Pirtobrutinib in Relapsed/Refractory (R/R) Waldenström macroglobulinemia (WM): Up to 5 years of follow-up from the Phase 1/2 BRUIN study

Abstract Background: Covalent Bruton tyrosine kinase inhibitors (cBTKi) have been an important advancement for the treatment of WM, but their effectiveness is limited by intolerance and resistance. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits BTK with low nM potency throughout the dosing interval. Pirtobrutinib has shown promising safety and efficacy in the phase 1/2 BRUIN study in patients (pts) with R/R MCL and CLL/SLL, including pts previously treated with a cBTKi. Here, we report final results for the full cohort of WM pts from the phase 1/2 BRUIN study (NCT03740529) with up to 5 years follow-up. Methods: Pts with previously treated WM were eligible for treatment with pirtobrutinib. Endpoints included investigator-assessed overall response rate (ORR) and duration of response (DoR), per IWWM6 as well as modified IWWM6 criteria (used for data presented herein) (Treon. Blood, 2015), and safety. The ORR included pts with a complete response (CR), very good partial response (VGPR), partial response (PR), or minor response (MR). A major response included pts achieving a CR, VGPR, or PR. A data cutoff of 27 January 2025 was utilized with a median study follow-up of 35 months (range 3-63). Results: Among the 80 WM pts treated with pirtobrutinib, of which 91% (73/80) received 200 mg as the starting dose, the median age was 69 years (range, 42-84). Of the 73 patients with their disease genotyped for MYD88, 65 (89%) had the L265P mutation. Fifty-four pts were genotyped for CXCR4, of which 12 (22%) had mutations present. The median number of prior therapies was 3 (range, 1-11), and included chemotherapy (86%, n=69) and an anti-CD20 antibody (93%, n=74). Overall, 63 (79%) pts had previously received a cBTKi, and 41 of these pts (65%) had discontinued prior cBTKi therapy due to disease progression (PD). The ORR for the 80 pts was 83% (95% CI, 72-90), including 1 CR (1%), 21 VGPR (26%), 36 PR (45%) and 8 MR (10%). The major response rate (MRR) was 73% (95% CI, 61-82), and the median DoR among the 58 pts with major response was 42 months (95% CI, 18-NE). The median PFS was 36 months (95% CI, 19–NE), and the median OS was not estimable (95% CI, NE-NE); the 36-month OS rate was 67% (95% CI, 55-77). In the subset of 63 pts who had previously received a cBTKi, the ORR was 81% (95% CI, 69-90), including 1 CR (2%), 15 VGPR (24%), 27 PR (43%) and 8 MR (13%). The MRR was 68% (95% CI, 55-79), and the median DoR among the 43 pts with major response was 20 months (95% CI, 16-NE). The median PFS was 20 months (95% CI, 15-39) in this subset. The median OS was not estimable (95% CI, 39-NE); the 36-month OS rate was 64% (95% CI, 50-76). Among 41 pts who discontinued any prior cBTKi due to PD, the MRR was 66% (95% CI, 49-80) and median PFS was 19 months (95% CI, 11-20). Among 21 pts who discontinued any prior cBTKi due to toxicity or other reasons, the MRR was 71% (95% CI, 48-89) and median PFS was not estimable (95% CI, 17-NE). In the subset of 17 pts who were BTKi naïve, both the ORR and MRR was 88% (95% CI, 64-99), including 6 VGPR (35%) and 9 PR (53%). The median DoR among the 15 pts with major response was not estimable (95% CI, 42-NE); the 36-month DoR rate was 87% (95% CI, 56-96). The median PFS was not estimable (95% CI, 14-NE) and median OS was also not estimable (95% CI, 20-NE); the 36-month PFS and OS rates were both 76% (95% CI, 49-90). Among all 80 pirtobrutinib treated pts, the most frequent TEAE, regardless of attribution, were COVID-19 (43%, n=34), diarrhea (25%, n=20), anemia (24%, n=19), headache (24%, n=19), fatigue (21%, n=17), and neutropenia (21%, n=17). The most frequent grade ≥3 TEAE was neutropenia (19%, n=15). Low rates of grade ≥3 TEAE of hypertension (4%, n=3), hemorrhage/hematoma (5%, n=4), and atrial fibrillation/flutter (1%, n=1) were observed. Treatment-related AE led to pirtobrutinib discontinuation in 4 (5.0%) and dose reduction in 2 (2.5%) pts. Conclusions: Pirtobrutinib was highly active in this cohort of R/R WM pts, including both BTKi-naïve and those who previously received a cBTKi, regardless of the pattern of prior therapy. The depth of response observed, as demonstrated by over 25% of pts achieving a CR+VGPR, may be noteworthy in the subset of pts who received prior cBTKi therapy. Pirtobrutinib was also well-tolerated with low-rates of dose reductions or discontinuation due to drug-related toxicity.