Single-agent pirtobrutinib is being investigated for safety and efficacy in heavily pretreated, BTK inhibitor–naïve patients with mantle cell lymphoma in the ongoing phase 3 BRUIN-MCL-321 trial.
Single-agent pirtobrutinib (LOXO-305) is being investigated for safety and efficacy in heavily pretreated, BTK inhibitor–naïve patients with mantle cell lymphoma (MCL) in the ongoing phase 3 BRUIN-MCL-321 trial (NCT04662255).
The primary end point of the study, which was addressed in a presentation at the 2022 European Hematology Association Congress, is progression-free survival (PFS) per Lugano criteria assessed by blinded independent central review (BICR).
“The purpose of this randomized study is to determine whether pirtobrutinib is superior to investigator’s choice of covalent BTK inhibitor in patients with previously treated MCL,” lead study author Martin Dreyling, MD, of Ludwig Maximilians University of Munich, said in the poster presentation.
Although covalent BTK inhibitors have enhanced the treatment landscape for patients with relapsed/refractory MCL, a majority of patients require additional treatment following these inhibitors. Moreover, covalent BTK inhibitors often provide inferior target coverage in proliferating tumors that present with high BTK protein turnover, including MCL.
However, the highly selective noncovalent BTK inhibitor, pirtobrutinib, provided promising results in the phase 1/2 BRUIN study (NCT03740529), which included favorable pharmacokinetics and efficacy, prompting further exploration in BRUIN-MCL-321.
To be eligible for the phase 3 trial, patients at least 18 years old with a confirmed diagnosis of MCL must have received at least 1 prior line of systemic therapy. Additional inclusion criteria include measurable by the Lugano criteria, a confirmed disease progression on a recent line of therapy, and an ECOG performance status between 0 and 2.2
Exclusion criteria include prior treatment with a BTK inhibitor, a history of bleeding diathesis, any central nervous system involvement, recent stem cell transplant or CAR T-cell therapy, or major surgery within 4 weeks of randomization.
The open-label, global, phase 3 trial will enroll approximately 500 patients, who will be randomized 1:1 to receive 200 mg of oral pirtobrutinib once daily or investigator’s choice of ibrutinib (Imbruvica), acalabrutinib (Calquence), or zanubrutinib (Brukinsa). Stratification factors comprise simplified MCL international prognostic index risk group (intermediate vs high), the intended BTK inhibitor by comparator (ibrutinib vs acalabrutinib/zanubrutinib), and prior lines of therapy (1 vs 2 or more).
Investigator-assessed PFS will be a secondary end point. Other secondary end points include BICR- and investigator-assessed overall response rate and duration of response, plus overall survival, event-free survival, time to treatment failure, time to next treatment, and safety.
The BRUIN-MCL-321 trial is an ongoing study that is actively recruiting patients, and data will be presented at a later date.