Pembrolizumab plus trastuzumab and chemotherapy as first-line treatment for unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma
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 (GEJ) cancer.
The current standard-of-care (SoC) first-line therapy for HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer consists of trastuzumab plus chemotherapy. Two previous phase II studies (MSKCC study and PANTHERA) suggested that adding pembrolizumab to SoC could provide additional antitumour activity with manageable safety. At the 2021 ESMO World Congress on Gastrointestinal Cancer, the initial results from the ongoing global, randomised, double-blind phase III Keynote-811 study, assessing whether adding pembrolizumab to trastuzumab and chemotherapy improves efficacy vs. trastuzumab and chemotherapy alone for participants with HER2-positive metastatic gastric/GEJ cancer, were presented.
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 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. The protocol-specified first interim analysis was planned when the first 260 participants enrolled had at least 8.5 months follow-up. The objective of this analysis was to assess whether adding pembrolizumab to SoC with trastuzumab and chemotherapy (pembrolizumab + SOC) significantly improved the objective response rate (ORR). At the data cut-off on June 17, 2020, 434 patients were enrolled (intention-to-treat [ITT] population). The efficacy population included the first 264 participants enrolled.
Clinically meaningful improvement in objective response rate
In the efficacy population, 133 participants were randomised to pembrolizumab + SoC while 131 patients received placebo + SoC. Chemotherapy with CAPOX was chosen for 87.1% of patients and median study follow-up was 12.0 months (range, 8.5-19.4). Almost all patients (97% for the pembrolizumab arm and 90% for the placebo arm) experienced a decrease from baseline in size of target lesions at the first interim analysis, with a decrease of at least 80% observed in 32% and 15% of patients, respectively. Pembrolizumab plus SoC provided an ORR of 74.4%, resulting in a statistically significant, clinically meaningful 22.7% improvement in ORR compared with placebo plus SoC (p= 0.00006). In total, 11% and 3% of patients in the pembrolizumab and placebo arms, respectively obtained a complete response. The disease control rate (DCR) was 96.2% for patients receiving pembrolizumab + SoC and 89.3% for patients receiving placebo + SoC. Results were consistent among prespecified subgroups. The median duration of response (DOR) was 10.6 months for the pembrolizumab arm and 9.5 months for the placebo arm with an estimated DoR ≥6 months and ≥9 months of 70% vs. 61% and 58% vs. 51%, respectively.
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% of participants in the pembrolizumab arm vs. 57% in the placebo arm and led to death in 3% vs. 5% of patients, respectively. Adverse events led to discontinuation of any drug in 24% of patients in the pembrolizumab arm and in 26% of patients in the placebo arm. The most common AEs in the pembrolizumab arm were diarrhoea (53%), nausea (49%), anaemia (41%), decreased appetite (31%) and vomiting (31%). The most common immune-mediated AEs were infusion-related reactions (18%), pneumonitis (5%), colitis (5%), hypothyroidism (5%) and hyperthyroidism (4%).
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. Analysis of overall survival and progression-free survival will be performed in the future in accordance with the analysis plan.
Janjigian Y, et al. Initial data from the phase 3 KEYNOTE-811 study of trastuzumab and chemotherapy with or without pembrolizumab for HER2-positive metastatic gastric or gastroesophageal junction (G/GEJ) cancer. Presented at 2021 ESMO World Congress on Gastrointestinal Cancer; Abstract LBA4.