Elsevier

The Lancet Oncology

Volume 17, Issue 6, June 2016, Pages 717-726
The Lancet Oncology

Articles
Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial

https://doi.org/10.1016/S1470-2045(16)00175-3Get rights and content

Summary

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.

Introduction

Gastric cancer is the fifth most common cancer worldwide, with a high incidence in east Asia.1 Most cases, especially in the USA and Europe, are diagnosed at a late stage, and treatment options are mostly restricted to cytotoxic chemotherapy, which is associated with poor outcomes.2 Despite the availability of trastuzumab for patients with HER2-positive disease and the approval of the anti-VEGFR2 monoclonal antibody ramucirumab as a second-line therapy,3, 4, 5 there remains a need for effective treatment options for advanced gastric cancer.

PD-1 is a negative co-stimulatory receptor expressed mainly on activated T cells,6 which downregulates excessive immune responses by binding to its ligands, PD-L1 and PD-L2.7, 8 PD-L1 is constitutively expressed in various tissues and can also be expressed in several tumour types, including gastric cancer.6, 9, 10, 11, 12 In tumour tissues, binding of PD-1 to PD-L1 inhibits effector T-cell function, leading to suppression of the antitumour immune response and enabling neoplastic growth.6, 7

Pembrolizumab is a selective, humanised, high-affinity IgG4-κ monoclonal antibody designed to bind to PD-1 and thus block the interaction between PD-1 and its ligands.13 Pembrolizumab has a manageable safety profile and has shown promising antitumour activity in several types of advanced solid tumours and haematological malignancies.14 Pembrolizumab is approved in several countries for the treatment of advanced melanoma and is approved in the USA for the treatment of metastatic non-small-cell lung cancer that has progressed on or after platinum-containing chemotherapy and expresses PD-L1, as assessed with the PD-L1 IHC 22C3 pharmDx kit (Dako North America, Carpinteria, CA, USA; approved by the US Food and Drug Administration).13, 14, 15

Findings from several studies support targeting of the PD-1 pathway in gastric cancer. Preclinical data suggest that PD-L1 expression is significantly upregulated following Helicobacter pylori infection and that the resulting decrease in T-cell proliferation can be reversed by anti-PD-L1 antibodies.16 PD-L1 expression has been detected in more than 40% of human gastric cancer samples in several studies.10, 11, 17, 18, 19 In view of the substantial unmet clinical need and molecular rationale for targeting of the PD-1 pathway, we examined the safety and antitumour activity of pembrolizumab in patients with PD-L1-positive advanced gastric or gastro-oesophageal junction cancer.

Research in context

Evidence before this study

We searched PubMed on April 22, 2016, to identify studies of PD-1 or PD-L1 inhibitors in stomach and gastro-oesophageal junction cancer. The search was limited to English-language articles published in the past 5 years. Search terms were (MK-3475 OR lambrolizumab OR pembrolizumab OR nivolumab OR BMS-936558 OR MPDL3280A OR atezolizumab OR BMS-936559 OR MEDI4736 OR durvalumab OR CT-011 OR pidilizumab) AND (gastric cancer OR stomach cancer OR gastroesophageal junction cancer). The search identified one case report of a patient with microsatellite-stable gastric cancer who had an objective response to pembrolizumab treatment. We did not identify any published studies of PD-1 or PD-L1 inhibitors in a larger cohort of patients with gastric cancer.

Added value of this study

To our knowledge, KEYNOTE-012 is the first study to report results from a cohort of patients with previously treated advanced gastric cancer who received an anti-PD-1 or anti-PD-L1 monoclonal antibody. Our results suggest that pembrolizumab can be safely given to patients with advanced gastric cancer and that it has clinically meaningful antitumour activity in a mostly pretreated population. Importantly, we saw no differences in the safety or antitumour activity profiles between patients enrolled in Asia and those enrolled in the rest of the world.

Implications of all the available evidence

Overall, these data support the importance of the PD-1 pathway in gastric cancer, show the safety and antitumour activity of pembrolizumab in patients with previously treated advanced gastric cancer, and support further investigation of pembrolizumab as an anticancer therapy for advanced gastric cancer.

Section snippets

Study design and participants

KEYNOTE-012 was a multicentre, open-label, phase 1b trial that included cohorts of patients with advanced gastric cancer, urothelial cancer, triple-negative breast cancer, and head and neck cancer. In this report, we describe the results of the cohort with advanced gastric cancer. This study was done at 13 cancer research centres in the USA, Israel, Japan, South Korea, and Taiwan (appendix p 1). The study protocol and all amendments were approved by the institutional review boards or ethics

Results

From Oct 23, 2013, to May 5, 2014, 39 patients (19 from east Asia and 20 from the rest of the world) were enrolled into the KEYNOTE-012 gastric cancer cohort. Baseline characteristics are shown in table 1. Microsatellite instability was analysed in samples from 24 patients. Four (17%) of 24 patients had microsatellite instability-high tumours (two [8%] patients from Asia and two [8%] patients from elsewhere) and 20 (83%) patients had tumours that were microsatellite stable. Epstein-Barr virus

Discussion

Our results show that in this mostly pretreated population of patients with PD-L1-positive advanced gastric cancer, pembrolizumab had a manageable toxicity profile and promising antitumour activity, although we did not reach our prespecified overall response of 31% by central review. Treatment with pembrolizumab elicited sustained antitumour responses in 22% of patients according to central review, our primary outcome, and in 33% of patients according to investigator review. Possible

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