Histology Classification Highlights Differences in Efficacy of S-1 versus Capecitabine, in Combination with Cisplatin, for HER2-Negative Unresectable Advanced or Recurrent Gastric Cancer with Measurable Disease

Simple Summary There is no clear preference between S-1 and capecitabine in combination with platinum agent as first-line therapy for patients with HER2-negative unresectable advanced or recurrent gastric cancer (GC) with measurable disease. Although a distinguishing use of S-1 versus capecitabine based on histological classification has been studied, the present integrated analysis, using 162 individual participant data of GC patients with measurable disease, is the first to show that S-1 plus cisplatin (SP) achieves deeper tumor shrinkage than capecitabine plus cisplatin (XP), leading a longer overall survival although no differences in response rate or progression-free survival in differentiated GC. On the other hand, in undifferentiated GC, SP consistently showed better clinical results than XP. These findings thus have implications for the choice of oral fluoropyrimidine in the era of first line therapy in combination with oxaliplatin and immune checkpoint inhibitor. Abstract It has been suggested that the therapeutic efficacy of S-1 + cisplatin (SP) and capecitabine + cisplatin (XP) may differ depending on the histology of the tumor, but no clear evidence exists. Individual participant data were obtained from three randomized phase II trials in which such patients received either SP (S-1 [40–60 mg twice daily for 21 days] plus cisplatin [60 mg/m2 on day 8], every 5 weeks) or XP (capecitabine [1000 mg/m2 twice daily for 14 days] plus cisplatin [80 mg/m2 on day 1], every 3 weeks). A total of 162 patients were included, with 79 patients in the SP arm and 83 patients in the XP arm. Although there was also no difference between arms in ORR according to histological classification, differentiated tumors showed a significantly better OS (but not PFS) for SP versus XP that was associated with a deeper tumor shrinkage. Undifferentiated tumors showed a consistently better OS, and PFS for SP versus XP, likely because cases without tumor shrinkage tended to be fewer for SP. Our data thus showed that SP was superior to XP in this setting, but there were qualitative differences in therapeutic efficacy dependent on tumor histology.