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

We evaluated the association between molecular subtypes of advanced gastric cancer (AGC) and the efficacy of standard chemotherapy or immune checkpoint inhibitors.

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.

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.

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.