Pirtobrutinib in treatment-naïve patients with CLL/SLL: Pooled results from BRUIN CLL-313 and BRUIN CLL-314.

7044 Background: Pirtobrutinib, a highly selective, non-covalent Bruton tyrosine kinase inhibitor (BTKi), is approved globally for patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) previously treated with a covalent BTKi. BRUIN CLL-313 and BRUIN CLL-314 are open-label, randomized phase 3 studies evaluating pirtobrutinib for therapy of pts with CLL/SLL, including in the treatment-naïve (TN) setting [versus bendamustine plus rituximab (BendaR; CLL-313, NCT05023980) and versus ibrutinib (CLL-314, NCT05254743)]. Methods: Pooled data from TN CLL pts randomized to receive pirtobrutinib from CLL-313 and CLL-314 were used to assess efficacy [overall response rate (ORR), progression-free survival (PFS) and overall survival (OS)] and safety. PFS and OS estimates were calculated by the Kaplan-Meier method. All pts (253) randomized within each study to receive pirtobrutinib are included in efficacy analyses and all pts (252) who received pirtobrutinib treatment are included in safety analyses. Results: A total of 253 TN pts, median age of 66 yrs, were assigned to receive pirtobrutinib (CLL-313 n=141; CLL-314 n=112); all but one received treatment. Among pts with evaluable samples 134/233 (58%) had unmutated IGHV, 14/253 (6%) had del(17p) and 21/220 (10%) had mutated TP53. Efficacy was consistent between the two studies (Table). Overall, ORR was 93.3%. Median PFS was not reached; the 24-month PFS rate was 93.2% (95%CI, 89.1-95.8). Median OS was also not reached; the 24-month OS rate was 97.5% (95%CI, 94.6-98.9). Median duration of therapy was 29.1 months. Treatment discontinuation due to TEAEs occurred in 4.8% of pts with 1.6% treatment related. Any-grade infection occurred in 59.9% of pts; neutropenia in 18.3% and grade ≥3 bleeding in 2.4%. Any-grade hypertension occurred in 10.7% of pts and atrial fibrillation/flutter was reported in 2.8%. Conclusions: In 253 TN pts with CLL randomized on two phase 3 studies, pirtobrutinib showed a high ORR and favorable 24-month PFS and OS rates. The safety profile was consistent with prior studies using pirtobrutinib in more heavily treated pts, with low rates of atrial fibrillation/flutter, hypertension and TEAE-related discontinuations. These findings reinforce the potential of pirtobrutinib as a meaningful and clinically relevant treatment option for pts with TN disease. Clinical trial information: NCT05023980 and NCT05254743 . Efficacy of pirtobrutinib in TN patients with CLL/SLL. Parameter CLL-313N = 141 CLL-314N = 112 Pooled TN ptsN=253 ORR ORR, % (95% CI) 94.3 (89.1, 97.5) 92.0 (85.3, 96.3) 93.3 (89.5, 96.0) PFS 24-month PFS rates, % (95% CI) 92.7 (86.8, 96.0) 94.3 (87.8, 97.4) 93.2 (89.1-95.8) Median FU, months 28.1 22.4 27.7 OS 24-month OS rates, % (95% CI) 97.8 (93.3, 99.3) 97.2 (91.5, 99.1) 97.5 (94.6-98.9) Median FU, months 32.7 26.7 29.5 ORR includes a best response of partial response or better.