BRUIN CLL-313: Randomized Phase III Trial of Pirtobrutinib Versus Bendamustine Plus Rituximab in Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

[PURPOSE] BRUIN CLL-313 is a randomized, open-label, global phase III study comparing the efficacy and safety of pirtobrutinib, a highly selective, noncovalent Bruton tyrosine kinase inhibitor (BTKi), against bendamustine plus rituximab (BendaR), a common frontline chemoimmunotherapy, in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

[METHODS] Patients with previously untreated CLL/SLL without del(17p) were randomly assigned 1:1 to continuous pirtobrutinib monotherapy or BendaR, stratified by immunoglobulin heavy chain gene mutation status and Rai stage. The primary end point was independent review committee (IRC)-assessed progression-free survival (PFS); secondary end points included overall survival (OS), investigator (INV)-assessed PFS, safety, and tolerability.

[RESULTS] Overall, 282 patients were randomly assigned to receive pirtobrutinib (n = 141) or BendaR (n = 141). IRC-assessed PFS was significantly improved with pirtobrutinib versus BendaR (hazard ratio [HR], 0.199 [95% CI, 0.107 to 0.367]; < .0001), and the 24-month PFS rate was 93.4% (95% CI, 87.6 to 96.5) and 70.7% (95% CI, 61.5 to 78.1), respectively. INV-assessed PFS similarly favored pirtobrutinib (HR, 0.186 [95% CI, 0.093 to 0.371]). Interim analysis of OS favored pirtobrutinib (median follow-up 32 months; HR, 0.257 [95% CI, 0.070 to 0.934]) despite an effective crossover rate of 52.9%. In patients receiving pirtobrutinib versus BendaR: adverse event (AE)-related dose reductions occurred in 3.6% versus 31.1% of patients; grade ≥3 treatment-emergent AEs (TEAEs) occurred in 40.0% versus 67.4% of patients; and treatment discontinuations because of TEAEs occurred in 4.3% versus 15.2% of patients, respectively.

[CONCLUSION] Pirtobrutinib demonstrated superiority over BendaR in IRC-assessed PFS in treatment-naïve CLL/SLL. OS trends favored pirtobrutinib despite the study design allowing for crossover. Pirtobrutinib was well tolerated, consistent with its known safety profile, and more favorable than BendaR.