KEYNOTE-859: 4.5-year median follow-up of pembrolizumab plus chemotherapy for previously untreated advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

4036 Background: In the phase 3KEYNOTE-859 study (NCT03675737), first-linepembrolizumab (pembro) + chemotherapy (chemo) continued to provide longer OS (HR, 0.79; 95% CI, 0.71-0.88) and PFS (HR, 0.76; 95% CI, 0.68-0.85), and a higher ORR (51.0% vs 42.0%) vs placebo + chemo in participants (pts) with HER2-negative G/GEJ adenocarcinoma, after a median follow-up of 41.6 mo (August 22, 2023). We present results after an additional 13 mo of follow-up. Methods: Eligible pts with untreated locally advanced or metastatic HER2-negative G/GEJ adenocarcinoma with PD-L1 status, measurable disease, and ECOG PS 0 or 1 were randomly assigned 1:1 to receive pembro 200 mg or placebo 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 September 27, 2024. Results: Median follow-up was 54.8 mo (Q1-Q3, 46.8-62.1). In all randomly assigned pts in the intention-to-treat population (N = 1579), 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 placebo + chemo (HR, 0.78; 95% CI, 0.70-0.86). In pts with PD-L1 CPS ≥1, median OS was 13.0 mo (95% CI, 11.6-14.2) vs 11.4 mo (95% CI, 10.5-12.0; HR, 0.74 [95% CI, 0.66-0.84]). In pts with PD-L1 CPS ≥10, 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, 0.53-0.77]). PFS, ORR, and DOR were also consistent between the intention-to-treat population and pts with PD-L1 CPS ≥1 and PD-L1 CPS ≥10 (Table). Treatment-related AEs were reported in 751 pts (95.7%; grade 3-5, 466 [59.4%]) for pembro + chemo and 736 (93.5%; grade 3-5, 404 [51.3%]) for placebo + chemo. Conclusions: Pembro + chemo continued to show improved OS, PFS, and ORR vs placebo + chemo after a median study follow-up of 54.8 mo, regardless of PD-L1 status. The findings further support pembro + chemo as a first-line treatment option for locally advanced or metastatic HER2-negative G/GEJ adenocarcinoma. Clinical trial information: NCT03675737 . All ptsN = 1579 PD-L1 CPS ≥1n = 1235 PD-L1 CPS ≥10n = 553 Pembro + chemo n = 790 Pbo + chemo n = 789 Pembro + chemo n = 618 Pbo + chemo n = 617 Pembro + chemo n = 280 Pbo + chemo n = 273 OS, median (95% CI), mo 12.9 (11.9-14.0) 11.5 (10.6-12.1) 13.0 (11.6-14.2) 11.4 (10.5-12.0) 15.8 (14.0-19.3) 11.8 (10.3-12.7) HR (95% CI) 0.78 (0.70-0.86) 0.74 (0.66-0.84) 0.64 (0.53-0.77) PFS, median (95% CI), mo 6.9 (6.3-7.2) 5.6 (5.5-5.7) 6.9 (6.0-7.2) 5.6 (5.4-5.7) 7.8 (6.8-8.5) 5.6 (5.4-6.7) HR (95% CI) 0.76 (0.68-0.85) 0.72 (0.64-0.82) 0.62 (0.51-0.76) ORR, % (95% CI) 51.1 (47.6-54.7) 42.0 (38.5-45.5) 51.9 (47.9-55.9) 42.6 (38.7-46.6) 60.4 (54.4-66.1) 43.2 (37.3-49.3) DOR, median (range), mo 8.0(1.2+ to 66.3+) 5.7(1.3+ to 58.1+) 8.3(1.2+ to 66.3+) 5.6(1.3+ to 58.1+) 10.0(1.2+ to 66.3+) 5.7(1.4+ to 55.0+)