Multicenter randomized phase II study of short course FOLFOX + nivolumab (Nivo) followed by maintenance Nivo +/- radiation (RT) in the first line treatment of metastatic or unresectable gastroesophageal adenocarcinoma (mGEA).

4060 Background: Standard 1L treatment of mGEA is chemotherapy with checkpoint inhibition (CPI). However, prolonged cytotoxic therapy can impair CPI efficacy by reducing effective immune infiltration over time. Alternatively, radiotherapy (RT) can augment CPI efficacy in multiple malignancies. In this randomized phase II multicenter study, we examined short course chemotherapy and the potential of RT in improving the efficacy of CPI. Methods: This was a multicenter study of FOLFOX + Nivo for 3 months followed by maintenance Nivo with or without RT (20Gy in 5 fractions to the dominant lesion). Eligible patients had adequate end organ function, measurable disease, and were CPI candidates, regardless of PD-L1 CPS expression. Patients without progression at 2 months were randomized 1:1 to Nivo or Nivo + RT. The primary objective was to demonstrate that adding RT to Nivo in the maintenance setting improved efficacy as measured by 12-month progression free survival (PFS) rate. A secondary objective was to demonstrate that the efficacy of short course chemo is similar to continuing FOLFOX until progression (from CM649, 12-mo PFS 34% 95% CI: 30-38% all pts). Results: Seventy-three evaluable pts enrolled from 7/11/2019 to 4/13/2023. Mean age 63.1, M:F 2.7:1. PD-L1 distribution: CPS > 5 in n=37 (50.7%), CPS 1-4 16 (22%), CPS <1 20 (27.4%). Seven (9.6%) patients progressed at 2 months and had a median OS of 90d (95%CI 44-178d). The remaining 66 patients were randomly assigned to Nivo maintenance (n=32), or Nivo + RT (n=34). The objective response rate for all evaluable pts is 43.8% (95%CI 32.5-55.2%). The 12-month and median PFS for all evaluable pts (n=73) is 29.5% (19.2- 40.7%) and 7.4 mo (5.7-8.6mo); for Nivo alone 34.4% (18.8- 50.6%) and 7.5mo (5.4-14.2mo), and Nivo + RT 30.0% (14.9-46.8%) and 7.8 mo (5.7-9.6mo) respectively (p=NS). The 12-month and median OS for all evaluable pts (n=73) is 60.9% (48.6-71.1%) and 16mo (10.8-22.4mo); for Nivo alone 71.9% (52.9- 84.3%) and 22.4mo (13.2-NAmo), and Nivo + RT 62.8% (43.7-76.9%) and 17.9 mo (10.3-24.5mo) respectively (p=NS). Forty-nine patients progressed after randomization, of which 30 patients were rechallenged with FOLFOX or CAPOX with continued response – median time to 2 nd progression 3.93mo (range 0.5-15.2mo). Amongst patients who were rechallenged with oxaliplatin based therapy, the median time to oxaliplatin failure was 13.76 mo (range 4.4–30mo). Conclusions: Short course FOLFOX + Nivo followed by maintenance Nivo has a similar progression free and overall survival to continuing FOLFOX + Nivo until progression. Patients who receive short course chemotherapy can successfully be rechallenged with oxaliplatin. The addition of RT to maintenance Nivo does not improve CPI efficacy. Short course FOLFOX with CPI is a safe and effective 1L option for mGEA. Clinical trial information: NCT04021108 .