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 patients with metastatic urothelial carcinoma (mUC). 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 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 ORRs were 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. The median OS rates were 24.74 and 16.43 months for the carboplatin 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 chemoimmunotherapy, versus carboplatin-based chemoimmunotherapy, did not yield a higher response rate, challenging assumptions based on preclinical data.