Background Expression of PD-L1 has been shown to be upregulated in some patients with gastric cancer. As part of the phase 1b KEYNOTE-012 study, we aimed to assess the safety and activity of the anti-PD-1 antibody pembrolizumab in patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Methods This study was a multicentre, open-label, phase 1b trial done at 13 cancer research centres in the USA, Israel, Japan, South Korea, and Taiwan. We enrolled patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Patients received intravenous pembrolizumab at 10 mg/kg once every 2 weeks for 24 months or until progression or unacceptable toxic effects occurred. Response was assessed every 8 weeks in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. The primary objectives were safety in patients who received at least one dose of pembrolizumab and the proportion of patients achieving overall responses in patients who received at least one pembrolizumab dose and who either had a post-baseline scan or who discontinued therapy because of clinical disease progression or a treatment-related adverse event before the first post-baseline scan. The study is registered with ClinicalTrials.gov, number NCT01848834, and is ongoing but no longer enrolling patients. Findings From Oct 23, 2013, to May 5, 2014, 39 patients were enrolled. 36 were evaluable for response by central assessment. Eight (22%, 95% CI 10–39) patients were judged to have had an overall response at central review; all responses were partial. All 39 patients were included in the safety analyses. Five (13%) patients had a total of six grade 3 or 4 treatment-related adverse events, consisting of two cases of grade 3 fatigue, one case each of grade 3 pemphigoid, grade 3 hypothyroidism, and grade 3 peripheral sensory neuropathy, and one case of grade 4 pneumonitis. No treatment-related deaths occurred. Interpretation In this population of patients with recurrent or metastatic PD-L1-positive gastric cancer, pembrolizumab had a manageable toxicity profile and promising antitumour activity, warranting further study in phase 2 and 3 trials. Funding Merck & Co.
Bibliographical noteFunding Information:
The study was designed by academic advisers and representatives of the study funder. All data were collected by the investigators and their site personnel. Data were analysed and interpreted by senior academic authors and representatives of the funder. All data used to prepare this article were fully accessible to all authors. The corresponding author (KM) wrote the first draft of the manuscript. The corresponding author and senior author (Y-JB) had the final responsibility to submit for publication. Medical writing and editorial assistance was funded by Merck & Co. All authors critically reviewed and edited all manuscript drafts, approved the submitted version, vouch for the accuracy and completeness of the reported data, and attest that the study was done in accordance with the protocol.
HCC has received grant support from Eli Lilly and GlaxoSmithKline and has been a consultant for Taiho, Eli Lilly, Celltrione, Merck, MSD, and Quintiles. VS has received support as an investigator for the conduct of the study from Merck and has received research funding from Bayer and Amgen. DTL has received support as an investigator for the conduct of the study and has received honoraria from Merck. BB has received support as an investigator for the conduct of the study from Merck, and received honoraria from Bayer (advisory board), Boehringer Ingelheim (steering committee), MedImmune (DSMC), Amgen (advisory board), VentiRx (DMSB), Merck (advisory board), and Johnson & Johnson (expert witness). AJM is an advisory board consultant for Celgene. Y-JB has received research grants and served in an advisory and consulting role for Merck. KP, JL, KE, JJ, and MK are employees of Merck & Co. KE also has stock ownership of Merck & Co, Bayer AG, and Johnson & Johnson, as well as spousal employment with and stock ownership in Celgene. KM, RG, DC, SG, JPE, TG, and C-CL declare no competing interests.
This study was funded by Merck & Co (Kenilworth, NJ, USA). We thank the patients and their families and caregivers for participating in the study; Roger Dansey (Merck & Co) for critical manuscript review; Jonathan Cheng (Merck & Co) for study oversight; Karl Heath (Merck & Co) for study support; Marisa Dolled-Filhart (Merck & Co) for PD-L1 immunohistochemistry expertise; Terri McClanahan (Merck & Co) for gene expression profiling expertise; and QualTek Molecular Laboratories (Santa Barbara, CA, USA) and Dako North America (Carpinteria, CA, USA) for PD-L1 immunohistochemistry assay testing. Medical writing and editorial assistance, funded by Merck & Co, were provided by Tricia Brown, Melanie Leiby, and Sarah Adai of the ApotheCom Merck oncology team (Yardley, PA, USA).
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