Research Summary

Pirtobrutinib Extends Disease Control in Bruton Tyrosine Kinase Inhibitor–Pretreated Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Miranda Manier, BA

Key Highlights

  • In patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma previously treated with covalent BTK inhibitors, pirtobrutinib prolonged progression-free survival (PFS) compared with idelalisib/rituximab or bendamustine/rituximab.
  • Median PFS was 14 months with pirtobrutinib versus 8.7 months with investigator’s choice therapy.
  • Median time to next treatment or death was more than doubled with pirtobrutinib (24 months vs 10.9 months).
  • Adverse events grade 3 or higher and treatment discontinuations were less frequent with pirtobrutinib.

Pirtobrutinib, a noncovalent Bruton tyrosine kinase inhibitor (BTKi), demonstrated superior outcomes compared with investigator’s choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had previously received covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. In this high-risk, heavily pretreated population, pirtobrutinib provided significant improvements in disease control and tolerability, establishing it as a meaningful treatment option in a setting where standard therapeutic options are limited.

The need for this study stems from the clinical challenge posed by patients with CLL/SLL who progress after cBTKi therapy. While cBTKis are effective, most patients eventually discontinue therapy due to disease progression or intolerance. Venetoclax has been used in this setting, but randomized data supporting its use are lacking, and real-world outcomes appear modest. To date, no prospective, randomized studies had evaluated therapies specifically in the post-cBTKi setting, leaving a major gap in treatment evidence. BRUIN CLL-321 was designed to address this unmet need.

This open-label, phase III, global, multicenter study enrolled 238 patients with relapsed/refractory CLL/SLL previously treated with a cBTKi. Participants were randomized 1:1 to receive pirtobrutinib 200 mg once daily or investigator’s choice of IdelaR or BR. Stratification factors included prior venetoclax use and del(17p) status. The primary endpoint was PFS assessed by independent review committee, with secondary endpoints including TTNT, overall survival (OS), and safety.

At the primary analysis cutoff, pirtobrutinib significantly prolonged PFS compared with IdelaR/BR, with a hazard ratio of 0.54 (95% CI, 0.39-0.75; P = .0002). Median PFS was 14 months with pirtobrutinib versus 8.7 months with investigator’s choice therapy. TTNT was also substantially longer in the pirtobrutinib group, reaching 24 months compared with 10.9 months in the control group (HR, 0.37; 95% CI, 0.25-0.52). OS was similar between groups (HR, 1.09; P = .7202), though interpretation was limited by a high crossover rate from the control arm to pirtobrutinib (76%). Importantly, fewer grade 3 or higher treatment-emergent adverse events were observed with pirtobrutinib (57.7%) compared with IdelaR/BR (73.4%). Treatment discontinuations due to adverse events occurred in 17.2% of patients in the pirtobrutinib group versus 34.9% with investigator’s choice.

The study’s limitations include its open-label design and the high rate of crossover from the control group, which may have confounded overall survival outcomes. Additionally, longer follow-up will be needed to fully assess the durability of benefit and long-term safety.

 “Pirtobrutinib improved PFS and TTNT, and demonstrated favorable tolerability, versus IdelaR/BR in exclusively cBTKi pretreated patients with CLL/SLL,” Sharman and colleagues concluded.

Reference
Sharman JP, Munir T, Grosicki S, et al. Phase III trial of pirtobrutinib versus idelalisib/rituximab or bendamustine/rituximab in covalent bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol. 2025;43(22):2538-2549. doi:10.1200/JCO-25-00166