Pirtobrutinib Earns Positive CHMP Opinion for R/R CLL After a Covalent BTK Inhibitor

The European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the approval of pirtobrutinib (Jaypirca) for the treatment of adult patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have been previously treated with a covalent BTK inhibitor.1

The positive opinion was supported by data from the phase 3 BRUIN CLL-321 trial (NCT04666038). Data presented at the 2024 ASH Annual Meeting showed that patients treated with pirtobrutinib (n = 119) achieved a median progression-free survival (PFS) of 14.0 months (95% CI, 11.2-16.6) per independent review committee (IRC) assessment at a median follow-up of 19.4 months compared with 8.7 months (95% CI, 8.1-10.4) at a median follow-up of 17.7 months for those given investigator’s choice of treatment comprising idelalisib (Zydelig) plus rituximab (Rituxan) or bendamustine plus rituximab (n = 119; HR, 0.54; 95% CI, 0.39-0.75; P = .0002).2

"Results from the BRUIN CLL-321 trial show that [pirtobrutinib] delivers clinically meaningful outcomes in a post–BTK inhibitor setting with markedly prolonged time to next treatment, including in those with high-risk characteristics often associated with poor prognosis," Paolo Ghia, MD, a professor of medical oncology at Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele in Milano, Italy, stated in a news release.1 "[Pirtobrutinib] allows for continued targeting of the BTK pathway following treatment with a covalent BTK inhibitor and has the potential to be an important new option in a setting with significant unmet need. The CHMP opinion is an important step toward bringing [pirtobrutinib] to patients in the European Union."

In December 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor.3 That regulatory decision was based on data from the phase 1/2 BRUIN trial (NCT03740529).

BRUIN CLL-321 Overview

The prospective, randomized trial enrolled patients at least 18 years of age with CLL or SLL requiring treatment per International Working Group CLL 2018 criteria.2 Prior treatment with a covalent BTK inhibitor was required, and there was no limit on prior lines of therapy. Notably, patients who had a history of atrial fibrillation were permitted to participate.

Patients were randomly assigned 1:1 to receive pirtobrutinib at 200 mg once per day or investigator’s choice of therapy with idelalisib plus rituximab or BR. Crossover to the experimental arm was permitted for those with confirmed progressive disease in the control arm.

Key stratification factors included 17p deletion (yes vs no) and prior venetoclax (Venclexta) treatment (yes vs no).

IRC-assessed PFS served as the trial’s primary end point. Secondary end points included investigator-assessed PFS, event-free survival (EFS), time to next treatment, overall survival (OS), and safety.

Additional Findings from BRUIN CLL-321

The investigator-assessed PFS at a median follow-up of 19.4 months for the pirtobrutinib arm and 17.5 months for the control arm was 15.3 months (95% CI, 12.8-19.9) and 9.2 months (95% CI, 7.3-10.6), respectively (HR, 0.48; 95% CI, 0.34-0.67; P < .0001).

The median EFS was 14.1 months (95% CI, 11.4-17.0) in the pirtobrutinib arm vs 7.6 months (95% CI, 4.8-8.8) in the investigator’s choice arm (HR, 0.39; 95% CI, 0.28-0.53; P < .0001). The median time to next treatment was 24.0 months (95% CI, 17.8-29.7) vs 10.9 months (95% CI, 8.7-12.5), respectively (HR, 0.37; 95% CI, 0.25-0.52; P < .0001).

Follow-up for OS was limited and confounded by the high rate of crossover (76%) to the pirtobrutinib arm. The 18-month OS rate was 73.4% (95% CI, 63.9%-80.7%) in the pirtobrutinib arm vs 70.8% (95% CI, 60.9%-78.7%) in the control arm (HR, 1.09; 0.68-1.75; P = .7202). However, an IPCW crossover-adjusted OS analysis produced an HR of 0.89 (95% CI, 0.52-1.53), and a 2-stage AFT crossover analysis showed an HR of 0.77 (95% CI, 0.45-1.26).

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 93.1% of patients in the pirtobrutinib arm (n = 116) vs 98.2% of patients in the investigator’s choice arm (n = 109). The most common any-grade TEAEs included infections (pirtobrutinib, 63.8%; investigator’s choice, 49.5%), anemia (19.8%; 17.4%), neutropenia (26.7%; 33.9%), cough (16.4%; 17.4%), diarrhea (16.4%; 31.2%), pyrexia (12.9%; 26.6%), fatigue (11.2%; 20.2%), nausea (11.2%; 20.2%), vomiting (6.9%; 17.4%), increased alanine aminotransferase levels (3.4%; 17.4%), increased weight (3.4%; 16.5%), and infusion-related reaction (0%; 17.4%).

References

1. Lilly's Jaypirca (pirtobrutinib) recommended by CHMP for approval in the European Union for adults with relapsed or refractory chronic lymphocytic leukemia (CLL) previously treated with a BTK inhibitor. News release. Lilly. February 28, 2025. Accessed February 28, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-recommended-chmp-approval-european
2. Sharman JP, Munir T, Grosicki S, et al. BRUIN CLL-321: randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood. 2024;144(suppl 1):886. doi:10.1182/blood-2024-198147
3. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 1, 2023. Accessed February 28, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic