Sonrotoclax Plus Zanubrutinib Yields High Response Rates in Relapsed/Refractory MCL

In patients with previously treated relapsed/refractory mantle cell lymphoma (MCL), the combination of sonrotoclax and zanubrutinib showed promising efficacy and safety, according to research presented by Constantine S. Tam, MD, from the Alfred Hospital and Monash University in Melbourne, Australia at the European Hematology Association (EHA) 2025 Congress in Milan, Italy.

While the phase III SYMPATICO study showed that treatment with venetoclax and ibrutinib was efficacious for patients with relapsed/refractory MCL, the authors stated, “treatment intolerance may impact its use.”

The authors hypothesized that sonrotoclax, a more selective inhibitor of BCL2 than venetoclax with a shorter half-life and no drug accumulation, with approved Bruton tyrosine kinase inhibitor (BTKi) zanubrutinib may represent a more tolerable treatment combination for this patient population.

Dr. Tam and colleagues presented findings from the ongoing open-label BGB-11417-101 study (NCT04277637) involving 49 patients with relapsed/refractory MCL who had undergone at least one prior therapy (median 1, range=1-4). The median age of patients was 68 years (range=45-85) and a majority (69.4%) were male. Three had previous BTKi exposure, 15 had undergone stem cell transplantation (14 autologous, 1 allogeneic), and 1 had received CAR T-cell therapy.

Patients received zanubrutinib 320mg once daily or 160mg twice daily for 8-12 weeks. This was followed by 80, 160, 320, or 640mg daily sonrotoclax until unacceptable toxicity or disease progression, with a dose ramp-up to mitigate the risk of tumor lysis syndrome (TLS). The maximum tolerated dose of sonrotoclax was not reached up to 640mg. Dose expansion occurred at 160mg and 320mg. The recommended phase II dose identified was 320mg.

The primary endpoint of the study was safety. No instances of laboratory or clinical TLS were reported. Neutropenia was the most common grade >3 treatment-emergent adverse event (TEAE), occurring in 20.4% of patients. TEAEs occurring in ≥30% of patients included contusion, COVID-19, diarrhea, and neutropenia. A total of 20 patients (40.8%) discontinued at least one study drug, while 13 discontinued combination therapy and 7 discontinued zanubrutinib only. Eight patients in the study died as a result of progressive disease.

Overall response rate (ORR) represented the secondary endpoint of the study. Among 45 response-evaluable patients, the ORR was 77.8% (n=35). The complete response (CR) rate was 62.2% (n=28). Median time to CR was 6.7 months. At data cutoff (median follow up of 16.2 months) 89% of patients who achieved CR remained in remission. In the dose expansion cohorts, the 160 and 320mg groups achieved respective CR rates of 53.8% and 61.9%.Two out of three patients previously treated with a BTKi achieved partial responses.

“Sonrotoclax plus zanu combination therapy was well tolerated and demonstrated encouraging antitumor activity,” the authors concluded. A phase III study is currently recruiting to further assess this combination, the authors reported.