Sonrotoclax plus zanubrutinib yielded deep, durable responses at the recommended phase 2 dose in relapsed/refractory MCL.
Treatment with the combination of sonrotoclax (Beqalzi) and zanubrutinib (Brukinsa) led to deep and durable responses in patients with relapsed/refractory mantle cell lymphoma (MCL) treated at the recommended phase 2 dose (RP2D) of sonrotoclax, according to updated data from the phase 1/1b BGB-11417-101 trial (NCT04277637) presented in a poster session at the
Findings showed that patients treated with sonrotoclax at the 320-mg per day RP2D (n = 27) achieved an overall response rate (ORR) of 81.5%, including a complete response (CR) rate of 59.3%. The median time to CR was 5.2 months (range, 1.5-32.5), and among 16 patients who achieved a CR, 87.5% remained in CR at data cutoff. The median duration of response (DOR) was not reached (NR); the 24-month DOR rate was 78.3% (95% CI, 51.3%-91.4%) at a median DOR follow-up of 25.8 months. The median progression-free survival (PFS) also was NR, with a 24-month PFS rate of 69.1% (95% CI, 47.3%-83.4%) at a median study follow-up of 24.1 months.
Across all evaluable patients at varying sonrotoclax dose levels (n = 51), the ORR and CR rate were 80.4% and 60.8%, respectively.
“Sonrotoclax plus zanubrutinib, an emerging combination therapy for B-cell malignancies, demonstrated a favorable safety profile, as well as deep and durable responses in patients with relapsed/refractory MCL,” lead study author Jacob D. Soumerai, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues wrote in a poster presentation of the data.
Notably, in May 2026,
Sonrotoclax is a next-generation BCL2 inhibitor described as more selective and pharmacologically potent than venetoclax (Venclexta), with a shorter half-life and no drug accumulation.1
BGB-11417-101 is an ongoing, global, dose-selection and -expansion study evaluating sonrotoclax as monotherapy or in combination with zanubrutinib in patients with mature B-cell malignancies. Patients in the MCL cohort were required to have relapsed/refractory disease after least 1 prior systemic therapy.
Zanubrutinib monotherapy was administered at 320 mg once daily or 160 mg twice daily for 8 to 12 weeks as lead-in dosing, followed by sonrotoclax plus zanubrutinib until disease progression, unacceptable toxicity, or protocol-defined elective discontinuation after week 96. Sonrotoclax target doses of 80, 160, 320, or 640 mg once per day were reached through a gradual ramp-up over approximately 4 weeks to mitigate the risk of tumor lysis syndrome (TLS).
As of March 1, 2026, a total of 51 patients with relapsed/refractory MCL were enrolled, including 27 treated with sonrotoclax at the 320-mg RP2D. At data cutoff, 46 of 51 patients (90.2%) had started sonrotoclax plus zanubrutinib—5 patients had disease progression during the zanubrutinib lead-in—and 43.1% remained on treatment. The median study follow-up was 28.3 months (range, 0.7-54.4).
The median patient age in the overall MCL cohort was 68 years (range, 45-85), TP53 mutations were present in 41.2% of patients, and the median number of prior lines of therapy was 1 (range, 1-4).
Among the patients with TP53 mutations (n = 21), the ORR was 62%, including a CR rate of 38%. Of 4 evaluable patients with prior BTK inhibitor exposure, 2 achieved a partial response. Across all patients, the median PFS was 52.5 months (95% CI, 24.7-not estimable).
Across all cohorts, the most common any-grade treatment-emergent adverse effects (TEAEs) were diarrhea (39.2%), neutropenia (33.3%), and COVID-19 (33.3%). In the sonrotoclax 320-mg cohort, the most common any-grade AE was diarrhea (55.6%; grade ≥3, 3.7%). Grade 3 or higher AEs occurred in 64.7% of all patients, with neutropenia (21.6%) representing the most common; in the 320-mg cohort, the most common grade 3 or higher AE was neutropenia (22.2%). One grade 3 AE of atrial fibrillation occurred in a patient with a prior history of atrial fibrillation. No laboratory or clinical TLS occurred.
Serious AEs occurred in 41.2% of patients, with pneumonia (15.7%) being the most common. AEs led to discontinuation of sonrotoclax plus zanubrutinib in 5 patients (9.8%) and of zanubrutinib alone in 3 patients (5.9%); none led to discontinuation of sonrotoclax only. AEs led to death in 4 patients (7.8%), attributed to pneumonia, pleural effusion due to disease progression, abdominal sepsis, and encephalopathy.
The combination of sonrotoclax and zanubrutinig is now under investigation in the phase 3 registrational CELESTIAL-RRMCL study (NCT06742996).
