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

February 2022 Clinical Practice Jolien Blokken

Treatment options for patients with HER2-positive advanced gastric cancer are limited and the prognosis for these patients is poor. Initial data from the phase III Keynote-811 study now support pembrolizumab plus trastuzumab and chemotherapy as a possible new first-line treatment option for HER2-positive, metastatic gastric or gastroesophageal junction cancer.


“These initial data support the use of pembrolizumab plus trastuzumab and chemotherapy as a potential new treatment option for metastatic HER2+ gastric and GEJ tumours.”

Human epidermal growth factor receptor 2 (HER2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas. 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 tumours. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer, there are preclinical and clinical rationales for adding pembrolizumab in HER2-positive disease. Two previous phase II studies suggested that adding pembrolizumab to SoC could provide additional antitumour activity with manageable safety. Now, the results of the protocol-specified first interim analysis of the randomised, 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 adenocarcinoma are published.

Keynote-811 study design

Eligible patients with previously untreated, unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma and an ECOG performance status of 0 or 1 were allocated (1:1) to receive pembrolizumab 200 mg intravenous (IV) once every three weeks  (Q3W) or placebo IV Q3W for up to 35 cycles or until intolerable toxicity or disease progression. Furthermore, all patients also received trastuzumab (6 mg/kg IV Q3W following an 8 mg/kg loading dose) and investigator’s choice of chemotherapy with 5-fluorouracil and cisplatin (FP) or capecitabine and oxaliplatin (CAPOX) at standard doses. Progression-free survival (PFS) and overall survival (OS) are the dual primary endpoints of this trial. At the data cut-off on June 17, 2020, 434 patients were enrolled. The efficacy population included the first 264 participants enrolled.


The efficacy population included 133 participants in the pembrolizumab group and 131 in the placebo group. Chemotherapy with CAPOX was chosen for 86.6% of patients and median study follow-up was 12.0 months (range, 8.5-19.4). Pembrolizumab plus SoC provided an objective response rate (ORR) of 74.4%, resulting in a statistically significant, clinically meaningful 22.7% improvement in ORR compared with placebo plus SoC (p= 0.00006). Responses in the pembrolizumab group were also deeper than those in the placebo group, and complete responses were more frequent (11.3% vs. 3.1%). Among responders, 50.5% in the pembrolizumab group and 44.1% in the placebo group had ongoing response at the data cut-off date. By Kaplan–Meier estimation, 70.3% of responders in the pembrolizumab group and 61.4% of responders in the placebo group had a response duration of at least 6 months and 58.4% and 51.1%, respectively, had a response duration of at least 9 months. The median response duration was 10.6 months in the pembrolizumab group and 9.5 months in the placebo group.

In the safety population, 217 participants received pembrolizumab + SoC while 216 received placebo + SoC. Median treatment duration in the safety population was 6.2 months for the pembrolizumab arm and 5.3 months for the placebo arm. Adverse events (AEs) were grade 3-5 in 57.1% of participants in the pembrolizumab arm vs. 57.4% in the placebo arm and led to discontinuation of any drug in respectively 24.4% and 25.9% of patients. The most common AEs in both groups were diarrhoea (52.5% in the pembrolizumab group vs. 44.4% in the placebo group), nausea (48.8% vs. 44.4%) and anaemia (41.0% vs. 44.0%). Adverse events with a possibly immune-mediated cause and/or infusion reactions occurred in 33.6% and 20.8% of participants, respectively. The most common of these events in the pembrolizumab group were infusion-related reactions (18.0% vs. 13.0% in the placebo group) and pneumonitis (5.1% vs. 1.4%). Seven (3.2%) participants in the pembrolizumab group and 10 (4.6%) in the placebo group died from adverse events.


Pembrolizumab plus trastuzumab and chemotherapy induced an ORR of 74.4%, representing a statistically significant and clinically meaningful 22.7% improvement in ORR to what was seen with placebo plus trastuzumab and chemotherapy. In addition, deeper and more durable responses were observed. The AE incidence was similar between arms and observed AEs were as expected, with no new safety concerns identified. KEYNOTE-811 is continuing as planned, and results for the primary endpoints of overall and progression-free survival will be assessed at a later date in accordance with the statistical analysis plan.


Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021;600;727-30.