Gemcitabine plus nivolumab with carboplatin or oxaliplatin in cisplatin-ineligible patients with metastatic urothelial carcinoma: a randomized phase II trial.

Purpose Oxaliplatin has demonstrated the ability to sensitize tumors to immune checkpoint blockade through its immunomodulatory properties in model systems of cancer. This randomized trial aimed to evaluate gemcitabine/oxaliplatin and gemcitabine/carboplatin, each combined with nivolumab, in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. Patients and Methods Cisplatin-ineligible patients with mUC were randomized 1:1 to gemcitabine/carboplatin plus nivolumab or gemcitabine/oxaliplatin plus nivolumab for up to 6 cycles, followed by nivolumab monotherapy. A pick-the-winner design was employed with objective response rate (ORR) as the primary endpoint. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory analyses evaluated plasma protein analytes, circulating immune cell populations, and circulating tumor cells. Results Forty-nine patients were enrolled (carboplatin arm, N = 25; oxaliplatin arm, N = 24). The ORR was 69.6% (95% confidence interval [CI] 0.48-0.87) for the carboplatin arm and 33.3% (95% CI 0.15-0.57) for the oxaliplatin arm. Median OS was 24.74 months and 16.43 months for the carboplatin group and oxaliplatin arms, respectively (hazard ratio 1.99, 95% CI 0.94-4.22; p = 0.07). Exploratory biomarker analyses revealed sustained adaptive immune activation in the carboplatin arm and features suggestive of tumor-promoting inflammation in the oxaliplatin arm. Conclusions Oxaliplatin-based chemo-immunotherapy, versus carboplatin-based chemo-immunotherapy, did not yield a higher response rate, challenging assumptions based on preclinical data.