Final analysis of the efficacy and safety of oral S-1 for locally advanced or recurrent/metastatic cutaneous squamous cell carcinoma: A multicenter retrospective study.

9586 Background: Anti–PD-1 antibodies are the standard systemic therapy for advanced cutaneous squamous cell carcinoma (cSCC). Recent clinical trials have reported objective response rates (ORRs) of 44–58.3% in locally advanced (LA) disease and 35.2–45.2% in recurrent or metastatic (R/M) disease, with grade ≥3 adverse events occurring in 31.1–34.5% of patients. S-1, an oral fluoropyrimidine, has been suggested as an alternative option with potential advantages, including favorable clinical response, lower toxicity, feasibility of outpatient initiation, and substantially lower cost; however, evidence remains limited to small case series. We therefore conducted a large multicenter retrospective study to evaluate the real-world efficacy and safety of S-1 in patients with advanced cSCC. Methods: This multicenter retrospective study included patients with LA or R/M cSCC who received oral S-1 between 2007 and 2024. S-1 was administered for 28 consecutive days, followed by 14 days off (one cycle). The primary endpoint was ORR assessed according to RECIST criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Exploratory subgroup analyses were performed based on concomitant radiotherapy use and primary tumor site. Results: A total of 150 patients were analyzed (LA, n = 44; R/M, n = 106). The median age was 76 years (interquartile range, 67–83), and ECOG performance status was 0–1 in 127 patients (85%). Fifty-four patients (36%) had received prior systemic treatment. Among the R/M cohort, 59 patients had nodal metastasis and 47 had distant metastasis. The median follow-up was 13.4 months (LA, 15.0 months; R/M, 12.7 months). ORR was 55% (95% confidence interval [CI], 39–70) in the LA cohort and 40% (95% CI, 30–50) in the R/M cohort. The 12-month PFS and OS rates were 80% and 92% (95% CI, 63–90 and 76–97) in the LA cohort, and 41% and 62% (95% CI, 30–50 and 51–71) in the R/M cohort. Grade ≥3 adverse events occurred in 14% of patients, most commonly anemia (n = 4), thrombocytopenia (n = 3), neutropenia (n = 3), decreased appetite (n = 3), and oral mucositis (n = 3); no grade 5 events were observed. In exploratory analyses, patients receiving concomitant radiotherapy demonstrated higher ORR and PFS compared with those without radiotherapy, while OS was comparable between the groups. Tumors originating in the head and neck region were associated with superior ORR, PFS, and OS compared with other primary sites. Conclusions: Oral S-1 demonstrated antitumor activity comparable to that reported for anti–PD-1 antibodies, albeit without direct comparison, with a lower incidence of severe adverse events, suggesting its potential role in selected patients with advanced cSCC.