; 95% CI, 0.43-0.75;
Pembro + chemo provided superior OS, PFS, and ORR vs chemo, with a manageable safety profile in pts with untreated, advanced esophageal and EGJ cancer. These data demonstrate that 1L pembro + chemo is a new standard of care in this pt population.
NCT03189719.
Luana Atherly-Henderson of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
K. Kato: Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy, Research grant/Funding (institution): Ono; Advisory/Consultancy, Research grant/Funding (institution): Beigene; Speaker Bureau/Expert testimony: Taiho; Speaker Bureau/Expert testimony: Eli Lilly; Research grant/Funding (institution): Shionogi; Research grant/Funding (institution): Merck Bio; Research grant/Funding (institution): Chugai. J-M. Sun: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Ono; Research grant/Funding (institution): MSD. M.A. Shah: Advisory/Consultancy: Daiichi; Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme Corp.; Research grant/Funding (institution): Boston Biomedical; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Oncolys. P.C. Enzinger: Honoraria (self), Advisory/Consultancy: Astellas; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self), Advisory/Consultancy: Daiichi-Sankyo; Honoraria (self), Advisory/Consultancy: Five-Prime; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Loxo; Honoraria (self), Advisory/Consultancy: Merck Sharp & Dohme Corp.; Honoraria (self), Advisory/Consultancy: Taiho; Honoraria (self), Advisory/Consultancy: Takeda; Honoraria (self), Advisory/Consultancy: Zymeworks. A. Adenis: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol Myers Squibb; Honoraria (self), Research grant/Funding (institution): Sanofi; Advisory/Consultancy: Servier; Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Sharp & Dohme Corp.; Research grant/Funding (institution): Pfizer. T. Doi: Honoraria (self), Research grant/Funding (institution): Bristol Myers Squibb; Honoraria (self): Ono Pharmaceutical; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Abbvie; Honoraria (self): Astellas Pharma; Honoraria (self): Oncolys BioPharma; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Taiho Pharmaceutical; Honoraria (self): Otsuka; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Sumitomo Dainippon; Advisory/Consultancy: Takeda; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Advisory/Consultancy: Rakuten Medical; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Kyowa Hakko Kirin; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): IQVIA. T. Kojima: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self): Oncolys BioPharma; Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy, Research grant/Funding (institution): Ono Pharmaceutical; Advisory/Consultancy: Merck; Research grant/Funding (institution): Astellas Amgen BioPharma; Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): Shionogi. J-P. Metges: Honoraria (self): MSD; Honoraria (self): Bayer; Honoraria (self): Bristol Myers Squibb. S-B. Kim: Advisory/Consultancy, Research grant/Funding (self): Novartis; Research grant/Funding (self): Sanofi-Aventis; Research grant/Funding (self): DongKook Pharma Co.; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Lilly; Advisory/Consultancy: Enzychem; Advisory/Consultancy: Dae Hwa Pharmaceutical Co. Ltd; Advisory/Consultancy: ISU Abxis; Advisory/Consultancy: Daiichi-Sankyo. B.C. Chul Cho: Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Roche; Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Ono; Advisory/Consultancy, Research grant/Funding (institution): Yuhan; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Advisory/Consultancy: Medpacto; Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines; Advisory/Consultancy, Shareholder/Stockholder/Stock options: KANAPH Therapeutic Inc.; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Brigebio Therapeutics; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Cyrus Therapeutics; Advisory/Consultancy: Guardant Health; Shareholder/Stockholder/Stock options: TheraCanVac Inc; Shareholder/Stockholder/Stock options, Officer/Board of Directors: Gencurix Inc; Research grant/Funding (institution), Shareholder/Stockholder/Stock options, Officer/Board of Directors: Interpark Bio Convergence Corp.; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): MOGAM Institute; Research grant/Funding (institution): Dong-A ST; Research grant/Funding (institution), Licensing/Royalties: Champions Oncology; Research grant/Funding (institution): Dizal Pharma; Advisory/Consultancy, Research grant/Funding (institution): MSD; Research grant/Funding (institution): Abbvie; Research grant/Funding (institution): Medpacto; Research grant/Funding (institution): GIInnovation; Leadership role, founder: DAAN Biotherapeutics; Advisory/Consultancy: Takeda. S-H. Li: Research grant/Funding (institution): MSD. M.A. Maqueda: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Servier; Honoraria (self), Advisory/Consultancy: Bristol Myers Squibb; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Lilly; Honoraria (self), Travel/Accommodation/Expenses: Roche; Honoraria (self), Travel/Accommodation/Expenses: Amgen. E. Goekkurt: Honoraria (self): MSD; Honoraria (self): Bristol Myers Squibb; Honoraria (self): Servier. Q. Liu: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. S. Shah: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. P. Bhagia: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. L. Shen: Advisory/Consultancy: Merck Sharp & Dohme Corp.; Advisory/Consultancy: Harbour; Research grant/Funding (self): Boehringer Ingelheim; Research grant/Funding (self): Beijing Xiantong Biomedical Technology; Research grant/Funding (self): Qilu Pharmaceutical; Research grant/Funding (self): Zaiding Pharmaceutical; Research grant/Funding (self): Jacobio Pharmaceuticals; Research grant/Funding (self): Beihai Kangcheng(Beijing)Medical Technology Co., Ltd. All other authors have declared no conflicts of interest.
The risk of recurrence after neoadjuvant CRT followed by surgery (trimodality therapy) remains high in EC/GEJC and there is no established adjuvant treatment. CheckMate 577 is the first global, randomized, double-blind, phase 3 study to report the efficacy and safety of a checkpoint inhibitor in the adjuvant setting after trimodality therapy for EC/GEJC.
Adults with resected (R0) stage II/III EC/GEJC who received neoadjuvant CRT and had residual pathologic disease were randomized 2:1 to nivolumab 240 mg or placebo Q2W for 16 weeks, followed by nivolumab 480 mg or placebo Q4W. Maximum treatment duration was 1 year. The primary endpoint was disease-free survival (DFS).
794 patients were randomized (nivolumab, 532; placebo, 262). Approximately 70% of patients had adenocarcinoma and almost 60% had a pathologic lymph node status ≥ypN1 in both groups. At a pre-specified interim analysis, adjuvant nivolumab showed a statistically significant improvement in DFS vs placebo (HR 0.69 [96.4% CI 0.56 -0.86]; P = 0.0003); median DFS was doubled (22.4 vs 11.0 mo, respectively; Table). The majority of treatment-related adverse events (TRAEs) were grade 1 or 2. The frequency of serious TRAEs and TRAEs leading to discontinuation were ≤ 9% with nivolumab and 3% with placebo (Table). Data including DFS rate and an analysis of DFS across pre-specified subgroups will be presented.
Efficacy Nivolumab Placebo Median DFS, mo (95% CI) HR (96.4% CI; Safety, n (%) Any-grade TRAEs Grade 3–4 Serious TRAEs Grade 3–4 TRAEs leading to discontinuation Grade 3–4
Adjuvant nivolumab is the first therapeutic to provide a statistically significant and clinically meaningful improvement in DFS vs placebo and a well-tolerated safety profile in patients with resected EC/GEJC, who have received neoadjuvant CRT. These results represent the first treatment advance in many years for these patients, potentially establishing adjuvant nivolumab as a new standard of care.
NCT02743494.
Writing and editorial assistance was provided by Patricia McChesney, PhD, CMPP, of Parexel International, funded by Bristol-Myers Squibb Company.
Bristol-Myers Squibb Company.
Bristol-Myers Squibb Company.
R.J. Kelly: Advisory/Consultancy, Research grant/Funding (institution), Advisory Board Member: Bristol Myers Squibb; Advisory/Consultancy, Advisory Board Member: Merck; Advisory/Consultancy, Advisory Board Member: Novartis ; Advisory/Consultancy, Research grant/Funding (institution), Advisory Board Member: Eli Lilly; Advisory/Consultancy, Advisory Board Member: Pieris Pharmaceuticals; Advisory/Consultancy, Advisory Board Member: Cardinal Health; Advisory/Consultancy, Advisory Board Member: Astellas; Advisory/Consultancy, Advisory Board Member: Takeda; Advisory/Consultancy, Advisory Board Member: Ono Pharmaceuticals; Advisory/Consultancy, Advisory Board Member: AstraZeneca. J.A. Ajani: Advisory/Consultancy, Research grant/Funding (institution): Bristol Myers Squibb. J. Kuzdzal: Research grant/Funding (institution): Bristol Myers Squibb; Research grant/Funding (institution): Roche. T. Zander: Advisory/Consultancy, advisory boards: Bristol Myers Squibb; Advisory/Consultancy, advisory boards: MSD; Advisory/Consultancy, advisory boards: Roche; Advisory/Consultancy, advisory boards: Lilly; Advisory/Consultancy, advisory boards: Novartis. E. Van Cutsem: Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Servier; Advisory/Consultancy, Research grant/Funding (institution): Bristol Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Celgene; Advisory/Consultancy: Merck Sharp & Dolme; Advisory/Consultancy, Research grant/Funding (institution): Merck KGaA; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Merck. G. Piessen: Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Amgen. J.L. Feliciano: Advisory/Consultancy, Research grant/Funding (institution), consulting fees: AstraZeneca; Advisory/Consultancy, consulting fees: Genentech; Advisory/Consultancy, Research grant/Funding (institution), consulting fees: Bristol Myers Squibb; Advisory/Consultancy, consulting fees: Merck; Advisory/Consultancy, consulting fees: Eli Lilly. A. Lièvre: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses, lectures, consulting, travel support: AAA; Honoraria (self), Advisory/Consultancy, lectures, consulting: Amgen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, lectures, consulting, travel support: Bayer; Honoraria (self), Travel/Accommodation/Expenses, lectures, travel support: Bristol Myers Squibb; Honoraria (self), lectures: Celgene; Honoraria (self), lectures: HalioDX; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses, lectures, consulting, travel support: Ipsen; Honoraria (self), Advisory/Consultancy, lectures, consulting: Lilly; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses, lectures, consulting, travel support: Merck; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses, lectures, consulting, travel support: Novartis; Honoraria (self), Advisory/Consultancy, lectures, consulting: Pierre Fabre; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses, lectures, consulting, travel support: Sandoz; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses, lectures, consulting, travel support: Servier; Travel/Accommodation/Expenses, equipment supply: Integragen; Advisory/Consultancy, Travel/Accommodation/Expenses, consulting, travel support: Incyte; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses, lectures, consulting, travel support: Roche; Travel/Accommodation/Expenses, travel support: Pfizer. H. Uronis: Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): Lycera; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Advaxis; Research grant/Funding (institution): Bristol Myers Squibb. E. Elimova: Advisory/Consultancy, Research grant/Funding (institution): Bristol Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Zymeworks; Spouse/Financial dependant: Merck Vaccines. C. Grootscholten: Research grant/Funding (institution): Bristol Myers Squibb. J. Zhang: Full/Part-time employment: Bristol Myers Squibb. L. Zhu: Full/Part-time employment: Bristol Myers Squibb. M. Lei: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol Myers Squibb. K. Kondo: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol Myers Squibb. J.M. Cleary: Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol Myers Squibb; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Esperas Pharma. M. Moehler: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Adboards: Bristol Myers Squibb. All other authors have declared no conflicts of interest.