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Targeted BTK inhibition with pirtobrutinib offers durable disease control and improved safety in relapsed CLL/SLL.

In a Phase III Trial study published in June 2025 issue of Journal of Clinical Oncology, researchers compared the efficacy and safety of pirtobrutinib vs investigator’s choice (IC) of idelalisib/rituximab (IdelaR) or bendamustine/rituximab (BR) in patients with R/R chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) previously treated with covalent Bruton tyrosine kinase inhibitors (BTKi). 

They randomized patients in a 1:1 ratio to receive either pirtobrutinib (200 mg once daily) or IC of IdelaR or BR, with stratification based on prior venetoclax use and presence of del(17p). The primary endpoint was progression-free survival (PFS), assessed by an independent review committee. Secondary endpoints included time to next treatment or death (TTNT), overall survival (OS), and safety. The primary PFS outcome was achieved at the interim analysis on August 29, 2023, and final OS results were collected as of August 29, 2024.  

The results showed that 238 patients were randomized equally to receive pirtobrutinib (n = 119) or IC; n = 119, including IdelaR (n = 82) and BR (n = 37). The PFS hazard ratio (HR) was 0.54 [95% CI, 0.39 to 0.75]; P = .0002, with a median PFS of 14 months [95% CI, 11.2 to 16.6] for pirtobrutinib and 8.7 months [95% CI, 8.1 to 10.4] for IC. The unadjusted OS HR was 1.09 [95% CI, 0.68 to 1.75]; P = .7202, and 18-month OS rates were 73.4% [95% CI, 63.9 to 80.7] in the pirtobrutinib group and 70.8% [95% CI, 60.9 to 78.7] in the IC group. Median TTNT was 24 months [95% CI, 17.8 to 29.7] for pirtobrutinib and 10.9 months [95% CI, 8.7 to 12.5] for IC HR, 0.37; 95% CI, 0.25 to 0.52. At a median follow-up of 17.2 months, grade ≥3 treatment-emergent adverse events (AEs) occurred in 57.7% of the pirtobrutinib group and 73.4% of the IC group. Treatment discontinuation due to AEs was reported in 17.2% (n = 20) of pirtobrutinib-treated patients and 34.9% (n = 38) of IC-treated patients.  

Investigators concluded that pirtobrutinib significantly enhanced PFS and time to the next treatment while maintaining better tolerability compared to IdelaR/BR in patients with CLL/SLL previously treated with covalent BTKi. 

Source: ascopubs.org/doi/10.1200/JCO-25-00166