KEYNOTE-811: final analysis for overall survival

Based on previously reported results of KEYNOTE-811, the combination of pembrolizumab with trastuzumab and chemotherapy was approved as a first line treatment for patients with a HER2-positive metastatic gastric or gastroesophageal junction (G/GEJ) cancer and a PD-L1 combined positive score (CPS) of ≥1. This approval was based on a significant benefit in objective response rate (ORR) and a significantly longer progression-free survival (PFS) with this regimen compared to trastuzumab and chemotherapy alone. During ESMO 2024, final overall survival (OS) data of this trial were presented. To discuss these pivotal findings, Prof Dr Eric Van Cutsem (University hospitals Leuven) meets up with Dr Sara Lonardi, digestive oncologist at the Instituto Oncologico Veneto IOV-IRCSS in Padova, Italy.

In KEYNOTE-811 a total of 698 patients with advanced, unresectable G/GEJ cancer who did not yet receive prior systemic therapy in the advanced setting and tested positive for HER2 on central review were randomly assigned to receive pembrolizumab (200 mg IV q3w) or placebo both in combination with trastuzumab and chemotherapy (5-fluorouracil + cisplatin, or CAPOX). After a median follow-up of 50.2 months, the pembrolizumab-containing regimen proved to be associated with a statistically significant 20% lower death risk than the control arm, with a median OS of 20.0 and 16.8 months, respectively (HR[95%CI]: 0.80[0.67-0.94]; p= 0.004). Updated results for PFS showed a HR of 0.73 in favour of pembrolizumab-trastuzumab-chemotherapy, with a 3-year PFS rate of 18% vs. 11% in the control arm (HR[95%CI]: 0.73[0.61-0.87]).

The clinical benefit obtained with the addition of pembrolizumab to trastuzumab-chemotherapy was even more pronounced in the subgroup of patients with a PD-L1 CPS ≥1 (85% of patients). In this subgroup, adding pembrolizumab to trastuzumab-chemotherapy prolonged the median OS with 4.4 months, which is an impressive achievement in this challenging tumour type (median OS: 20.1 vs. 15.7 months). Corresponding 3-year OS rates were 29% and 23%, respectively. The toxicity with the pembrolizumab-trastuzumab-chemotherapy was mainly driven by the chemotherapy backbone, with only a slightly higher incidence of grade 3/4 immune-related adverse events compared to trastuzumab-chemotherapy alone (11% vs. 3%)

In conclusion, the final OS data from KEYNOTE-811 solidify pembrolizumab in combination with trastuzumab and chemotherapy as the preferred first-line treatment for patients with unresectable or metastatic HER2+ gastric/GEJ adenocarcinoma with PD-L1 CPS ≥1 and establish this regimen as a new benchmark for future clinical trials in this setting.