Tremelimumab with or without durvalumab in combination with paclitaxel in metastatic urothelial cancer: phase I/II ICRA trial

New therapeutic strategies for patients with therapy-refractory metastatic urothelial carcinoma (mUC) are still needed. In the phase I-II ICRA trial, a multicenter, open-label, phase Ib-II clinical trial (NCT03871036), we evaluated whether paclitaxel plus tremelimumab, with or without durvalumab, could induce a tumor response in mUC following platinum chemotherapy and immune checkpoint inhibition (ICI). Patients were randomized between three arms: A (n = 20) paclitaxel plus T750mg; B (n = 12) paclitaxel plus T300mg plus D1500mg; C (n = 12) T750mg. The primary outcome, objective response rate, was met with 26% in arm A (88% CI = [14,36%]) versus 17% (88% CI = [3,42%]) in arm B and 8% (88% CI = [0.3,33%]) in arm C. Secondary outcomes included safety, duration of response and survival. Grade 3-4 treatment-related adverse events occurred in (A) 45%, (B) 75%, and (C) 25% of patients. Murine experiments showed attenuated tumor outgrowth for paclitaxel plus anti-CTLA-4 compared to monotherapy with either agent. Transcriptomic analyses showed upregulation of inflammation signatures in on-treatment tumor tissue biopsies. This study demonstrated encouraging antitumor activity in therapy-refractory mUC treated with paclitaxel plus high-dose anti-CTLA-4 and suggests immune induction may still be possible after failure to anti-PD-(L)1 therapy. Therapeutic options for patients with treatment-refractory metastatic urothelial carcinoma (mUC) are much needed. Here, the authors report the outcomes and translational analysis of the phase I/II ICRA trial evaluating whether paclitaxel plus tremelimumab (anti-CTLA-4) with or without durvalumab (anti-PD-L1) induces a tumor response in patients with mUC.