Pirtobrutinib Versus Ibrutinib in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

PURPOSE Pirtobrutinib, a highly selective, noncovalent Bruton tyrosine kinase inhibitor (BTKi), has shown efficacy and safety in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received prior covalent BTKi. We report results, to our knowledge, from the first randomized head-to-head comparison of pirtobrutinib versus ibrutinib in BTKi-naïve CLL/SLL in both treatment-naïve (TN) patients and patients with relapsed/refractory (R/R) disease. PATIENTS AND METHODS Patients (N = 662) were randomly assigned 1:1 to receive pirtobrutinib or ibrutinib. All patients were BTKi-naïve. Primary end points were overall response rate (ORR) by independent review committee (IRC) among all randomly assigned patients (intention to treat ITT) and in patients with R / R disease. RESULTS The study met its primary end points, demonstrating statistically significant noninferiority (NI) of IRC-ORR for pirtobrutinib versus ibrutinib in both the ITT (87.0% 95% CI, 82.9 to 90.4 v 78.5% 95% CI, 73.7 to 82.9; ORR ratio = 1.11 95% CI, 1.03 to 1.19; two-sided P < .0001) and R/R populations (n = 437; 84.0% 95% CI, 78.5 to 88.6 v 74.8% 95% CI, 68.5 to 80.4; ORR ratio = 1.12 95% CI, 1.02 to 1.24; two-sided P < .0001). In TN patients (n = 225), IRC-ORR was 92.9% (95% CI, 86.4 to 96.9) with pirtobrutinib versus 85.8% (95% CI, 78.0 to 91.7) with ibrutinib. Investigator assessed ORR results were consistent. Investigator-assessed progression-free survival (PFS) favored pirtobrutinib in the ITT (hazard ratio HR, 0.57 95% CI, 0.39 to 0.83), R/R (HR, 0.73 95% CI, 0.47 to 1.13), and TN (HR, 0.24 95% CI, 0.10 to 0.59) populations. Cardiac adverse event rates of atrial fibrillation/flutter and hypertension were lower with pirtobrutinib. CONCLUSION Pirtobrutinib demonstrated NI of ORR versus ibrutinib, with a favorable early PFS trend, particularly in TN patients, and a favorable safety profile including low rates of atrial fibrillation and hypertension.