Pembrolizumab (pembro) + chemotherapy (chemo) for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer: Updated results from the KEYNOTE-859 study.

4045 Background: At the protocol-specified interim analysis of the KEYNOTE-859 study (NCT03675737), first-line pembro + chemo significantly improved OS (HR, 0.78; 95% CI, 0.70-0.87; P<0.0001), PFS (HR, 0.76; 95% CI, 0.67-0.85; P<0.0001), and ORR (51.3% vs 42.0%; P=0.00009) vs placebo (pbo) + chemo in patients (pts) with HER2-negative G/GEJ cancer. We report results after an additional 11 months of follow-up. Methods: Pts with previously untreated locally advanced or metastatic HER2-negative G/GEJ cancer, measurable disease per RECIST v1.1, ECOG PS 0 or 1, and known PD-L1 combined positive score (CPS) were eligible. Pts were randomly assigned 1:1 to receive pembro 200 mg or pbo IV Q3W for ≤35 cycles + investigator’s choice of chemo (5-FU + cisplatin FP vs capecitabine + oxaliplatin CAPOX). The primary end point was OS. Secondary end points included PFS, ORR, and DOR, all per RECIST v1.1 by BICR, and safety. The data cutoff was August 22, 2023. Results: The intention-to-treat (ITT) population comprised 1579 pts (pembro + chemo, n=790; pbo + chemo, n=789). Median follow-up from randomization to data cutoff was 41.6 mo (range, 33.6-48.9). In the ITT population, median OS was 12.9 mo (95% CI, 11.9-14.0) for pembro + chemo vs 11.5 mo (95% CI, 10.6-12.1) for pbo + chemo (HR, 0.79; 95% CI, 0.71-0.88), median PFS was 6.9 mo (95% CI, 6.3-7.2) vs 5.6 mo (95% CI, 5.5-5.7; HR, 0.76 95% CI, 0.68-0.85), ORR was 51.0% vs 42.0%, and median DOR was 8.0 mo (range, 1.2+ to 52.6+) vs 5.7 mo (range, 1.3+ to 44.3+). In pts with PD-L1 CPS ≥1 (pembro + chemo, n=618; pbo + chemo, n=617), median OS was 13.0 mo (95% CI, 11.6-14.2) vs 11.4 mo (95% CI, 10.5-12.0; HR, 0.75 95% CI, 0.66-0.85), median PFS was 6.9 mo (95% CI, 6.0-7.2) vs 5.6 mo (95% CI, 5.4-5.7; HR, 0.73 95% CI, 0.64-0.83), ORR was 51.8% vs 42.6%, and median DOR was 8.3 mo (range, 1.2+ to 52.6+) vs 5.6 mo (range, 1.3+ to 44.3+). In pts with PD-L1 CPS ≥10 (pembro + chemo, n=280; pbo + chemo, n=273), median OS was 15.8 mo (95% CI, 14.0-19.3) vs 11.8 mo (95% CI, 10.3-12.7; HR, 0.64 95% CI, 0.53-0.78), median PFS was 7.8 mo (95% CI, 6.8-8.5) vs 5.6 mo (95% CI, 5.4-6.7; HR, 0.63 95% CI, 0.51-0.77), ORR was 60.0% vs 43.2%, and median DOR was 10.0 mo (range, 1.2+ to 52.6+) vs 5.7 mo (range, 1.4+ to 41.0+). Among all treated pts, treatment-related AEs were reported in 751 (95.7%; grade 3-5, 466 59.4%) for pembro + chemo and 736 (93.5%; grade 3-5, 404 51.3%) for pbo + chemo. Conclusions: With a median follow-up of 41.6 months, use of pembro + chemo continued to show improved OS, PFS, and ORR vs pbo + chemo, regardless of PD-L1 expression. These results continue to support pembro + chemo as a first-line treatment option for pts with locally advanced or metastatic HER2-negative G/GEJ adenocarcinoma. Clinical trial information: NCT03675737 .