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Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer

List of authors.
  • Ronan J. Kelly, M.B., B.Ch., M.B.A.,
  • Jaffer A. Ajani, M.D.,
  • Jaroslaw Kuzdzal, M.D., Ph.D.,
  • Thomas Zander, M.D.,
  • Eric Van Cutsem, M.D., Ph.D.,
  • Guillaume Piessen, M.D., Ph.D.,
  • Guillermo Mendez, M.D.,
  • Josephine Feliciano, M.D.,
  • Satoru Motoyama, M.D., Ph.D.,
  • Astrid Li豕vre, M.D., Ph.D.,
  • Hope Uronis, M.D.,
  • Elena Elimova, M.D.,
  • Cecile Grootscholten, M.D., Ph.D.,
  • Karen Geboes, M.D., Ph.D.,
  • Syed Zafar, M.D.,
  • Stephanie Snow, M.D.,
  • Andrew H. Ko, M.D.,
  • Kynan Feeney, M.D.,
  • Michael Schenker, M.D., Ph.D.,
  • Piotr Kocon, M.D., Ph.D.,
  • Jenny Zhang, M.D., Ph.D.,
  • Lili Zhu, Ph.D.,
  • Ming Lei, Ph.D.,
  • Prianka Singh, Pharm.D., M.P.H.,
  • Kaoru Kondo, M.Sc.,
  • James M. Cleary, M.D., Ph.D.,
  • and Markus Moehler, M.D., Ph.D.
  • for the CheckMate 577 Investigators*

Abstract

Background

No adjuvant treatment has been established for patients who remain at high risk for recurrence after neoadjuvant chemoradiotherapy and surgery for esophageal or gastroesophageal junction cancer.

Methods

Download a PDF of the Research Summary.

We conducted CheckMate 577, a global, randomized, double-blind, placebo-controlled phase 3 trial to evaluate a checkpoint inhibitor as adjuvant therapy in patients with esophageal or gastroesophageal junction cancer. Adults with resected (R0) stage II or III esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy and had residual pathological disease were randomly assigned in a 2:1 ratio to receive nivolumab (at a dose of 240 mg every 2 weeks for 16 weeks, followed by nivolumab at a dose of 480 mg every 4 weeks) or matching placebo. The maximum duration of the trial intervention period was 1 year. The primary end point was disease-free survival.

Results

The median follow-up was 24.4 months. Among the 532 patients who received nivolumab, the median disease-free survival was 22.4 months (95% confidence interval [CI], 16.6 to 34.0), as compared with 11.0 months (95% CI, 8.3 to 14.3) among the 262 patients who received placebo (hazard ratio for disease recurrence or death, 0.69; 96.4% CI, 0.56 to 0.86; P<0.001). Disease-free survival favored nivolumab across multiple prespecified subgroups. Grade 3 or 4 adverse events that were considered by the investigators to be related to the active drug or placebo occurred in 71 of 532 patients (13%) in the nivolumab group and 15 of 260 patients (6%) in the placebo group. The trial regimen was discontinued because of adverse events related to the active drug or placebo in 9% of the patients in the nivolumab group and 3% of those in the placebo group.

Conclusions

Among patients with resected esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy, disease-free survival was significantly longer among those who received nivolumab adjuvant therapy than among those who received placebo. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 577 ClinicalTrials.gov number, NCT02743494.)

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Nivolumab in Esophageal or Gastroesophageal Junction Cancer
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Funding and Disclosures

Supported by Bristol Myers Squibb and Ono Pharmaceutical.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Dr. Kelly reports receiving advisory board fees from Astellas Pharma, AstraZeneca, Daiichi Sankyo, Eisai, EMD Serono, Merck, Novartis, Ono Pharmaceutical, Pieris Pharmaceuticals, and Takeda Oncology, grant support, paid to Johns Hopkins University, and advisory board fees from Bristol Myers Squibb, lecture fees from Cardinal Health, and grant support, paid to the Baylor Scott and White Research Institute, and advisory board fees from Eli Lilly; Dr. Ajani, receiving advisory board fees from Amgen and AstraZeneca, grant support, paid to the University of Texas M.D. Anderson Cancer Center (MDACC), and consulting fees from Astellas Pharma and Merck, consulting fees from BeiGene, grant support, paid to his institution, and advisory board fees from Bristol Myers Squibb, grant support, paid to MDACC, and advisory board fees from Daiichi Sankyo, Genentech, Taiho Oncology, and Zymeworks, and grant support, paid to MDACC, from Delta-Fly Pharma, Gilead Sciences, and Leap Therapeutics; Dr. Kuzdzal, receiving fees for serving as a principal investigator from Bristol Myers Squibb; Dr. Zander, receiving grant support, paid to the University Hospital Cologne, from AstraZeneca and consulting fees from Bristol Myers Squibb, F. Hoffmann每La Roche, Lilly Deutschland, Merck, and Novartis; Dr. Van Cutsem, receiving advisory board fees from Array BioPharma, Astellas Pharma, AstraZeneca, Bayer Healthcare, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Eli Lilly, F. Hoffmann每La Roche, GlaxoSmithKline, Halozyme Therapeutics, Incyte, Ipsen Biopharmaceuticals, Merck, Novartis, Pierre Fabre Pharmaceuticals, Sirtex Medical, and Taiho Pharmaceutical; Dr. Piessen, receiving consulting fees from Amgen, Bristol Myers Squibb, Medtronic, Merck, Nestl谷 Healthcare Nutrition, Roche, and Stryker; Dr. Mendez, receiving consulting fees and travel support from Amgen, AstraZeneca, Eli Lilly, Merck, Roche, and Servier Pharmaceuticals; Dr. Feliciano, receiving advisory board fees from AstraZeneca, Eli Lilly, and Genentech and consulting fees from Merck; Dr. Motoyama, receiving advisory board fees and lecture fees from Bristol Myers Squibb, fees for serving as principal investigator, paid to his institution, from BeiGene, fees for serving as principal investigator, paid to his institution, and lecture fees from Chugai Pharmaceutical, grant support, paid to Akita University, and lecture fees from Kaken Pharmaceutical, Otsuka Pharmaceutical, and Otsuka Pharmaceutical Factory, advisory board fees from Merck Sharp and Dohme, grant support, paid to Akita University, fees for serving as principal investigator, paid to his institution, advisory board fees, and lecture fees from Ono Pharmaceutical, grant support, paid to Akita University, and fees for serving as principal investigator from Shionogi, and grant support, paid to Akita University, from Taiho Pharmaceutical and Takeda; Dr. Li豕vre, receiving consulting fees from Advanced Accelerator Applications, Amgen, F. Hoffmann每La Roche, Incyte, and Sandoz, grant support, paid to Centre Hospitalier Universitaire Rennes, consulting fees, and travel support from Bayer, meeting registration reimbursement from Boehringer Ingelheim and Merck Sharp and Dohme, consulting fees and travel support from Ipsen Biopharmaceuticals, grant support, paid to Francophone Federation of Digestive Cancer Research, from Lilly Deutschland, lecture fees from Mylan Pharmaceuticals and Sanofi Pasteur, consulting fees, meeting registration reimbursement, and travel support from Novartis, travel support from Pfizer, and meeting registration reimbursement and consulting fees from Pierre Fabre Pharmaceuticals; Dr. Uronis, receiving grant support, paid to Duke University, for serving as principal investigator from Bristol Myers Squibb, Merck, and Leap Therapeutics; Dr. Elimova, receiving advisory board fees from Bristol Myers Squibb and Zymeworks and fees, paid to her institution, for serving as principal investigator from Bristol Myers Squibb and Zymeworks and being the spouse of an employee of Merck; Dr. Geboes, receiving grant support, paid to Ghent University Hospital, and advisory board fees from Amgen, Bayer, Eli Lilly, Ipsen Biopharmaceuticals, Merck, and Servier Laboratories; Dr. Zafar, receiving advisory board fees from AstraZeneca, Bristol Myers Squibb, and Karyopharm Therapeutics; Dr. Snow, receiving advisory board fees and fees for serving as principal investigator from Bristol Myers Squibb Canada, EMD Serono, and Merck; Dr. Ko, receiving grant support, paid to his institution, and fees for serving as principal investigator from Apexigen, Astellas Pharma, Bristol Myers Squibb, and Merck and fees for serving on a data and safety monitoring board from Genentech and Imugene; Dr. Schenker, receiving grant support from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer Healthcare, Bristol Myers Squibb, Celgene, Clovis Oncology, Eli Lilly, F. Hoffmann每La Roche, Gilead Sciences, GlaxoSmithKline, Merck, Merck Sharp and Dohme, Mylan, Novartis, Pfizer, Regeneron Pharmaceuticals, and Tesaro; Dr. Kocon, receiving fees for serving as a trial investigator from Bristol Myers Squibb and F. Hoffmann每La Roche; Dr. Zhang, being employed by and owning stock in Bristol Myers Squibb; Dr. Zhu, being employed by Bristol Myers Squibb; Drs. Lei and Singh, and Ms. Kondo, being employed by and owning stock in Bristol Myers Squibb; Dr. Cleary, receiving grant support from AbbVie, AstraZeneca, Esperas Pharma, Genentech, Merck, Merus, and Tesaro and grant support, consulting fees, and travel support from Bristol Myers Squibb; and Dr. Moehler, receiving grant support, paid to University Medical Center of Johannes Gutenberg每University Mainz, from Arbeitsgemeinschaft Internistische Onkologie, Amgen, Bristol Myers Squibb, European Organization for Research and Treatment of Cancer, Leap Therapeutics, and Merck Darmstadt, advisory board and consulting fees from Amgen, Astellas Pharma, BeiGene, Bristol Myers Squibb, Falk Foundation, Lilly Deutschland, Merck Sharp and Dohme, Pierre Fabre Pharmaceuticals, Servier Laboratories, and Taiho Pharmaceutical, and travel support from Bristol Myers Squibb, Merck Darmstadt, and Merck Sharp and Dohme. No other potential conflict of interest relevant to this article was reported.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank the patients and their families for making this trial possible; the investigators and the clinical trial teams at Bristol Myers Squibb (Princeton, NJ) and Ono Pharmaceutical (Osaka, Japan) for CheckMate 577 trial support; Jamie Yingst, the CheckMate 577 protocol manager; Steven Blum (Bristol Myers Squibb, Princeton, NJ) and Fiona Taylor (Adelphi Values, Boston) for support with analysis of patient-reported outcomes; Dako (Agilent Technologies, Santa Clara, CA) for collaborative development of the PD-L1 IHC 28-8 pharmDx assay; and Jennifer Klem of Parexel International for medical-writing assistance with an earlier draft of the manuscript.

Author Affiliations

From the Charles A. Sammons Cancer Center at Baylor University Medical Center, Dallas (R.J.K.), and the University of Texas M.D. Anderson Cancer Center, Houston (J.A.A.); Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland (J.K., P.K.); the University Hospital Cologne, Department of Internal Medicine, Center for Integrated Oncology Aachen每Bonn每Cologne每Duesseldorf, Gastrointestinal Cancer Group Cologne, Cologne (T.Z.), and University Medical Center of Johannes Gutenberg每University Mainz (M.M.) 〞 both in Germany; University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven (E.V.C.), and Ghent University Hospital, Ghent (K.G.) 〞 both in Belgium; University Lille, Claude Huriez University Hospital, Lille (G.P.), and Pontchaillou University Hospital, Department of Gastroenterology, University of Rennes 1, INSERM Unit谷 1242, Rennes (A.L.) 〞 both in France; Fundaci車n Favaloro, Buenos Aires (G.M.); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore (J.F.); Akita University Hospital, Akita, Japan (S.M.); Duke Cancer Institute, Durham, NC (H.U.); Princess Margaret Cancer Centre, Toronto (E.E.), and Queen Elizabeth II Health Sciences Centre, Halifax, NS (S.S.) 〞 both in Canada; the Netherlands Cancer Institute每Antoni van Leeuwenhoek Hospital, Amsterdam (C.G.); Florida Cancer Specialists and Research Institute, Fort Myers (S.Z.); University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco (A.H.K.); St. John of God Murdoch Hospital, Murdoch, WA, Australia (K.F.); Sfantul Nectarie Oncology Center, Craiova, Romania (M.S.); Bristol Myers Squibb, Princeton, NJ (J.Z., L.Z., M.L., P.S., K.K.); and Dana每Farber Cancer Institute, Boston (J.M.C.).

Address reprint requests to Dr. Kelly at the Charles A. Sammons Cancer Center at Baylor University Medical Center, 3410 Worth St., Suite 550, Dallas, TX 75246, or at .

A complete list of the CheckMate 577 sites and investigators is provided in the Supplementary Appendix, available at NEJM.org.

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