LAUSR

Recent therapeutic advances for mantle cell lymphoma (MCL) include inhibitors of Bruton’s tyrosine kinase (BTK), a critical component in the B-cell receptor signaling pathway [1, 2]. Remarkably, approximately two thirds of patients with relapsed/refractory (R/R) MCL treated with ibrutinib, the first-in-class BTK inhibitor, achieve a durable response [3–5]. However, ibrutinib treatment also commonly produces off-target adverse events (AEs) such as bleeding, atrial fibrillation, diarrhea, and infection. Second-generation BTK inhibitors with greater selectivity include tirabrutinib (GS/ONO-4059), acalabrutinib, and BGB-3111 [6]. In 2017, acalabrutinib received FDA approval for the treatment of MCL based on a complete response (CR) rate of 40% and an overall response rate (ORR) of 81% at a median follow-up of 15.2 months in a phase 2 study [7]. Tirabrutinib has demonstrated significant activity without major drug-related toxicities in a phase 1 study in R/R B-cell malignancies [8] and on extended, 3-year follow-up of patients with chronic lymphocytic leukemia [9]. Here, we provide 3-year follow-up data from patients with MCL in the phase 1 tirabrutinib extension study (NCT02457559). Tirabrutinib was evaluated in six patient cohorts (at doses ranging from 20 to 600 mg daily) with R/R B-cell malignancies for safety and tolerability in the POE001 phase 1 clinical study (NCT01659255). Of the 90 patients who received treatment between September 2012 and January 2015, those with continuing response or stable disease were eligible for the subsequent long-term extension study and continued at the tirabrutinib dose received in the parent study. Once safety was established, dose increases were permitted at the discretion of the investigator. Independent ethics committees at each study site approved the protocol, and all patients provided written informed consent. All statistical analyses of safety and efficacy endpoints included all patients who were enrolled in the parent study and received ≥1 dose of tirabrutinib. Kaplan-Meier methods were used to analyze progression-free survival (PFS) (the time from start of treatment until definitive progressive disease [PD] or death). ORR (the proportion of patients achieving CRs or partial responses [PRs]), duration of response (DOR), and overall survival were also assessed. Sixteen patients with R/R MCL were enrolled in the extension study. The median patient age was 64 years (range 52–81); 75% of patients were male. Patients had a median of three prior therapies (range 2–8) and five patients (31%) had received previous transplants (n= 3 autologous * Simon A. Rule [email protected]