Efficacy and biomarker analysis for nivolumab in cancer of unknown primary: results from an investigator-initiated expanded access program

BACKGROUND: Cancer of unknown primary (CUP) remains a challenging malignancy with a poor prognosis. Although immune checkpoint inhibitors have shown activity in CUP, available data remains limited. We describe clinical outcomes and a comprehensive biomarker analysis from an expanded access trial of nivolumab in CUP. METHODS: Patients with CUP were enrolled regardless of treatment history and received intravenous nivolumab (240 mg every 2 weeks or 480 mg every 4 weeks) until disease progression, unacceptable toxicity, or withdrawal. Enrollment concluded after regulatory approval of nivolumab for CUP in Japan. The primary objective was safety; secondary endpoints addressed efficacy, and exploratory biomarker analyses were performed. RESULTS: A total of 53 patients (31 previously treated, 22 untreated) received nivolumab. Adverse events (AEs) occurred in 77.4% of patients, including 24.5% grade 3-4 and 15.1% serious AEs; no treatment-related deaths occurred. The objective response rate was 17.0% (95% confidence interval [CI] 8.1-29.8%) overall and 20.5% (95% CI 9.8-35.3%) in the response-evaluable subset. Median progression-free survival was 4.5 months (95% CI 2.9-7.9) and median overall survival was 17.5 months (95% CI 11.9-25.1). Higher PD-L1 expression was associated with better efficacy, whereas no meaningful differences were observed across estimated tissue-of-origin subgroups. CONCLUSIONS: This study provides additional prospective evidence consistent with the preceding NivoCUP trial, supporting the reproducibility of the efficacy and safety of nivolumab for patients with CUP. These findings support PD-1-targeted therapy as a feasible treatment option for this rare malignancy. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) identifier, jRCT2051200146.