Sonrotoclax Plus Zanubrutinib Generates Durable Responses in R/R Mantle Cell Lymphoma

The addition of the novel BCL-2 inhibitor sonrotoclax (BGB-11417) to zanubrutinib (Brukinsa) led to deep and durable responses across dose levels in the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL), according to updated data from the phase 1/1b BGB-11417-101 trial (NCT04277637) presented at the 2025 EHA Congress.

Data showed that at a median follow-up of 16.4 months (range, 0.7-42.4), patients treated across all dose levels (n = 47) achieved an overall response rate (ORR) of 79%, including a complete response (CR) rate of 66% and a partial response (PR) rate of 13%. The rates of stable disease (SD) and progressive disease (PD) were 6% and 15%, respectively. Notably, all patients with a best response of PD experienced disease progression during lead-in dosing with zanubrutinib. The median time to CR was 6.7 months (range, 1.5-28.2).

In patients treated with sonrotoclax at a dose of 320 mg plus zanubrutinib (n = 23), the ORR was 78% at a median follow-up of 13.2 months (range, 0.7-31.6). The respective CR, PR, SD, and PD rates were 70%, 9%, 4%, and 17%.

“Antitumor activity was promising, with high response rates and early, durable, and deep responses in patients with relapsed/refractory MCL,” presenting study author Raul Cordoba, MD, PhD, head of the Lymphoma Unit at the Fundacion Jimenez Diaz University Hospital in Madrid, Spain, said in a presentation of the data.

Regarding safety, no dose-limiting toxicities (DLTs) were reported, and the maximum tolerated dose (MTD) of sonrotoclax was not reached after it was evaluated up to 640 mg. The 320-mg dose was selected as the recommended phase 2 dose (RP2D).

Trial Deep Dive

BGB-11417-101 was a global study that evaluated sonrotoclax with or without zanubrutinib or obinutuzumab (Gazyva) in patients with B-cell malignancies. The analysis presented at EHA 2025 focused on patients with relapsed/refractory MCL treated with sonrotoclax plus zanubrutinib. The study also included patients with relapsed/refractory or treatment-naive chronic lymphocytic leukemia or small lymphocytic lymphoma.

In the MCL cohorts, patients received 8 to 12 weeks of zanubrutinib during the lead-in period, with the agent dosed at 320 mg once per day or 160 mg twice per day. Sonrotoclax and zanubrutinib were then administered together until disease progression, intolerance, or elective discontinuation. Treatment could also be stopped after 96 weeks at patient discretion, and these patients remained on the trial protocol while following the procedures for elective discontinuation. Sonrotoclax was evaluated at doses of 80 mg (n = 6), 160 mg (n = 13), 320 mg (n = 27), and 640 mg (n = 5); the 160-mg and 320-mg doses were selected for the expansion portion of the study.

The study’s primary end points were safety and determining the MTD/RP2D.

In the overall MCL population (n = 51), the median age was 68.0 years (range, 45-85). Most patients were male (70.6%) and had an ECOG performance status of 1 (56.9%). Notably, 13.7% of patients had high tumor bulk. Ki-67 proliferation index was below 30% in 29.4% of patients and 30% or higher in 19.6% of patients; Ki-67 data were missing for 51.0% of patients. Additionally, TP53 mutations were reported in 11.8% of patients; 13.7% did not harbor TP53 mutations, and TP53 status was missing for 74.5% of patients.

Patients received a median of 1 prior line of therapy (range, 1-4), and 7.8% received a prior BTK inhibitor. The median duration of exposure to a prior BTK inhibitor was 8.4 months (range, 0.3-24.1).

Additional Data

Further efficacy findings showed that the median duration of response (DOR) was not reached (NR; 95% CI, 34.8-not evaluable [NE]) in the overall population; the estimated 24-month DOR rate was 84.0% (95% CI, 65.3%-93.1%).

The median DOR was NR (95% CI, 3.3-NE) in the 320-mg group, with an estimated 24-month DOR rate of 80.1% (95% CI, 49.4%-93.3%). The 18-month duration of CR rate in this group was 84.4% (95% CI, 50.4%-95.9%).

In the overall population, any-grade treatment-emergent adverse effects (TEAEs) occurred in 94.1% of patients, including 54.9% of patients who experienced grade 3 or higher TEAEs. Serious TRAEs were reported in 29.4% of patients. TEAEs led to death in 5.9% of patients, discontinuation of zanubrutinib in 15.7% of patients, and dose reductions of zanubrutinib in 3.9% of patients.

In patients who received sonrotoclax (n = 46), TEAEs led to death in 2.0% of patients and discontinuation of sonrotoclax in 9.8% of patients. No dose reductions were required due to TEAEs.

In all patients, the most common TEAEs reported in at least 15% of patients comprised neutropenia (grade 1/2, 12%; grade ≥3, 20%), COVID-19 (27%; 2%), diarrhea (27%; 2%), contusion (29%; 0%), thrombocytopenia (16%; 12%), fatigue (20%; 0%), headache (16%; 2%), cough (18%; 0%), nausea (18%; 0%), pneumonia (4%; 12%), and peripheral edema (16%; 0%).

The ongoing phase 3 CELETIAL-RRMCL trial (NCT06742996) is further evaluating the combination of sonrotoclax and zanubrutinib in patients with relapsed/refractory MCL.

Disclosures: Cordoba reported receiving consultancy fees, honoraria, travel support, and serving on an advisory board for AbbVie, AstraZeneca, BeOne Medicines, Gilead, Incyte, Johnson & Johnson, Lilly, and Roche.

Reference

Tam CS, Lasica M, Soumerai JD, et al. Combination treatment with novel BCL2 inhibitor sonrotoclax (BGB-11417) + zanubrutinib induces high rate of complete remission for patients with relapsed/refractory mantle cell lymphoma. Presented at: 2025 EHA Congress; June 12-15, 2025; Milan, Italy. Abstract S234.