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<p>New therapeutic strategies for&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Sarah M. H. Einerhand,
  • Hamza Ali,
  • Stephen Q. Wong,
  • Jeroen van Dorp,
  • Tatum van Maanen,
  • Jeantine M. de Feijter,
  • Maurits L. van Montfoort,
  • Thierry N. Boellaard,
  • Linde M. Braaf,
  • Wim Brugman,
  • Daniel J. Vis,
  • Cindy M. J. Hollander,
  • Antonios Daletzakis,
  • Helga A. Schrijver,
  • Karen Snapper,
  • Sjoukje F. Oosting,
  • Cheryl P. Bruijnen,
  • Lodewyk F. A. Wessels,
  • Keith S. Chan,
  • Britt B. M. Suelmann,
  • Michiel S. van der Heijden

摘要

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.