CHMP Recommends Pirtobrutinib for EU Approval in Pretreated R/R CLL

Pirtobrutinib demonstrated PFS benefit compared with standard of care in patients with relapsed or refractory CLL in the BRUIN CLL-321 trial.

The Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of pirtobrutinib (Jaypirca), a non-covalent BTK inhibitor, as a treatment for adult patients in the EU with relapsed or refractory chronic lymphocytic leukemia (CLL) who were previously treated with a BTK inhibitor, according to a press release from the developer, Eli Lilly and Company.1

The European Commission is anticipated to make their decision on approving pirtobrutinib in the next 1 to 2 months. The agent has received conditional marketing authorization by the European Medicines Agency for the treatment of mantle cell lymphoma (MCL).

Previously, pirtobrutinib was granted accelerated approval by the FDA in December 2023 for CLL and small lymphocytic lymphoma (SLL).2

Supporting data for the recommendation came from the randomized, open-label phase 3 BRUIN CLL-321 trial (NCT04666038) evaluating the efficacy of pirtobrutinib vs standard of care in patients with CLL or SLL previously treated with a BTK inhibitor. Results were shared at the 2024 American Society of Hematology Annual Meeting & Exposition (ASH).3

“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,” stated Paolo Ghia, MD, professor of medical oncology at Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, Italy.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 [EU].”

The median progression-free survival (PFS), as assessed by an independent review committee (IRC), at a median follow-up of 19.4 months in the pirtobrutinib arm and 17.7 months in the comparator arm, was 14.0 months (95% CI, 11.2-16.6) vs 8.7 months (95% CI, 8.1-10.4), respectively (HR, 0.54; 95% CI, 0.39-0.75; P = .0002). Per IRC, the risk of progression or death was reduced by 46% with pirtobrutinib.

Investigator-assessed median PFS was 15.3 months (95% CI, 12.8-19.9) in the pirtobrutinib arm vs 9.2 months (95% CI, 7.3-10.6) in the comparator arm (HR, 0.48; 95% CI, 0.34-0.67; P <.0001), and pirtobrutinib was found to reduce the risk of progression or death by 52%.

The median time to next treatment or death, at a median follow-up of 20.0 months in the pirtobrutinib arm and 20.2 months in the comparator arm, 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). The risk of starting next treatment or death was 63% lower with pirtobrutinib.

Regarding overall survival (OS), investigators noted that follow-up was “limited and confounded by high rate of post-progression crossover.” However, the 18-month OS rate was 73.4% (95% CI, 63.9%-80.7%) with pirtobrutinib compared with 70.8% (95% CI, 60.9%-78.7%) with standard of care (HR, 1.09; 95% CI, 0.68-1.75; P = .7202). The crossover rate was 76%, as 50 of 66 patients who experienced a progressive disease event other than death switched to pirtobrutinib treatment, and the inverse-probability-of-censoring weighting crossover adjusted OS analysis had a hazard ratio of 0.89 (95% CI, 0.52-1.53).

Pirtobrutinib PFS benefit was consistent across all key risk factors.

A total of 238 patients were randomly assigned to receive either 200 mg of oral pirtobrutinib daily or standard of care with either bendamustine (Treanda) plus rituximab (Rituxan) or idelalisib (Zydelig) plus rituximab.

Eligible patients were 18 years or older with confirmed CLL or SLL requiring treatment and prior covalent BTK inhibitor treatment with no limit on the number of prior lines of therapy. Patients also had an ECOG performance status from 0 to 2, and prior history of atrial fibrillation was allowed.

The primary trial end point was IRC-assessed PFS. Secondary end points were investigator-assessed PFS, event-free survival, time to next treatment, OS, and safety.

At least 1 treatment-emergent adverse event (TEAE) of any grade and grade 3 or higher was observed in 93.1% and 57.7% of the pirtobrutinib arm and 98.2% and 73.4% of the comparator arm. The most common TEAEs of grade 3 or higher were infections (29.3% with pirtobrutinib vs 23.9% with standard of care), neutropenia (20.7% vs 27.5%), pneumonia (17.2% vs 11.1%), alanine transaminase increased (0.9% vs 9.2%), and anemia (11.2% vs 7.3%).

Treatment-related AEs led to discontinuation in 5.2% of the pirtobrutinib arm and 21.1% of the standard of care arm.

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. Eli Lilly and Company. February 28, 2025. Accessed March 3, 2025. https://tinyurl.com/23fneks8
2. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. News release. FDA. December 1, 2023. Accessed March 3, 2025. https://bit.ly/48011OO
3. 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