Efficacy of Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Relapsed / Refractory Waldenström Macroglobulinemia: Results from the Phase 1/2 BRUIN Study

Abstract

Background: Covalent Bruton tyrosine kinase inhibitors (BTKi) have been an important advancement for the treatment of Waldenström macroglobulinemia (WM), but these agents are non-curative, and treatment effectiveness can be limited by intolerance and resistance. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib is well tolerated and has demonstrated promising efficacy in patients (pts) with poor-prognosis B-cell malignancies following prior therapy, including prior covalent BTKi (Mato et al. Lancet, 2021). Here, we report the first sizeable cohort of WM pts from the BRUIN study (NCT03740529). Methods: Pts with previously treated B-cell malignancies, including previously treated WM, were eligible for treatment with pirtobrutinib monotherapy in either the dose escalation or expansion portion of the multicenter phase 1/2 BRUIN study. Key endpoints included investigator-assessed overall response rate (ORR) and duration of response (DoR), per modified IWWM6 criteria (Treon. Blood, 2015), and safety. A major response was defined as a patient achieving a complete response (CR), very good partial response (VGPR), or partial response (PR). The response evaluable cohort consisted of all relapsed/refractory (R/R) WM pts enrolled to either phase 1 or 2 who had undergone their first response assessment or discontinued therapy. The safety cohort consisted of all pts with B-cell malignancies who received at least one dose of pirtobrutinib monotherapy (n=725). A data cut of 31 January 2022 was utilized. Results: Among the 78 WM pts, the median age was 68 (range, 42-84) years and the median number of prior therapies was 3 (range, 1-11). Overall, 66 (85%) pts had received chemotherapy + anti-CD20 antibody, 61 (78%) pts had received ≥1 prior BTKi (≥2 BTKi in 13/61, 21%), and 50 (64%) pts had received chemotherapy + anti-CD20 antibody + BTKi. Of the 61 pts who received ≥1 prior BTKi, 40 (66%) discontinued prior BTKi therapy due to disease progression. Overall, 91% (71/78) of pts received the recommended phase 2 dose (200 mg once daily) as starting dose. The major response rate for the 72 response-evaluable pts was 68% (95% CI, 56-79), including 17 VGPRs (24%) and 32 PRs (44%). At a median response follow-up time of 7.7 months, the median DoR among the 49 responding pts was not reached (95% CI, 10-NE). The 6-month estimated DoR rate was 86% (95% CI, 69-94). In the subset of 55 response-evaluable pts who had received ≥1 prior BTKi, the major response rate was 64% (95% CI, 50-76), including 13 VGPRs (24%) and 22 PRs (40%). In this BTKi-pretreated subset, the median DoR was also not reached (95% CI, 8-NE) and the 6-month estimated DoR rate was 83% (95% CI, 60-93). In the subset of 60 response-evaluable pts who had received chemotherapy + anti-CD20 antibody, the major response rate was 68% (95% CI, 55-80), including 13 VGPRs (22%) and 28 PRs (47%). In the subset of 44 response-evaluable pts who had received chemotherapy + anti-CD20 antibody + BTKi, the major response rate was 64% (95% CI, 48-78), including 9 VGPRs (21%) and 19 PRs (43%). In the safety cohort of all pirtobrutinib treated pts with B-cell malignancies (n=725), the most frequent TEAEs, regardless of attribution, were fatigue (26%, n=191), diarrhea (22%, n=160), and contusion (19%, n=138). The most frequent Grade ≥3 TEAE was neutropenia (20%, n=143). Low rates of Grade ≥3 TEAEs of hypertension (3%, n=20), hemorrhage (2%, n=16), and atrial fibrillation/flutter (1%, n=7) were observed. Overall, 15 (2%) pts discontinued due to a treatment-related AE. Conclusions: In this cohort of heavily pretreated R/R WM pts, pirtobrutinib was highly active, regardless of the pattern of prior therapy. The depth of response observed, as demonstrated by the favorable VGPR rate, is noteworthy in the subset of pts with prior covalent BTKi therapy. Pirtobrutinib was well-tolerated with low-rates of discontinuation due to drug-related toxicity.