Next-Gen BCL2 Inhibitor Approved for Aggressive Lymphoma

The FDA granted accelerated approval to sonrotoclax (Beqalzi) as the first BCL2 inhibitor for relapsed or refractory mantle cell lymphoma (MCL), a rare and often aggressive subtype of non-Hodgkin lymphoma.

A next-generation product in the drug class, sonrotoclax is indicated for adults previously treated with two or more lines of therapy that includes a Bruton’s tyrosine kinase (BTK) inhibitor.

In a phase I/II trial of 103 MCL patients previously treated with anti-CD20-based therapy and a BTK inhibitor, 52% responded to sonrotoclax, including complete responses in 16%. The median duration of response was 15.8 months, with a median time to response of 1.9 months.

Roughly 3,300 new cases of MCL are diagnosed each year in the U.S., accounting for approximately 5% to 7% of all non-Hodgkin lymphomas.

“The data supporting the approval of sonrotoclax in the U.S. confirm its role as a foundational therapy for mantle cell lymphoma in the post-BTK inhibitor setting, and demonstrate that it can deliver robust disease control when treatment choices are limited and outcomes are poor,” said investigator Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, in a press release from BeOne Medicines, the drug’s developer.

“From a clinical perspective, this provides physicians with an important new option grounded in both efficacy and tolerability, fundamentally changing how we think about sequencing therapy in this disease,” added Wang.

Common adverse events in the safety analysis included pneumonia (16%) and fatigue (16%), with serious adverse events occurring in 37% — most frequently pneumonia (10%). Common grade 3/4 laboratory abnormalities (≥15%) included decreases in lymphocytes and neutrophils.

Prescribing information for sonrotoclax includes warnings and precautions for tumor lysis syndrome, embryo-fetal toxicity, neutropenia, and serious infections. The regimen requires a ramp-up phase to reduce the risk of tumor lysis syndrome, a known class effect.

As part of the accelerated approval pathway, continued approval is contingent upon confirmation of clinical benefit. To that end, a phase III study (CELESTIAL-RRMCL) testing zanubrutinib (Brukinsa) with either sonrotoclax or placebo in pretreated MCL is currently underway, said BeOne Medicines.

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