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

Abstract

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.

Keywords: ibrutinib; paclitaxel; pembrolizumab; urothelial carcinoma.

Figure 1

PFS per investigator assessment for (A) single-agent ibrutinib, (B) ibrutinib plus pembrolizumab, and (C) ibrutinib plus paclitaxel. Abbreviations: NE, not evaluable; PFS, progression-free survival.

Figure 2

OS with (A) single-agent ibrutinib, (B) ibrutinib plus pembrolizumab, and (C) ibrutinib plus paclitaxel. Abbreviations: NE, not evaluable; OS, overall survival.

Figure 3

Relevant kinase expression in baseline tumor samples from the ibrutinib plus paclitaxel cohort. Included two patients from phase 1b who received ibrutinib 560 mg. Abbreviations: BTK, Bruton’s tyrosine kinase; CR, complete response; EGFR, epidermal growth factor receptor; ERBB2, ERB-B2 receptor tyrosine kinase 2; ETK/BMX, epithelial and endothelial tyrosine kinase/bone marrow X kinase; ITK, interleukin-2–inducible T-cell kinase; PD, progressive disease; PR, partial response; SD, stable disease.