Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in Richter transformation: Results from the phase 1/2 BRUIN study

Background: Richter transformation (RT) usually presents as an aggressive diffuse large B-cell lymphoma (DLBCL), has no approved therapies, and is associated with an extremely poor prognosis, with an estimated median overall survival (OS) of 3-11 months. This devastating complication is estimated to occur in up to 10% of patients (pts) with chronic lymphocytic leukemia (CLL), although the rate may rise as more pts experience progression following treatment with Bruton tyrosine kinase inhibitors (BTKi) and BCL-2 inhibitors. 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 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 RT pts from the BRUIN study (NCT03740529). Methods: Pts with previously treated B-cell malignancies, including those with CLL and histologically confirmed RT (all DLBCL) were eligible for treatment with pirtobrutinib monotherapy in either the dose escalation or expansion portion of the multicenter phase 1/2 BRUIN study. Initially only pts with previously treated RT were eligible. Beginning with Amendment 10, pts with untreated RT were eligible. Key endpoints included investigator-assessed overall response rate (ORR) and duration of response (DoR) per Lugano 2014 criteria, and safety. The response evaluable cohort consisted of all RT 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 57 RT pts, the median age was 67 (range, 33-86) years and 91% (n=52) received at least 1 prior RT-directed therapy. The median number of prior RT-directed therapies was 2 (range, 0-7) and the median number of CLL-directed therapies prior to developing RT was 2 (range, 0-13). Prior RT-directed therapies included anti-CD20 antibody (86%, n=49), chemotherapy (79%, n=45), BCL-2 inhibitor (35%, n=20), BTKi (28%, n=16), PI3K inhibitor (12%, n=7), CAR-T (9%, n=5), immunodulator (5%, n=3), stem cell transplant (4%, n=2), or other systemic therapy (33%, n=19). Prior CLL-directed therapies included BTKi (60%, n=34), anti-CD20 antibody (60%, n=34), chemotherapy (47%, n=27), BCL-2 inhibitor (42%, n=24), immunodulator (9%, n=5), PI3K inhibitor (7%, n=4), stem cell transplant (7%, n=4), CAR-T (2%, n=1), or other systemic therapy (11%, n=6). Overall, 98% (56/57) of pts received the recommended phase 2 dose of 200 mg once daily as starting dose. In this group of pts with predominantly heavily pre-treated RT, the ORR for the 50 response evaluable pts was 54% (95% CI, 39-68) including 5 complete responses and 22 partial responses. At a median response follow-up time of 5.5 months, the median DoR was 8.6 months (95% CI, 1.9-NE) with 63% of responses censored at the time of data cut. At a median study follow-up of 9.7 months, the median OS was 13.1 months (95% CI, 7.1-NE). Six pts electively discontinued pirtobrutinib in ongoing response to pursue curative-intent therapy (allogeneic transplant, n=6 with median time-on-therapy of 3.8 [range, 2.5-11.5] months). 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 predominantly heavily pretreated RT cohort with an extremely poor prognosis, pirtobrutinib demonstrated promising preliminary efficacy, including among pts who received prior RT-directed chemoimmunotherapy and covalent BTKi. Pirtobrutinib was well-tolerated with low-rates of discontinuation due to drug-related toxicity.