Pirtobrutinib Outperforms Investigators’ Choice Treatment in Relapsed or Refractory CLL and SLL

Pirtobrutinib improved progression-free survival (PFS) compared with idelalisib plus rituximab or bendamustine plus rituximab in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) pretreated with a covalent bruton tyrosine kinase inhibitor, according to the phase 3 BRUIN CLL-321 trial.

The global, open-label, multicenter, randomized study, led by Jeff Sharman, MD, of the Willamette Valley Cancer Institute and Research Center, was published in the Journal of Clinical Oncology.

A total of 238 patients were randomly assigned 1:1 to receive pirtobrutinib (n=119) at 200 mg once daily or investigator’s choice of idelalisib and rituximab (n=82) or bendamustine and rituximab (n=37). Patients had a median of three prior lines of treatment, which the researchers stratified by del(17p) status and prior venetoclax treatment.

The primary end point was PFS, and secondary end points included time to next treatment or death (TTNT), overall survival (OS), and safety. The median follow-up was 17.2 months (95% CI, 9.7-23).

Pirtobrutinib demonstrated a superior PFS of 14 months, compared with 8.7 months with investigator’s choice treatment (HR, 0.58; 95% CI, 0.38- 0.89; P=0.011). The study team replicated the PFS benefit across various subgroups, including patients with a TP53 mutation or del(17p), unmutated IGHV, and those with a complex karyotype. Pirtobrutinib improved PFS regardless of whether patients received prior venetoclax treatment, the authors noted.

Patients in the pirtobrutinib group also had longer event-free survival (14.1 months vs 7.6 months, respectively) and TTNT (24 months vs. 10.9 months, respectively) compared with the investigator’s choice groups. However, the 18-month OS rate was comparable among the pirtobrutinib and investigator’s choice groups, at 73.4% and 70.8%, respectively. The authors noted that the high crossover rate (76%) confounded their OS assessment.

Most patients experienced any grade treatment-emergent adverse events (TEAEs), specifically 93.1% in the pirtobrutinib group and 98.2% in the investigator’s choice groups. Grade 3 or more TEAEs occurred in 57.7% and 73.4% of patients, respectively. The most common TEAEs were pneumonia, anemia, and neutropenia with pirtobrutinib and diarrhea, pyrexia, fatigue, and nausea with investigator’s choice. Fewer patients receiving pirtobrutinib discontinued treatment due to AEs compared to investigator’s choice (17.2% vs 34.9%, respectively).

“This study demonstrated a significant, clinically meaningful improvement in PFS and a more favorable safety profile with pirtobrutinib versus IdelaR/BR [idelalisib plus rituximab or bendamustine plus rituximab] in patients with CLL/SLL,” Dr. Sharman and colleagues concluded. “TTNT and EFS showed robust benefit in this population where no effective standard of care exists. These data may be relevant for future treatment sequencing strategies.”