KEYNOTE-811: 6-year median follow-up of pembrolizumab plus trastuzumab and chemotherapy for previously untreated advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma.

Abstract

4040 Background: At the final analysis of the phase 3 KEYNOTE-811 trial (NCT03615326), first-line (1L) pembrolizumab (pembro) plus trastuzumab and chemotherapy (chemo) showed superior OS and consistently improved PFS and ORR with durable responses vs placebo plus trastuzumab and chemo in participants (pts) with HER2-positive (HER2+) advanced or metastatic gastric or gastroesophageal (G/GEJ) adenocarcinoma, particularly in pts with PD-L1 combined positive score (CPS) ≥1 tumors. Results supported the approval of pembro plus trastuzumab and chemo for 1L treatment of advanced or metastatic HER2+ G/GEJ adenocarcinoma with PD-L1 CPS ≥1. We report results after an additional 20 months of follow-up. Methods: Eligible pts with untreated advanced or metastatic HER2+ G/GEJ adenocarcinoma, measurable disease, and ECOG PS 0 or 1 were randomly assigned 1:1 to receive pembro 200 mg or placebo IV Q3W for up to 35 cycles plus trastuzumab 6 mg/kg (after loading dose of 8 mg/kg) and chemo (CAPOX or FP). Dual primary end points were OS and PFS per RECIST v1.1 by BICR. Secondary end points included ORR and DOR (per RECIST v1.1 by BICR), and safety. Data cutoff date was November 12, 2025. Results: Overall, 698 pts were randomly assigned to the pembro group (n = 350) or placebo group (n = 348). Median follow-up was 70.0 months (range, 50.9-84.2). In the intention-to-treat (ITT) population (all randomly assigned pts), median OS was 20.0 months (95% CI, 17.8-22.1) in the pembro group vs 16.8 months (95% CI, 14.9-18.7) in the placebo group. In pts with PD-L1 CPS ≥1, median OS was 20.1 months (95% CI, 17.9-22.9) vs 15.7 months (95% CI, 13.5-18.5). PFS, ORR, and DOR were also consistent between the ITT population and pts with PD-L1 CPS ≥1 (Table). Treatment-related AEs occurred in 341 pts (97.4%; grade ≥3, 206 [58.9%]) in the pembro group and 335 (96.8%; grade ≥3, 177 [51.2%]) in the placebo group. Conclusions: Pembro plus trastuzumab and chemo continued to show improved OS, PFS, and ORR vs placebo plus trastuzumab and chemo after a median study follow-up of 70 months, especially in pts with PD-L1 CPS ≥1. No new safety signals were seen. The findings continue to support pembro plus trastuzumab and chemo as the preferred 1L treatment for advanced or metastatic HER2+ G/GEJ adenocarcinoma. Clinical trial information: NCT03615326 . ITTN = 698 PD-L1 CPS ≥1n = 594 Pembro group n = 350 Placebo group n = 348 Pembro group n = 298 Placebo group n = 296 OS, median (95% CI), months 20.0 (17.8-22.1) 16.8 (14.9-18.7) 20.1 (17.9-22.9) 15.7 (13.5-18.5) HR (95% CI) 0.81 (0.69-0.95) 0.79 (0.66-0.94) PFS, median (95% CI), months 10.0 (8.6-12.2) 8.1 (7.0-8.5) 10.9 (8.5-12.5) 7.3 (6.8-8.4) HR (95% CI) 0.73 (0.61-0.87) 0.72 (0.60-0.87) ORR, % (95% CI) 72.6 (67.6-77.2) 60.1 (54.7-65.2) 73.2 (67.7-78.1) 58.4 (52.6-64.1) DOR, median (range), months 11.3 (1.1+ to 80.0+) 9.5 (1.4+ to 79.6+) 11.3 (1.1+ to 80.0+) 9.6 (1.4+ to 79.6+)