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The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer

Abstract

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas1,2,3. More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours4. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer5, there are preclinical6,7,8,9,10,11,12,13,14,15,16,17,18,19 and clinical20,21 rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma22 (https://clinicaltrials.gov, NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate.

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Fig. 1: Best percentage change from baseline in the size of target lesions among participants in the efficacy population.

Data availability

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD) is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data-sharing documentation (http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the US and EU or after product development is discontinued; an exception will be made for this ongoing trial such that data will be made available for request after the protocol-specified primary endpoint analyses have been reported. There are circumstances that may prevent MSD from sharing requested data, including country or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to a SAS portal so that the requestor can perform the proposed analyses.

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Acknowledgements

This study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Y.Y.J. was additionally supported by Memorial Sloan Kettering Cancer Center National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748. We thank the patients and their families and caregivers for participating in the study; the investigators and site personnel; and the following employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA: C. S. Shih for study oversight and M. A. Leiby for medical writing and editorial assistance.

Author information

Authors and Affiliations

Authors

Contributions

Y.Y.J., L.S., K.S., S.Q., E.V.C., J.T., P.B. and H.C.C. conceived, designed and planned the study. Y.Y.J., A.K., P.Y., N.L., S.L., O.K., O.B., Y.B., L.S., Y.T., L.S.W., J.X. and H.C.C. collected data. P.B. provided study oversight. L.L. performed the statistical analysis. Y.Y.J., L.L., S.S. and P.B. prepared the first draft of the manuscript. Y.Y.J., A.K., P.Y., N.L., S.L., O.K., O.B., Y.B., L.S., Y.T., L.S.W., J.X., K.S., S.Q., E.V.C., J.T., L.L., S.S., P.B. and H.C.C. interpreted the results, provided critical review and revision of the drafts, and approved the decision to submit for publication.

Corresponding author

Correspondence to Yelena Y. Janjigian.

Ethics declarations

Competing interests

Y.Y.J. has received research funding to the institution from Merck Sharp & Dohme, the National Cancer Institute, the US Department of Defense, Cycle for Survival, Fred’s Team, Rgenix, Bayer, Genentech/Roche, Bristol-Myers Squibb, and Eli Lilly, has served on advisory boards for Rgenix, Merck Serono, Bristol-Myers Squibb, Eli Lilly, Pfizer, Bayer, Imugene, Merck Sharp & Dohme, Daiichi-Sankyo, Zymeworks, SeaGen, Basilea Pharmaceutical and AstraZeneca, and has equity in Rgenix. A.K. has received research funding to the institution from Merck Sharp & Dohme, Ono Pharmaceutical Co., Ltd. and Taiho Pharmaceutical Co., Ltd., and received honoraria for lectures, presentations, speakers’ bureaus, or educational events from Ono Pharmaceutical Co., Ltd. and Taiho Pharmaceutical Co., Ltd. P.Y. has received research funding to the institution and travel support from Merck Sharp & Dohme. N.L. has received research funding to the institution from Merck Sharp & Dohme. S.L. has received research funding to the institution from Merck Sharp & Dohme, Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, and Bristol-Myers Squib, consulting fees from Amgen, Merck Serono, Lilly, AstraZeneca, Incyte, Daiichi Sankyo, Bristol-Myers Squibb, and Servier, and payment or honoraria for lectures, presentations, speakers’ bureaus, or educational events from Roche, Lilly, Bristol-Myers Squibb, Servier, Merck Serono, Pierre-Fabre, GSK, and Amgen. O.K. has received research funding to the institution from Merck Sharp & Dohme. O.B. has received research funding to the institution from Merck Sharp & Dohme, has received honoraria for serving as a speaker from Eli Lilly, travel support from Bristol-Myers Squibb and Roche, participated as an advisor for Bristol-Myers Squibb and Roche, and has a leadership role in the Sociedad Chilena de Oncología Medica. Y.B. has received research funding to the institution from Merck Sharp & Dohme. L.S. has received research funding to the institution from Merck Sharp & Dohme, Beijing Xiantong Biomedical Technology, Qilu Pharmaceutical, ZaiLab Pharmaceutical (Shanghai), Jacobio Pharmaceuticals, and Beihai Kangcheng (Beijing) Medical Technology, has received consulting fees from Merck Sharp & Dohme, Merck, Mingji Biopharmaceutical, Haichuang Pharmaceutical, Harbour BioMed, and Boehringer Ingelheim, has received payment for speakers bureaus from Hutchison Whampoa, Henrui, ZaiLab, and CSTONE Pharmaceutical, and has participated on an advisory board for Rongchang Pharmaceutical, Zailab, and CSTONE Pharmaceutical. Y.T. has received research funding to the institution from Merck Sharp & Dohme. L.S.W. has received research funding to the institution from Merck Sharp & Dohme. J.X. has received research funding to the institution from Merck Sharp & Dohme. K.S. has received research funding to the institution from Merck Sharp & Dohme, Astellas, Lilly, Ono, Sumitomo Dainippon, Daiichi Sankyo, Taiho, Chugai, Medi Science, and Eisai, has received consulting fees from Astellas, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono, Merck Sharp & Dohme, Taiho, Novartis, AbbVie, GlaxoSmithKline, Daiichi Sankyo, Amgen, and Boehringer Ingelheim, and has received honoraria for lectures from Novartis, AbbVie, and Yalkult. S.Q. has received consulting fees from Merck Sharp & Dohme for serving on an advisory board. E.V.C. has received funding to the institution from Merck Sharp & Dohme, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck KGaA, Novartis, Roche, and Servier and has received consulting fees from Array, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Halozyme, GSK, Incyte, Ipsen, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre-Fabre, Roche, Servier, Sirtex, and Taiho. J.T. has received funding to the institution from Merck Sharp & Dohme, has received consulting fees from Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd., Genentech Inc., HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, Merck Sharp & Dohme, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, SeaGen, Servier, Taiho, Tessa Therapeutics, and TheraMyc, and has received payment for educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource (PER). L.L. receives salary for full-time employment from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. S.S. receives salary for full-time employment from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and owns stock and/or has stock options in Merck & Co., Inc., Kenilworth, NJ, USA. P.B. receives salary for full-time employment from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and owns stock and/or has stock options in Merck & Co., Inc., Kenilworth, NJ, USA. H.C.C. has received funding to the institution from Merck Sharp & Dohme, Lilly, GlaxoSmithKline, Merck-Serono, Bristol-Myers Squibb/Ono, Taiho, Amgen, BeiGene, Incyte, and Zymeworks, has served on advisory boards for Taiho, Celltrion, Merck Sharp & Dohme, Lilly, Bristol-Myers Squibb, Merck-Serono, Gloria, BeiGene, Amgen, and Zymeworks, and has received honoraria for lectures from Merck-Serono and Lilly. Y.Y.J, A.K., P.Y., N.L., S.L., O.K., O.B., Y.B., L.S., Y.T., L.S.W., J.X., K.S., S.Q., E.V.C., J.T., L.L., S.S., P.B., and H.C.C. received medical writing support for this manuscript (no payment) from Merck Sharp & Dohme.

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Extended data figures and tables

Extended Data Fig. 1 Treatment difference in objective response in subgroups of the efficacy population.

Response was assessed per RECIST, version 1.1, by blinded, independent central review. The estimated treatment difference between the pembrolizumab and placebo groups in the overall population was calculated using the Miettinen and Nurminen method stratified by geographic region (Australia/Europe/Israel/North America [Aus/Eur/Isr/NAm] vs Asia vs rest of world), PD-L1 combined positive score ([CPS]; ≥1 vs <1), and chemotherapy choice (5-fluorouracil plus cisplatin [FP] vs capecitabine plus oxaliplatin [CAPOX]); differences in subgroups were calculated using the unstratified Miettinen and Nurminen method. The efficacy population included the first 264 participants randomly allocated to treatment. The treatment regimen included trastuzumab and chemotherapy in both groups. Diamonds represent the estimated treatment difference in objective response, the error bars represent the 95% confidence interval (CI) of the estimated treatment difference, and the region shaded in dark grey represents the 95% CI for the treatment difference in the overall population. ECOG, Eastern Cooperative Oncology Group; GEJ, gastro-oesophageal junction; IHC, immunohistochemistry; ISH, in situ hybridization.

Extended Data Table 1 Follow-up duration calculated as time from randomization to the date of death or the database cutoff date, whichever was earliest
Extended Data Table 2 Disposition of study treatment
Extended Data Table 3 Demographic and disease characteristics at baseline
Extended Data Table 4 Adverse events that occurred in 10% or more of participants in either group of the as-treated population
Extended Data Table 5 Adverse events with a possible immune-mediated cause and infusion reactions in the as-treated population
Extended Data Table 6 Adverse events leading to death in the as-treated population

Supplementary information

Supplementary Information

This file contains a list of investigators, sites, and ethics committees; data monitoring committee; protocol cover letter and study protocol

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Janjigian, Y.Y., Kawazoe, A., Yañez, P. et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature 600, 727–730 (2021). https://doi.org/10.1038/s41586-021-04161-3

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