Results from the KEYNOTE-811 clinical trial indicate pembrolizumab added to trastuzumab plus chemotherapy improves response in HER2-positive gastric or gastroesophageal junction cancer.
Gastric cancer is typically diagnosed in advanced stages, which confers a poor prognosis (5-year survival is around 5%).1 HER2 is a proto-oncogene that produces a tyrosine kinase receptor and promotes cell proliferation and cancer development.1 Testing for HER2 is recommended in all patients with gastric cancer, as patients who are positive for HER2 are candidates for treatment with trastuzumab, a monoclonal antibody that targets HER2.1 As such, the recommended standard-of-care first-line therapy for patients with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer is trastuzumab plus chemotherapy. Combining trastuzumab and chemotherapy with the PD-1 inhibitor pembrolizumab has demonstrated efficacy and acceptable safety in 2 phase 2 trials.
The KEYNOTE-811 study was a double-blind, randomized, placebo-controlled phase 3 multicenter clinical trial that investigated whether the addition of pembrolizumab to trastuzumab and chemotherapy improves efficacy for the treatment of metastatic gastric or GEJ cancer. The initial results of the KEYNOTE-811 study were presented at the 2021 American Society of Clinical Oncology Annual Meeting. Patients with untreated unresectable or metastatic HER2-positive gastric or GEJ cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for the study.
Initial enrollment was 264 participants, with 133 patients receiving 200 mg pembrolizumab intravenously every 3 weeks plus trastuzumab and either 5-fluorouracil and cisplatin (FP) or capecitabine and oxaliplatin (CAPOX). In the placebo group, 131 patients received placebo intravenously every 3 weeks plus trastuzumab and either FP or CAPOX. CAPOX was given to 87.1% of the patients. Microsatellite instability–high tumors were present in 0.8% of the study population. Treatment continued for up to 2 years or until disease progression or toxicity. The study’s primary end points were progression-free survival and overall survival. Secondary end points were objective response rate (ORR), duration of response (DOR), and safety. The median study follow-up was 12 months.
In patients treated with pembrolizumab and standard of care, the ORR was 74.4%, the complete response rate was 11.3%, and disease control rate (DCR) was 96.2%. When the same factors were analyzed for the placebo group, the ORR was 51.9%, the complete response rate was 3.1%, and DCR was 89.3%. The median DOR was 10.6 months for the pembrolizumab-treated group and 9.5 months for the placebo group. Analysis of adverse events (AEs) found 57.1% of the pembrolizumab-treated group experienced grade 3 to 5 AEs and 57.4% of the placebo group experienced AEs. Patient discontinuation of any drug due to AEs occurred in 24.4% of the pembrolizumab group and 25.9% of the placebo group. AEs were severe enough to lead to death in 3.2% of the pembrolizumab group and 4.6% of the placebo group.
Pembrolizumab added to trastuzumab plus chemotherapy improved response in the study population.
Source: Janjigian Y, Kawazoe A, Yanez P, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: initial findings of the global phase 3 KEYNOTE-811 study. J Clin Oncol. 2021;39(suppl_15):4013.
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