Nivolumab plus ipilimumab combined with chemotherapy as first-line treatment for HER2-negative unresectable advanced or recurrent gastric/gastroesophageal junction cancer: A randomized phase 3 trial (ATTRACTION-6).

4006 Background: Anti-PD-1 antibodies combined with chemotherapy (Chemo) are established as a standard first-line (1L) treatment for HER2-negative gastric/gastroesophageal (G/GEJ) cancer. Nivolumab (NIVO) and ipilimumab (IPI), an anti-CTLA-4 antibody, have complementary mechanisms of action on tumor immunity. Combining NIVO plus Chemo with IPI is expected to suppress disease progression durably and prolong survival, as suggested in other types of tumors. Methods: ATTRACTION-6 is a randomized, phase 3 trial conducted in Japan, Korea, and Taiwan. Previously untreated patients with HER2-negative unresectable advanced or recurrent G/GEJ cancer were randomized 1:1 to receive NIVO 360 mg every 3 weeks, IPI 1 mg/kg every 6 weeks in addition to Chemo (S-1 plus oxaliplatin SOX or capecitabine plus oxaliplatin CAPOX) or Chemo alone. Randomization was stratified by PD-L1 (CPS≥5 or CPS < 5, indeterminate), ECOG PS (0 or 1), countries (Japan or Korea/Taiwan), and disease status (advanced or recurrent). Primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), objective response rate (ORR) per RECIST v1.1 assessed by site investigator, and safety. Results: Between November 2021 and August 2023, 626 patients were randomized 1:1 to the NIVO + IPI + Chemo arm (N = 315) or the Chemo arm (N = 311). At the median follow-up of 31.3 months, the primary endpoint of OS was not met (HR 0.90; 95.8% CI 0.74-1.09; P = 0.267; median OS 15.7 vs 15.8 months). Median PFS was 8.9 vs 7.7 months (HR 0.83; 95% CI 0.69-1.00). Among patients with ≥1 measurable lesion at baseline, ORR was 57.9% vs 38.5%. Grade≥3 adverse events (AEs) and grade≥3 treatment-related AEs occurred in 80.0% and 64.8% in the NIVO + IPI + Chemo arm, respectively, and 62.4% and 42.9% in the Chemo arm, respectively. Treatment-related deaths occurred in 0.3% vs 0%, and the only observed event was gastroenteritis in the NIVO + IPI + Chemo arm. Conclusions: In ATTRACTION-6 study, NIVO + IPI + Chemo did not improve OS compared with Chemo as 1L treatment for patients with HER2-negative unresectable advanced or recurrent G/GEJ cancer. Although toxicity increased with the addition of NIVO and IPI, no new safety signals were observed. Clinical trial information: NCT05144854 .