Dr Pearse on Efforts to Elucidate the Optimal Sequencing of BTK Inhibitors in MCL

William B. Pearse, MD, assistant professor, medicine, University of California, San Diego School of Medicine, discusses unanswered questions regarding the sequencing of pirtobrutinib and other approved BTK inhibitors in mantle cell lymphoma (MCL), as well as ongoing research seeking to elucidate the benefit of this drug class agents when used in earlier lines of therapy.

Although the FDA approval of pirtobrutinib (Jaypirca) in patients with relapsed/refractory MCL that progressed on or during at least 2 prior therapies has led to advances in the use of BTK inhibitors in this patient population. However, questions remain regarding the agents’ optimal role within the current treatment paradigm, Pearse begins. The noncovalent BTK inhibitor was approved in January, 2023 based on primary findings from a subset of patients with MCL in the phase 1/2 BRUIN trial (NCT03740529). Long-term follow-up data from the trial confirmed pirtobrutinib's efficacy, with an overall response rate (ORR) of 49.3% (95% CI, 41.1%-57.6%) and a median time to first response of 1.8 months (range, 0.8-13.8) in covalent BTK inhibitor–exposed patients with MCL (n = 152). The agent also demonstrated a manageable toxicity profile with no new safety signals observed.

The ongoing phase 3, open-label-randomized MCL 135 study (NCT04662255) is evaluating pirtobrutinib compared with investigator’s choice of BTK inhibitor in previously treated, BTK inhibitor–naive MCL, Pearse continues. This investigates whether pirtobrutinib may offer improved safety or efficacy compared with other BTK inhibitors, such as acalabrutinib (Calquence) or zanubrutinib (Brukinsa), when moved up to the second line in the relapsed/refractory setting, he explains.

The MCL 135 trial has the potential to provide valuable insights into the role of pirtobrutinib in the treatment of MCL, Pearse states, adding that it may also contribute informative phase 3 data comparing different BTK inhibitors in patients who have not previously received these agents to the MCL paradigm. Prospective data comparing various BTK inhibitors in the second-line relapsed/refractory setting are currently limited, making this trial an important opportunity to address key questions regarding the optimal BTK inhibitor sequencing approach for patients with MCL, he concludes.