In the KEYNOTE-811 study, the addition of pembrolizumab to trastuzumab and chemotherapy significantly improved the overall (OS) and progression-free survival (PFS) together with a significant increase in the response rate.
Based on previous interim analyses of the KEYNOTE-811 study, 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. In these interim analyses, this treatment combination was shown to be associated with a significantly better objective response rate (ORR) than trastuzumab plus chemotherapy alone (74% vs. 52%, p= 0.00006). More importantly, this ORR benefit also translated into a statistically significant benefit in PFS in the subgroup of patients with a PD-L1 CPS ≥1 (median: 10.8 vs. 7.2 months, HR: 0.70). During ESMO 2024, the results of the per protocol final analysis for OS in KEYNOTE-811 were presented.
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). Patients were treated until progression, unacceptable toxicity or withdrawal, with a maximum of 35 cycles. The dual primary endpoints in this trial were PFS and OS, with ORR, duration of response (DoR) and safety as secondary objectives.
The median age of patients in the study was 62 years, 80% was male and 85% had a PD-L1 CPS ≥1. After a median follow-up of 50.2 months, the pembrolizumab-containing regimen proved to be associated with a statistically significant 20% lower risk of death 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). At 36 months, this translated into a 5% absolute benefit in OS rate for patients receiving pembrolizumab-trastuzumab-chemotherapy (28% vs. 23%). 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]). In the final analysis, the ORR was reported at 72.6% in the experimental arm (17% complete responses [CR]) as compared to 60.1% in the control arm (11.8% CR). Responses to the pembrolizumab-containing regimen were also more durable with a 3-year DoR rate of 24% as compared to 15% with the control regimen (median DoR: 11.3 vs. 9.5 months).
In the subgroup of patients with a PD-L1 CPS ≥1, the median OS with pembrolizumab-trastuzumab-chemotherapy was reported at 20.1 months as compared to 15.7 months in the control arm (HR[95%CI]: 0.79[0.66-0.95]). Corresponding 3-year OS rates were 29% and 23%, respectively. In contrast, no significant OS benefit was observed with pembrolizumab in the subgroup of patients with a PD-L1 <1 (median OS 18.2 months vs. 20.4 months in the control arm, HR[95%CI]: 1.10[0.72-1.68]).
The incidence of grade ≥3 adverse events (AEs) with the pembrolizumab regimen was 58% as compared to 50% with trastuzumab and chemotherapy alone. AEs led to treatment discontinuation in 37% of patients in the experimental arm, which was fairly similar to the 34% discontinuation rate in the control arm. Immune mediated grade ≥3 AEs occurred in 11% of patients with the pembrolizumab-trastuzumab-chemotherapy regimen as compared to 3% in the control arm.
The final analysis of the KEYNOTE-811 study solidifies the combination of pembrolizumab, trastuzumab and chemotherapy as the standard of care for patients with HER2-positive metastatic G/GEJ cancer and a PD-L1 CPS ≥1. In this patient population, the addition of pembrolizumab to the regimen reduced the risk of death by 21%. No new safety signals were observed with longer follow-up.
Reference
Janjigian Y, et al. Final overall survival for the phase 3, KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for HER2+ advanced, unresectable or metastatic G/GEJ adenocarcinoma. Presented at ESMO 2024; Abstract 1400O.
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