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Correlative Studies in Protocol GU16-287, which Studied Gemcitabine + (Carboplatin or Oxaliplatin) + Nivolumab in Metastatic Urothelial Cancer, which Included Collaboration with CIMAC-CIDC (Cohort 1 of 3)

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.