Multinational phase 3 trial of pirtobrutinib versus bendamustine plus rituximab for previously untreated CLL/SLL

The multinational phase 3 BRUIN CLL-313 trial evaluated the noncovalent Bruton tyrosine kinase inhibitor pirtobrutinib for treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without del(17p). Patients were randomized to continous pirtobrutinib monotherapy (n=141) or the common frontline chemoimmunotherapy bendamustine plus rituximab (BendaR; n=141). The primary endpoint was progression-free survival by independent review. PFS was significantly improved with pirtobrutinib versus BendaR (HR 0.199; p<0.0001) with 24-month PFS rate 93.4% (95% CI 87.6-96.5) versus 70.7% (61.5-78.1). Interim analysis of overall survival after median follow-up of 32 months) also favored pirtobrutinib (HR 0.257; 95% CI 0.070-0.934) despite a crossover rate of 52.9%. In patients receiving pirtobrutinib versus BendaR, adverse events-related dose reductions occurred in 3.6% versus 31.1%, grade ≥ 3 treatment-emergent adverse events occurred in 40.0% versus 67.4%, and discontinuations because or TEAEs occurred in 4.3% versus 15.2%, respectively. The authors conclude that pirtobrutinib demonstrated PFS superiority over BendaR in treatment-naïve CLL/SLL, with a favorable safety profile.