Pitobrutinib/pitobrutinib receives positive CHMP review for R/R CLL following use of covalent BTK inhibitor

The European Medicines Agency (EMA) recommends approval of Pirtobrutinib for the treatment of adult patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have been previously treated with a covalent BTK inhibitor.

Data from the BRUIN CLL-321 Phase 3 trial (NCT04666038) support this positive view. Data presented in 2024 showed that over a median follow-up period of 19.4 months, the median progression-free survival (PFS) for patients treated with pitobrutinib (n=119) was 14.0 months (95% CI, 11.2-16.6), as assessed by the Independent Review Committee (IRC), while those who received the investigator's choice Patients whose treatment options included idelalisib (Zydelix) plus rituximab (Rituxan) or bendamustine plus rituximab (n=119; HR, 0.54; 95% CI, 0.39-0.75; P=0.0002) were followed for a median of 8.7 months (95% CI, 8.1-10.4).

Results from the BRUIN CLL-321 trial demonstrate that pitobrutinib provides clinically meaningful results in the post-BTK inhibitor setting, with significantly longer time to next treatment, including those with high-risk features typically associated with poor prognosis. Pittobrutinib is available to patients in the European Union. In December 2023, the U.S. Food and Drug Administration (FDA) accelerated approval of pitobrutinib for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) who have received at least 2 previous treatments, including BTK inhibitors and BCL2 inhibitors. The regulatory decision is based on data from the Phase 1/2 BRUIN trial (NCT03740529).

This prospective, randomized trial enrolled patients at least18 years old with CLL or SLL who required treatment according to the International Working Group on CLL 2018 criteria. 2 requires prior treatment with a covalent BTK inhibitor and has no restrictions on previous treatment routes. Of note, patients with a history of atrial fibrillation were allowed to participate. Patients were randomly assigned in a ratio of 1:1 to take 200 mg of pitobrutinib once a day, or idelalisib combined with rituximab or BR at the investigator's choice. Patients diagnosed with progressive disease in the control group were allowed to cross over to the experimental group.

Key stratification factors included17p deletion (yes vs. no) and prior venetoclax treatment (venetoclax (yes vs. no)). PFS assessed by IRC was the primary endpoint of the trial. Secondary endpoints include investigator-assessed progression-free survival (PFS), event-free survival (EFS), time to next treatment, overall survival (OS), and safety.

The investigators assessed progression-free survival at a median follow-up of 19.4 months in the pitobrutinib group and 17.5 months in the control group. It was estimated that the median follow-up was 15.3 months (95% CI, 12.8-1.9) and 9.2 months (95% CI, 7.3-10.6) respectively (HR, 0.48; 95% CI, 0.34-0.67; P<0.0001). Median EFS was 14.1 months (95% CI, 11.4-17.0) in the pitobrutinib group and 7.6 months (95% CI, 4.8-8.8) in the investigator's choice group (HR, 0.39; 95% CI, 0.28-0.53; P<0.0001). The median time to the next treatment was 24.0 months (95% CI, 17.8-29.7) and 10.9 months (95% CI, 8.7-12.5) respectively (HR, 0.37; 95% CI, 0.25-0.52; P<0.0001).

Follow-up of OS was limited and confounded by the high crossover rate in the pitobrutinib group (76%). The 18-month OS rate was 73.4% (95% CI, 63.9%-80.7%) in the pitobrutinib group and 70.8% (95% CI 60.9%-78.7%) in the control group (HR, 1.09; 0.68-1.75; P=0.7202). However, the IPCW crossover-adjusted OS analysis yielded a HR of 0.89 (95% CI, 0.52-1.53), and the two-stage AFT crossover analysis yielded a HR of 0.77 (95% CI: 0.45-1.26).

Regarding safety, 93.1% of patients in the pitobrutinib group (n=116) experienced treatment adverse effects (TEAEs) of any grade, compared with 98.2% of patients in the investigator-selected group (n=109). The most common TEAEs of any grade include infection, anemia, neutropenia, cough, diarrhea, pyrexia, fatigue, nausea, and vomiting.

References:https://www.onclive.com/view/pirtobrutinib-earns-positive-chmp-opinion-for-r-r-cll-after-a-covalent-btk-inhibitor