Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory CLL/SLL: Results from the first randomized phase III study comparing a non-covalent and covalent BTK inhibitor

Abstract Introduction: Covalent Bruton tyrosine kinase inhibitors (cBTKi) are a mainstay of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treatment. Pirtobrutinib is a highly selective, non-covalent BTKi with proven efficacy in CLL/SLL patients (pts) previously treated with a cBTKi. We report results from the first head-to-head comparison of pirtobrutinib versus ibrutinib in treatment-naïve (TN) pts and pts with cBTKi-naive relapsed/refractory (R/R) CLL/SLL (NCT05254743). Methods: Eligible pts were randomized 1:1 to receive pirtobrutinib (200 mg QD) or ibrutinib (420 mg QD), stratified by del(17p) status and number of prior lines of therapy (0 vs 1 vs ≥ 2). Treatment was administered until progression or development of unacceptable toxicity. Primary endpoints were non-inferiority (NI) of overall response rate (ORR; partial response or better by independent review committee [IRC]/iwCLL 2018), in intent-to-treat (ITT) and R/R populations, with ORR ratio NI margins of 0.88 and 0.86, respectively. PFS was a secondary endpoint to be tested for superiority at a future timepoint. We present the final ORR analyses in ITT and R/R populations, and descriptive analyses of secondary endpoints, including in the TN population, using a 10June2025 data cut. Results: From 18August2022 to 17June2024, 662 pts were randomized to receive pirtobrutinib (n=331) or ibrutinib (n=331). For both arms, the median age was 67 (pirtobrutinib range, 39-90; ibrutinib, 34-86), and the median number of prior therapies was 1. The ITT population included 225 TN and 437 R/R pts. Among pirtobrutinib vs ibrutinib pts with evaluable samples, unmutated IGHV was 68% (199/293) vs 66% (183/277), complex karyotype ≥3 abnormalities was 40% (104/259) vs 34% (78/227), and del(17p) was 15% (50/331) vs 16% (52/331), respectively. The study met its primary endpoint demonstrating statistically significant NI of ORR of pirtobrutinib vs ibrutinib in both the ITT population (87.0% [95%CI,82.9-90.4] vs 78.6% [95%CI,73.7-82.9]; ORR ratio=1.11 [95%CI,1.03-1.19]; 2-sided p<0.0001) and R/R population (84.0% [95%CI,78.5-88.6] vs 74.8% [95%CI,68.5-80.4]; ORR ratio=1.12 [95%CI,1.02-1.24]; 2-sided p<0.0001), respectively. In the TN population, ORR was 92.9% (95%CI,86.4-96.9) with pirtobrutinib vs 85.8% (95%CI,78.0-91.7) with ibrutinib. ORR consistently favored pirtobrutinib vs ibrutinib across subgroups in both the ITT and R/R population, including del(17p) (ITT, 80.0% vs 75.0%; R/R, 80.6% vs 80.0%) and without del(17p) (ITT, 88.3% vs 79.2%; R/R, 84.7% vs 73.8%). PFS data were not yet mature, but favored pirtobrutinib in ITT (HR, 0.57 [95%CI,0.39-0.83]), R/R (HR, 0.73 [95%CI,0.47-1.13]), and TN (HR, 0.24 [95%CI,0.10-0.59]) pts, with a median follow up of 21.8 months, 18.2 months, and 22.5 months, respectively. The 18-month PFS rates (95%CI) in pirtobrutinib and ibrutinib arms were86.9% (82.4-90.3) vs 82.3% (77.3-86.3) in ITT, 81.7% (75.1-86.7) vs 79.2% (72.3-84.6) in R/R, and 95.3% (89.1-98.0) vs 87.6% (79.7-92.6) in TN, respectively. There was no detriment in overall survival (HR, 0.961 [95%CI,0.55-1.69]) for the ITT population. The most common treatment-emergent adverse events were similar between arms. Adverse events (AE) of interest, such as atrial fibrillation/flutter occurred in 2.4% of pirtobrutinib and 13.5% of ibrutinib pts; hypertension in 10.6% and 15.1% of pts, respectively. Fewer AE-related dose reductions were seen with pirtobrutinib (7.9%) vs ibrutinib (18.2%). Treatment discontinuation due to progressive disease was more common with ibrutinib (pirtobrutinib, n=15 [4.5%] vs ibrutinib, n=36 [10.9%]), and similar for AE (pirtobrutinib, n=26 [7.9%] vs ibrutinib, n=24 [7.3%]). Treatment is ongoing in 81.3% of pirtobrutinib and 69.5% of ibrutinib pts. Conclusion:In this first head-to-head study, in cBTKi-naïve CLL/SLL, including pts with treatment naïve CLL, pirtobrutinib demonstrated NI of ORR vs ibrutinib in both ITT and R/R populations. PFS, while not yet mature, trended in favor of pirtobrutinib, with the most pronounced effect in the TN population, which had the longest follow-up at this data cut.