Results from a Phase 1b/2 Study of Ibrutinib Combination Therapy in Advanced Urothelial Carcinoma

• Published in: Cancers Vol. 15; no. 11; p. 2978
• Main Authors: Mar, Nataliya, Zakharia, Yousef, Falcon, Alejandro, Morales-Barrera, Rafael, Mellado, Begona, Duran, Ignacio, Oh, Do-Youn, Williamson, Stephen K, Gajate, Pablo, Arkenau, Hendrik-Tobias, Jones, Robert J, Teo, Min Yuen, Turan, Tolga, McLaughlin, Robert T, Peltier, Hillary M, Chong, Elizabeth, Atluri, Harisha, Dean, James P, Castellano, Daniel
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30.05.2023; MDPI
• Subjects: Cancer; Carcinoma; Care and treatment; Cell survival; Chemotherapy; Drug dosages; Graft-versus-host reaction; Hypotheses; Hypothesis testing; ibrutinib; Immunosuppressive agents; Kinases; Lymphocytes B; Malignancy; Medical prognosis; Oral administration; Paclitaxel; Pembrolizumab; Product development; Protein-tyrosine kinase; Response rates; Safety; Tyrosine; Urothelial carcinoma; Spain; United States > US; ibrutinib; paclitaxel; pembrolizumab; urothelial carcinoma
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15112978

Ibrutinib is a first-in-class Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. We evaluated the safety and efficacy of ibrutinib, alone or combined with standard-of-care regimens, in adults with advanced urothelial carcinoma (UC). Once-daily ibrutinib was administered orally at 840 mg (single-agent or with paclitaxel) or at 560 mg (with pembrolizumab). Phase 1b determined the recommended phase 2 dose (RP2D) of ibrutinib, and phase 2 assessed progression-free survival (PFS), overall response rate (ORR), and safety. Thirty-five, eighteen, and fifty-nine patients received ibrutinib, ibrutinib plus pembrolizumab, and ibrutinib plus paclitaxel at the RP2D, respectively. Safety profiles were consistent with those of the individual agents. The best-confirmed ORRs were 7% (two partial responses) with single-agent ibrutinib and 36% (five partial responses) with ibrutinib plus pembrolizumab. Median PFS was 4.1 months (range, 1.0-37.4+) with ibrutinib plus paclitaxel. The best-confirmed ORR was 26% (two complete responses). In previously treated patients with UC, ORR was higher with ibrutinib plus pembrolizumab than with either agent alone (historical data in the intent-to-treat population). ORR with ibrutinib plus paclitaxel was greater than historical values for single-agent paclitaxel or ibrutinib. These data warrant further evaluation of ibrutinib combinations in UC.