Neoadjuvant and adjuvant pembrolizumab plus chemotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: Outcomes from the microsatellite instability-high population of the phase 3 KEYNOTE-585 study.

4074 Background: In the randomized phase 3 KEYNOTE-585 study (NCT03221426), perioperative pembrolizumab (pembro) plus chemotherapy (chemo) significantly improved pathologic complete response (pCR) vs placebo (pbo) plus chemo (diff, 10.9%; 95% CI, 7.5-14.8; P < 0.00001), with no new safety signals in participants (pts) with locally advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. We present outcomes for the microsatellite instability-high (MSI-H) population. Methods: Eligible pts had untreated resectable locally advanced G/GEJ adenocarcinoma (including Siewert type 2 or 3 tumors); MSI was centrally assessed. Pts enrolled in the main cohort (n = 804) received neoadjuvant pembro 200 mg intravenously (IV) every 3 weeks (Q3W) or pbo plus chemo (cisplatin + capecitabine or 5-FU) for 3 cycles; after surgery, pts received adjuvant pembro or pbo plus chemo Q3W for 3 cycles, then adjuvant pembro or pbo Q3W for 11 cycles. Pts in the fluorouracil, docetaxel, and oxaliplatin (FLOT) cohort (n = 203) received neoadjuvant pembro 200 mg IV Q3W or pbo Q3W for 3 cycles plus FLOT Q2W for 4 cycles; after surgery, pts received adjuvant pembro or pbo Q3W for 3 cycles plus FLOT Q2W for 4 cycles, then adjuvant pembro or pbo Q3W for 11 cycles. End points were pCR (blinded independent central review [BICR]), event-free survival (EFS; RECIST v1.1 by BICR), overall survival (OS), and safety. We report outcomes in the main and FLOT cohorts combined. The data cutoff date was February 16, 2024 (final analysis). Results: Data from the 81 pts with MSI-H status were analyzed (n = 43, pembro + chemo; n = 38, pbo + chemo). The pCR rate was 39.5% (95% CI, 25.0-55.6) in the pembro group and 0% (95% CI, 0.0-9.3) in the pbo group (diff, 39.5%; 95% CI, 26.3-54.5). The median EFS was not reached (NR; 95% CI, 49.9-NR) and 60.1 months (95% CI, 18.6-NR), respectively (HR, 0.58; 95% CI, 0.26-1.31); 24/48-month EFS rates were 78%/73% in the pembro group and 68%/68% in the pbo group. The median OS was NR (95% CI, NR-NR) in both treatment groups (HR, 0.50; 95% CI, 0.19-1.30); 24/48-month OS rates were 91%/86% in the pembro group and 76%/74% in the pbo group. Treatment-related adverse events (AEs) occurred in all 43 pts (100%) in the pembro group and 37 (97%) in the pbo group. Grade 3-5 treatment-related AEs occurred in 32 (74%) and 25 (66%) pts, respectively. Discontinuation of any drugs due to treatment-related AEs occurred in 15 pts (35%) in the pembro group and 12 (32%) in the pbo group. No deaths due to treatment-related AEs were reported. Conclusions: In this post hoc analysis, efficacy outcomes for pts with MSI-H G/GEJ adenocarcinoma suggested a consistent trend with numerically more pronounced difference between the treatment groups, with a manageable safety profile. Further studies in this population are warranted. Clinical trial information: NCT03221426 .