TY - JOUR
T1 - Tremelimumab with or without durvalumab in combination with paclitaxel in metastatic urothelial cancer
T2 - phase I/II ICRA trial
AU - Einerhand, Sarah M.H.
AU - Ali, Hamza
AU - Wong, Stephen Q.
AU - van Dorp, Jeroen
AU - van Maanen, Tatum
AU - de Feijter, Jeantine M.
AU - Montfoort, Maurits L.van
AU - Boellaard, Thierry N.
AU - Braaf, Linde M.
AU - Brugman, Wim
AU - Vis, Daniel J.
AU - Hollander, Cindy M.J.
AU - Daletzakis, Antonios
AU - Schrijver, Helga A.
AU - Snapper, Karen
AU - Oosting, Sjoukje F.
AU - Bruijnen, Cheryl P.
AU - Wessels, Lodewyk F.A.
AU - Chan, Keith S.
AU - Suelmann, Britt B.M.
AU - van der Heijden, Michiel S.
N1 - Publisher Copyright:
© The Author(s) 2026.
PY - 2026
Y1 - 2026
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105046397229
U2 - 10.1038/s41467-026-74570-3
DO - 10.1038/s41467-026-74570-3
M3 - Article
C2 - 42310313
AN - SCOPUS:105046397229
SN - 2041-1723
VL - 17
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 7679
ER -