Adjuvant nivolumab vs placebo in resected esophageal or gastroesophageal junction cancer following neoadjuvant chemoradiotherapy: First report of comprehensive biomarker analyses from CheckMate 577

Adjuvant nivolumab demonstrated statistically significant and clinically meaningful improvement in disease-free survival (DFS) vs placebo and an acceptable safety profile in patients with resected esophageal or gastroesophageal junction cancer (EC/GEJC) who received neoadjuvant chemoradiotherapy (CRT) in CheckMate 577. We present new exploratory biomarker analyses from this study.

Whole exome sequencing (WES) of baseline post-CRT tumor tissue and matching blood was performed to assess microsatellite instability (MSI), tumor mutational burden (TMB), and select gene mutations. TMB-high (TMB-H) was defined as ≥ 199 mutations/exome. RNA sequencing of baseline post-CRT tumor tissue was performed to assess gene expression signatures (GES), including 4-gene inflammatory, 44-gene proliferation, 3-gene M2 macrophage, 5-gene endothelial, and 15-gene fibroblast signatures. GES subgroups were defined by signature score tertiles.

794 patients were randomized to nivolumab or placebo, and the DFS unstratified hazard ratio (HR) for nivolumab vs placebo was 0.68 (95% confidence interval [CI], 0.56–0.83). 374 patients were evaluable for WES (nivolumab 47%, placebo 47%), and the DFS unstratified HR was 0.81 (95% CI, 0.60–1.08). Of these, 5 patients were MSI-high (MSI-H), and 13 patients were TMB-H. All MSI-H patients had adenocarcinoma and were also TMB-H. DFS benefit with nivolumab vs placebo was observed regardless of mutational status of select genes, including PIK3CA, NOTCH1, CDKN2A, and ARID1A. 376 patients were evaluable for GES (nivolumab 46%, placebo 50%), and the DFS unstratified HR was 0.84 (95% CI, 0.63–1.11). GES subgroups were categorized based on high (n = 126; 34%), medium (n = 125; 33%) or low (n = 125; 33%) tertiles. Improved DFS benefit with nivolumab vs placebo was observed in multiple GES subgroups (unstratified HR [95% CI]), including those with higher expression of inflammatory (high 0.75 [0.44–1.28]; medium 0.74 [0.46–1.21]; low 1.04 [0.65–1.68]) and proliferation (high 0.66 [0.41–1.09]; medium 0.71 [0.44–1.15]; low 1.27 [0.75–2.15]) GES and lower expression of M2 macrophage (high 1.34 [0.76–2.35]; medium 0.70 [0.44–1.13]; low 0.67 [0.40–1.10]), endothelial (high 1.16 [0.68–1.99]; medium 1.07 [0.66–1.74]; low 0.46 [0.28–0.76]), and fibroblast (high 1.07 [0.64–1.77]; medium 1.10 [0.67–1.82]; low 0.51 [0.31–0.85]) GES. First results analyzing the dynamics of tumor programmed death ligand 1 expression pre-/post-CRT and its association with efficacy will be presented.

These biomarker results further support the benefit of adjuvant nivolumab vs placebo and indicate improved DFS benefit in multiple subgroups. The clinical utility of these biomarkers should be validated in future trials.

NCT02743494.

Christiane Dresch, Parexel International.

Bristol Myers Squibb.

Bristol Myers Squibb.

R. Kelly: Honoraria (self): Bristol Myers Squibb; Advisory / Consultancy: Bristol Myers Squibb; Speaker Bureau / Expert testimony: Bristol Myers Squibb; Research grant / Funding (institution): Bristol Myers Squibb. M. Moehler: Honoraria (self): Falk, Nordic, Amgen, mci, Lilly, MSD, Taiho, Merck, Pfizer, FifePrime, BMS, ESMO, Novartis, Beigene ; Advisory / Consultancy: Lilly, BMS, MSD, Amgen, Merck, Pfizer, Beigene, Taiho, Nordic, Servier; Leadership role: Head GI Oncology, Mainz university Center; Research grant / Funding (institution): Merck, Amgen, BMS, MSD, AIO, EORTC, Taiho DFG, BMBF, Horizon Europe; Travel / Accommodation / Expenses: BMS, MSD, Amgen, Merck, Nordic, Servier. J. Ajani: Honoraria (self): BeiGene, Novartis, AZ, Astellas, BMS, Zymeworks, Servier, Gilead, Merck, Amgen, novartis, ; Research grant / Funding (institution): BMS, LaNova, Leap, Merck, Amgen, Roche, Zymeworks, Taiho, Prolinx, Beigene, Leap. J. Yao: Shareholder / Stockholder / Stock options: Bristol-Myers Squibb; Full / Part-time employment: Bristol-Myers Squibb. J. Kuzdzal: Honoraria (self): Bristol Myers Squibb; Research grant / Funding (self): Bristol Myers Squibb. E. Van Cutsem: Advisory / Consultancy: Array BioPharma, Astellas Pharma, Astrazeneca, Bayer, Biocartis, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, GSK, Halozyme, Incyte, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis,Pierre Fabre, Roche, SERVIER, Sirtex Medical, Taiho Pharmaceutical; Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier . G. Piessen: Advisory / Consultancy: BMS, Astellas, Nestlé; Travel / Accommodation / Expenses: medtronic. G. Mendez: Honoraria (self): Merck, MSD, BMS, Roche, Amgen, Servier, Biotoscana Lab, Eli Lilly, Pfizer; Advisory / Consultancy: Merck, BMS, MSD, Pfizer; Speaker Bureau / Expert testimony: Merck, MSD, BMS, Roche, Amgen, Servier, Biotoscana Lab, Eli Lilly, Pfizer; Travel / Accommodation / Expenses: Servier, Pfizer, Amgen, Merck. J. Feliciano: Advisory / Consultancy: Bristol Myers Squibb, AstraZenica, Merck, Pfizer, Eli Lilly, Genentech; Research grant / Funding (institution): Bristol Myers Squibb, AstraZenica, Merck, Genentech. S. Motoyama: Advisory / Consultancy: Chugai Pharmaceutical; Speaker Bureau / Expert testimony: Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Otsuka Pharmaceutical, Otsuka Pharmaceutical Factory, Kaken Pharmaceutical; Research grant / Funding (institution): Otsuka Pharmaceutical, Otsuka Pharmaceutical Factory, Taiho, Kaken Pharmaceutical and Shionogi. A. Lièvre: Honoraria (self): BMS; Honoraria (Institution): Amgen, Bayer, Bristol Myers Squibb (Mexico), Incyte, Ipsen, LEO Pharma, Mylan, Novartis, Pierre Fabre, Roche, SERVIER, Viatris, Advanced Accelerator Applications; Advisory / Consultancy: BMS, Astellas, Incyte, Pierre Fabre, SERVIER, Advanced Accelerator Applications, Amgen, Bayer, Ipsen, Merck, Novartis, Sandoz; Research grant / Funding (self): Bayer, Lilly, IntegraGen, Novartis; Research grant / Funding (institution): Lilly; Travel / Accommodation / Expenses: MSD Oncology, Boehringer Ingelheim, Ipsen, Mylan, Roche, SERVIER, Bayer, Merck, Novartis, Sandoz, Incyte, Pfizer. H. Uronis: Advisory / Consultancy: Bristol Myers Squibb, Astra Zeneca; Research grant / Funding (institution): Bristol Myers Squibb; Adaptimmune, Merck; Arcus, Leap Therapeutics; Travel / Accommodation / Expenses: Bristol Myers Squib. E. Elimova: Honoraria (Institution): BMS, Zymeworks, Beigene; Advisory / Consultancy: Adaptimmune, BMS; Research grant / Funding (institution): BMS, Zymeworks, Astra zeneca, Amgen; Spouse / Financial dependant: Merck. K. Geboes: Advisory / Consultancy: SERVIER, MSD, Ipsen, Bristol Myers Squibb; Speaker Bureau / Expert testimony: MSD; Research grant / Funding (self): Bayer, Merck KGaA. Y. Yang: Shareholder / Stockholder / Stock options: Bristol Myers Squibb; Full / Part-time employment: Bristol Myers Squibb. J. Zhang: Shareholder / Stockholder / Stock options: Bristol Myers Squibb; Full / Part-time employment: Bristol Myers Squibb. R. Novosiadly: Shareholder / Stockholder / Stock options: Bristol Myers Squibb & Eli Lilly. J. Cleary: Honoraria (self): Syros Pharmaceuticals, Blueprint Medicines, Incyte; Research grant / Funding (self): Merck, Apexigen, Esperas Pharma, Bayer, and Tesaro, Astrazeneca, Arcus Biosciences; Research grant / Funding (institution): MErus, Roche, BMS. M. Lei: Travel / Accommodation / Expenses: Bristol Myers Squibb; Shareholder / Stockholder / Stock options: Bristol Myers Squibb; Full / Part-time employment: Bristol Myers Squibb. All other authors have declared no conflicts of interest.