KEY TAKEAWAYS
- The study aimed to offer a third interim analysis of the phase III KEYNOTE-585 study that compared pembro vs. chemo alone in locally advanced G/GEJ cancer.
- The endpoints were pCR, PFS, and OS.
- Pembro with chemo boosted complete response in resected G/GEJ cancer but didn’t extend event-free survival compared to standard chemo.
Researchers in the KEYNOTE-585 Phase 3 trial assessed the efficacy of neoadjuvant/adjuvant pembrolizumab (pembro) or placebo (pbo) combined with chemotherapy (chemo). The trial was followed by adjuvant pembro compared to pbo in patients with locally advanced, resectable gastric or gastroesophageal junction (G/GEJ) cancer. The outcomes from a distinct cohort receiving pembro with FLOT were presented based on the pre-defined third interim analysis (IA3).
Patients with untreated, locally advanced, resectable G/GEJ cancer were randomly assigned in a 1:1 ratio to receive neoadjuvant pembro (200 mg IV Q3W) or pbo, along with chemo (cisplatin + capecitabine or cisplatin + 5-FU) for 3 cycles. Post-surgery, patients received adjuvant pembro or pbo with chemo Q3W for 3 cycles, followed by adjuvant pembro or pbo Q3W for 11 cycles (main cohort). In the FLOT cohort, patients were randomized 1:1 to receive pembro with docetaxel, oxaliplatin, leucovorin, and 5-FU Q2W.
The primary endpoints included pathologic complete response rate (assessed by BICR), event-free survival (evaluated by RECIST 1.1, investigator), overall survival (OS) [main cohort], and safety [FLOT cohort].
As a part of the study, a total of 804 patients were randomized in the main cohort (402 pembro; 402 pbo) and 1007 in the main + FLOT cohort (502 pembro; 505 pbo). The median follow-up was 47.7 months (mo) for the main cohort and 46.3 mo for the main + FLOT cohort. In the main cohort, the pathologic (pathCR) complete response significantly improved with pembro + chemo (12.9% [95% CI, 9.8-16.6]) compared to pbo + chemo (2.0 [95% CI, 0.9-3.9]), Δ (10.9% [95% CI, 7.5-14.8]; P<0.00001).
Event-free survival (EFS) was prolonged with pembro vs pbo (median 44.4 vs 25.3 mo; HR 0.81, 95% CI: 0.67-0.99; P=0.0198), but did not reach significance. OS is pending final analysis; at IA3, median OS was 60.7 vs 58.0 mo (HR 0.90, 95% CI: 0.73-1.12). Grade ≥3 drug-related adverse event rates were 65% with pembro + chemo and 63% with pbo + chemo.
The result showed that adding pembrolizumab to chemo in operable G/GEJ cancer ups the eradication rate but fails to lengthen the time to relapse compared to chemo alone.
Clinical Trial: https://clinicaltrials.gov/study/NCT03221426
K. Shitara, S.Y. Rha, L.S. Wyrwicz, et al. Pembrolizumab plus chemotherapy vs. chemotherapy as neoadjuvant and adjuvant therapy in locally-advanced gastric and gastroesophageal junction cancer: The phase III KEYNOTE-585 study. ESMO 2023; Abstract LBA74.
