Clinical benefit of PD-1 antibody plus chemotherapy in advanced HER2 negative gastric or gastro-oesophageal junction adenocarcinoma according to PD-L1 levels: Post-hoc analysis of RATIONALE-305 and pooled analysis of individual patient-level data.

While multiple phase III trials have established the survival benefit of adding a programmed cell death protein 1 (PD-1) antibody to first-line chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, evidence across different programmed cell death ligand 1 (PD-L1) expression levels remains limited, preventing definitive conclusions about the superiority of combination therapy in certain subgroups. We firstly performed a post-hoc analysis of the RATIONALE-305 trial, finding only marginal benefit in the 1 ≤ tumor area positivity (TAP) < 5 and 1 ≤ combined positive score (CPS) < 5 subgroups. Subsequently, we performed a pooled analysis of individual patient-level data from RATIONALE-305 and four additional phase III trials (CheckMate 649, KEYNOTE-062, KEYNOTE-859, and ORIENT-16). The pooled analysis demonstrated that adding a PD-1 antibody to chemotherapy significantly improved overall survival in patients with intermediate PD-L1 levels (1 ≤ CPS < 10: HR, 0.84; 95% CI, 0.75-0.93), including the lower intermediate subset (1 ≤ CPS < 5: HR, 0.85; 95% CI, 0.75-0.97), but not in the CPS < 1 subgroup (HR, 0.96; 95% CI, 0.82-1.14). Progression-free survival results were consistent with those for overall survival, and improvements in objective response rate were observed across all subgroups. In conclusion, this study provides novel evidence that the combination therapy is superior to chemotherapy alone in patients with advanced HER2-negative G/GEJ adenocarcinoma and PD-L1 CPS ≥ 1.