Sonrotoclax Shows Promising Efficacy, Improved Tolerability in Heavily Pretreated MCL

At ASH 2025, an abstract highlighted emerging data for sonrotoclax, a next-generation BCL2 inhibitor evaluated in the relapsed/refractory setting. In this interview, Michael Wang, MD, emphasized the unmet need this agent aims to address, noting that while frontline mantle cell lymphoma (MCL) therapy has expanded to include multiple BTK inhibitors and a growing array of CD20 antibodies, venetoclax remains the only approved BCL2 inhibitor, despite limitations in efficacy and tolerability.

Sonrotoclax represents a potential advance within this drug class. Preclinical data suggest it is approximately 14 times more potent than venetoclax and 6 times more selective for BCL2. Importantly, sonrotoclax has a shorter half-life—about 5 hours compared with venetoclax’s 26 hours—reducing drug accumulation and potentially mitigating toxicity, particularly tumor lysis syndrome (TLS), a major concern with BCL2 inhibition.

In the reported study, sonrotoclax was evaluated as a single-agent oral therapy in a heavily pretreated MCL population. Patients had received a median of three prior lines of therapy, and 87% were refractory to their most recent treatment. Despite this high-risk profile, sonrotoclax achieved an overall response rate of 52%, including a complete response rate of 16%, outcomes that compare favorably with historical benchmarks for first-generation BTK inhibitors in similar populations. Among patients treated after only two prior lines of therapy, the ORR increased to 61%.

Safety findings were also notable. TLS events were infrequent and largely laboratory-based, with only two mild clinical TLS cases that were reversible and without serious consequences. Cytopenias, including neutropenia, thrombocytopenia, and anemia, were observed but were generally transient, manageable, and reversible. Rates of atrial fibrillation were very low, contributing to an overall favorable tolerability profile.

Based on these efficacy and safety data, the interviewee characterized sonrotoclax as a practice-changing agent at ASH 2025. An ongoing phase 3 trial comparing sonrotoclax with placebo is expected to support