Randomized controlled phase II trial comparing nivolumab, ipilimumab plus radiotherapy versus nivolumab plus ipilimumab for metastatic or recurrent esophageal cancer: Japan Clinical Oncology Group study JCOG2311 (ART NOUVEAU).

TPS461 Background: Nivolumab plus ipilimumab (NIVO+IPI) is one of the standard first-line treatments for advanced or recurrent esophageal squamous cell carcinoma. It has shown encouraging sustained response duration in some patients; however, early treatment failure is an issue to be addressed. The immunogenic cell death (ICD) induced by radiotherapy (RT) has the potential to enhance the systemic antitumor effects of immune checkpoint inhibitors (ICIs). Some randomized phase II trials suggested that ICD induced by RT with ICIs decreased early treatment failures without new safety concerns. NIVO+IPI, dual ICI regimen, is consideredmost promising combination for synergistic effect with RT in patients with advanced or recurrent esophageal squamous cell carcinoma. Methods: We have designed a randomized phase II trial to compare RT followed by NIVO+IPI with NIVO+IPI alone. Eligibility criteria include the followings: histologically confirmed esophageal squamous cell carcinoma, adenosquamous carcinoma, or basaloid squamous cell carcinoma; known tumor proportion score; advanced/recurrent disease; at least two separate lesions: one of which is measurable according to the RECIST version 1.1, and the other of which is amenable to RT; 18 years or older, ECOG performance status 0 or 1; and adequate organ function. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, response rate, duration of response, and adverse events. Enrolled patients will be randomized (1:1) to either NIVO (240 mg/body every 2 weeks or 360 mg/body every 3 weeks)+IPI (1mg/kg every 6 weeks) or RT of 24 Gy/3 fractions or 25 Gy/5 fractions, followed by NIVO+IPI. We assumed a six-month PFS of 35% in NIVO+IPI and expected a 15% increase for RT followed by NIVO+IPI (hazard ratio, 0.66). The total required sample size was calculated as 70 (35 per arm) to achieve a power of 80% for comparison with a one-sided alpha of 20%, an accrual period of 2.5 years, and a follow-up period of 1 year. The planned sample size was 74 patients. This trial, registered as jRCT1031240461, commenced on November 5, 2024, and 12 patients were enrolled as of July 29, 2025. Clinical trial information: jRCT1031240461 .