ONO-4578 combined with nivolumab (NIVO) and chemotherapy (chemo) as first-line (1L) treatment for patients with HER2-negative unresectable advanced or recurrent (adv/rec) gastric/gastroesophageal junction cancer (G/GEJ): A randomized, double-blind, phase 2 trial (ONO-4578-08).

Abstract

4007 Background: Anti-PD-1 antibodies combined with chemo are the standard 1L treatment for HER2-negative G/GEJ cancer. Prostaglandin E 2 (PGE 2 )-EP4 signaling is known to induce immunosuppressive tumor microenvironment, by inducing the differentiation of MDSCs and M2 macrophages, potentially contributing to resistance to immunotherapy. ONO-4578, an EP4 antagonist, is expected to modulate tumor immunosuppression through inhibiting the PGE 2 -EP4 signaling and to enhance the efficacy of anti-PD-1 antibody. The addition of ONO-4578 appeared to augment the efficacy of NIVO in patients with G/GEJ cancer in the previous phase 1 trial. This study aimed to evaluate the efficacy and safety of ONO-4578 combined with NIVO and chemo compared with placebo combined with NIVO and chemo as 1L treatment for patients with unresectable adv/rec G/GEJ cancer. Methods: ONO-4578-08 study is a randomized, double-blind, phase 2 trial conducted in Japan, Korea, and Taiwan. Chemo-naïve patients with HER2-negative adv/rec G/GEJ cancer were randomized in a 2:1 ratio (ONO-4578 group:placebo group), stratified by PD-L1 expression level (CPS < 5 vs CPS≥5), ECOG performance status (0 vs 1), presence of peritoneal metastasis (yes vs no). Patients in each group received ONO-4578 40 mg or placebo once daily, and all received NIVO 360 mg every 3 weeks and chemo (SOX [S-1 + oxaliplatin]/CAPOX [capecitabine + oxaliplatin]). The primary endpoint was investigator-assessed progression-free survival (PFS), powered (two-sided α = 0.10) to detect a HR of 0.65 with 117 events in a planned enrollment of 210 patients; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results: Between December 2023 and September 2024, 226 patients were randomized to each group (150 vs 76 patients). With a median follow-up of 8.5 months, PFS was significantly longer in the ONO-4578 group than the placebo group with a hazard ratio (HR) of 0.67 (90% confidence interval [CI]: 0.48–0.92; P = 0.040; median PFS: 9.0 vs 6.9 months). At a minimum follow-up of 7.4 months, OS favored the ONO-4578 group (median OS: not reached vs 12.7 months; HR: 0.60 [95% CI: 0.37–0.96]). ORR was also higher in the ONO-4578 group (62.0% vs 48.7%). The most common treatment-emergent adverse events (TEAEs) in the ONO-4578 group were diarrhea (55.7% vs 45.3%), anemia (55.0% vs 34.7%), and peripheral sensory neuropathy (50.3% vs 46.7%). Serious TEAEs occurred in 53.7% of patients in the ONO-4578 group and 42.7% in the placebo group. Conclusions: ONO-4578 combined with NIVO and chemo significantly improved PFS compared with placebo combined with NIVO and chemo in treatment-naive patients with HER2-negative unresectable adv/rec G/GEJ cancer with no new safety concerns. Clinical trial information: NCT06256328 .