The Impact of Molecular Subtype on Efficacy of Chemotherapy and Checkpoint Inhibition in Advanced Gastric Cancer

Purpose: We evaluated the association between molecular sub-types of advanced gastric cancer (AGC) and the efficacy of standard chemotherapy or immune checkpoint inhibitors. Experimental Design: Patients with AGC who received systemic chemotherapy from October 2015 to July 2018 with available molecular features were analyzed. We investigated the efficacy of standard first- (fluoropyrimidine + platinum +/- trastuzumab) and second-line (taxanes +/- ramucirumab) chemotherapy, and subsequent anti-PD-1 therapy in patients with four molecular subtypes: MMR-D (mismatch repair deficient), EBV+, HER2+, and all negative. Results: 410 patients were analyzed: MMR-D 5.9%, EBV+ 4.1%, HER2+ 13.7%, and all negative 76.3%. In 285 patients who received standard first-line chemotherapy, the median progression-free survival (PFS) times were 4.2, 6.0, 7.5, and 7.6 months and the objective response rates (ORR) were 31%, 62%, 60%, and 49% in MMR-D, EBV+, HER2+, and all-negative subtypes, respectively. Multivariate analysis showed shorter PFS in MMR-D versus all-negative patients [HR, 1.97; 95% CIs, 1.09-3.53; P = 0.022]. In second-line setting, there were no significant differences in efficacy. In 110 patients who received anti-PD-1 therapy, median PFS times were 13.0, 3.7, 1.6, and 1.9 months and the ORRs were 58%, 33%, 7%, and 13%, respectively. Twelve patients with MMR-D received subsequent anti-PD-1 therapy and showed longer PFS compared with that in 10 (83%) patients who received earlier-line chemotherapy. Conclusions: MMR-D might result in shorter PFS with first-line chemotherapy for AGC. Subsequent anti-PD-1 therapy achieved higher ORR and longer PFS than prior chemotherapy in most patients with MMR-D, supporting the earlier use of immune checkpoint inhibitors.