The FDA has granted accelerated approval to pembrolizumab (Keytruda®, Merck & Co.) in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for first-line treatment of patients with locally advanced unresectable or metastatic HER2- positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.
"The PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1) pathway is an important regulatory component of the immune response and plays a critical role in tumor evasion of immune surveillance," wrote Hyun Cheol Chung, MD, Director of the Yonsei Song-Dang Institute for Cancer Research, and colleagues, in the November 2020 publication of the KEYNOTE-811 (NCT03615326) trial. "A growing body of evidence indicates that PD-1 and PD-L1 are frequently overexpressed in gastric cancer and that their upregulation may be prognostic of poor outcome. Consequently, PD-1 and PD-L1 represent promising targets for the treatment of gastric cancer. Pembrolizumab is a highly selective, humanized, monoclonal immunoglobulin G4-κ antibody that binds to PD-1 and blocks its interactions with PD-L1 and PD-L2 (programmed cell death 1 ligand 2), thereby releasing PD-1 pathway-mediated inhibition of the antitumor immune response."
The approval was based on the interim analysis of the ongoing KEYNOTE-811 trial. Data from 264 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not previously been treated with systemic therapy for metastatic disease were analyzed. Patients were randomized in a 1:1 ratio to be treated with either pembrolizumab 200 mg or placebo every three weeks, in combination with trastuzumab and either fluorouracil plus cisplatin or capecitabine plus oxaliplatin. The main efficacy measure used for the interim analysis was overall response rate. The overall response rate was 74% in the pembrolizumab group and 52% in the placebo group.
Adverse events described in the prescribing information that occurred in at least 20% of patients treated with pembrolizumab in combination with chemotherapy include fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, and weight loss.
"There is promising evidence that pembrolizumab used in combination with trastuzumab + chemotherapy may provide significant clinical benefit with manageable toxicity in patients with advanced gastric cancer," concluded Dr. Chung and colleagues. "It is hoped that the results of KEYNOTE-811 will further define the role of pembrolizumab and the feasibility of a dual antibody strategy in patients with advanced gastric cancer."
The recommended dose of pembrolizumab for patients with locally advanced unresectable or metastatic HER2 positive gastric or GEJ adenocarcinoma in combination with trastuzumab and chemotherapy is 200 mg every three weeks or 400 mg every six weeks.
For More Information
Chung HC, Bang YJ, Fuchs CS, et al (2020). First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Future Oncol, 17(5):491-501. DOI:10.2217/fon-2020-0737
Clinicaltrials.gov (2021). Pembrolizumab/placebo plus trastuzumab plus chemotherapy in human epidermal growth factor receptor 2 positive (HER2+) advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma (MK-3475-811/KEYNOTE-811). NLM identifier: NCT03615326.
US Food & Drug Administration (2021). FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer
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