Pirtobrutinib in relapsed/refractory MCL patients: update from the BRUIN trial

BTKi has demonstrated efficacy in MCL; however, a substantial number of patients experience relapse during treatment. Pirtobrutinib, a non-covalent third-generation BTKi, exhibits enhanced effectiveness in the post-covalent BTKi setting and greater selectivity compared to earlier agents. The OR for pirtobrutinib is 58%, with a CR observed in 20% of patients. The favourable pharmacokinetics of pirtobrutinib, maintaining concentrations above the IC90 24/7, facilitate once-daily oral administration. Its limited occurrence of grade 3 adverse effects enhances its usability and potential for combination with future therapeutic agents.

The Bruin study, a phase 1/2 trial, established the optimal daily dose of pirtobrutinib at 200 mg. In this study 152 MCL patients previously treated with BTKi and 14 treatment-naive MCL patients were enrolled. Approximately half of these patients with known TP53 mutation status exhibited the mutation, while two-thirds with known Ki-67 status had a proliferative index of 30% or greater.

A remarkable improvement in the overall burden of disease was evident, with an overall median time to the first response of 1.8 months, corresponding to the initial disease assessments in the trial. Regardless of the subgroup, the OR remained consistently around 45-50%. Patients discontinuing previous BTKi treatment due to toxicity exhibited a notably high OR, aligning with expectations.

Updated survival curves revealed a median DoR of 21.6 months, a median PFS of 5.6 months, and a median OS of 23.5 months. Analysis of high-risk subgroups indicated that TP53-mutated patients and those with a Ki-67 status over 30% exhibited a lower response rate and shorter PFS to pirtobrutinib. However, when a response occurred, its duration was prolonged, suggesting potential benefits for this patient subset.

In a smaller cohort of treatment-naive patients, the OR was an impressive 86%, with half achieving CR and the other half partial response. After almost 2 years of follow-up, median DoR, OS, and PFS were not reached. Despite the limited patient pool, these findings are encouraging.

Throughout the study, no unexpected safety issues emerged, and few grade 3 adverse events were noted, affirming the safety and ease of use of pirtobrutinib in relapsed/refractory MCL patients.

Reference:

Cohen JB, Pirtobrutinib in Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) Patients with Prior cBTKi: Safety and Efficacy Including High-Risk Subgroup Analyses from the Phase 1/2 BRUIN Study. ASH2023. #981

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