Comparison between nivolumab plus ipilimumab, FOLFOX and nivolumab plus FOLFOX therapy as first-line treatment for cisplatin-unfit advanced esophageal squamous cell carcinoma.

388 Background: Nivolumab plus platinum-based chemotherapy and nivolumab plus ipilimumab (Nivo+Ipi) therapy are standard first-line treatments for advanced esophageal squamous cell carcinoma (ESCC) based on the results of the CheckMate 648 trial. However, patients with renal or cardiac dysfunction, as well as elderly patients might be unfit for cisplatin-containing regimens because of their toxicities and needs for hydration. Therefore, leucovorin, 5-FU, and oxaliplatin (FOLFOX) therapy is one of the treatment options in cisplatin-unfit population. In addition, Nivo+Ipi and nivolumab plus FOLFOX (Nivo+FOLFOX) therapy might be alternative options for these population. However, there are no data on these regimens in cisplatin-unfit population. Methods: This retrospective study included cisplatin-unfit patients with histologically confirmed advanced ESCC treated with Nivo+Ipi, FOLFOX, or Nivo+FOLFOX in our hospital from March 2021 to July 2025 for the first-line treatment. Efficacy was evaluated by objective response rate (ORR) assessed by the RECIST ver.1.1, progression-free survival (PFS), and overall survival (OS). To evaluate safety, adverse events were assessed by CTCAE ver. 5.0. Results: Fifty patients were included (median age, 75 range: 51–86 years; male/female, 82/18%; performance status 0/1/≥2, 20/70/10%; disease status advanced/recurrent, 60/40%; tumor location Ce/Ut/Mt/Lt, 14/18/48/20%; metastatic location lymph node/liver/lung/bone, 82/16/26/6%). Eighteen (36%), 18 (36%), and 14 (28%) patients received Nivo+Ipi, FOLFOX, and Nivo+FOLFOX therapy, respectively. Median follow-up time was 11.1 (range: 1–39) months. PFS was significantly longer with Nivo+Ipi than with FOLFOX (median 9.4 vs 3.2 months; hazard ratio HR 0.26, 95% CI 0.11–0.65, p = 0.002). There were no significant differences in OS (median 16.2 vs 13.3 months; HR 0.78, 95% CI 0.28–2.18, p = 0.640) and ORR (38% vs 24%, p = 0.383) between the Nivo+Ipi and FOLFOX groups. Nivo+FOLFOX group showed significant improvements in PFS (median 6.7 vs 3.2 months; HR 0.34, 95% CI 0.14–0.83, p = 0.013) and ORR (75% vs 24%, p = 0.006) compared with FOLFOX group. There were no significant differences in OS (median 15.6 vs 13.3 months; HR 0.88, 95% CI 0.29–2.64, p = 0.805) between the Nivo+FOLFOX and FOLFOX groups. The most common any grade adverse events were rash in Nivo+Ipi group (n = 3, 17%) and neutropenia in FOLFOX (n = 5, 28%) and Nivo+FOLFOX (n = 6, 43%) group. Grade ≥3 immune-related adverse events were observed in 11% (1: pneumonia, 1: hypophysitis) and 21% (2: pneumonia, 1: erythema multiforme) of patients in the Nivo+Ipi and Nivo+FOLFOX group, respectively. Conclusions: Nivo+Ipi and Nivo+FOLFOX seemed to show better efficacy compared to FOLFOX alone and be well-tolerated for cisplatin-unfit advanced ESCC.