Phase 1/2 Study Data of Combination Sonrotoclax (BGB-11417) Plus Zanubrutinib in Treatment-Naïve CLL/SLL

Given that the combination of BCL2 and Bruton Tyrosine Kinase (BTK) inhibitors show synergistic activity in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), the next-generation BCL2 inhibitor sonrotoclax (BGB-11417) plus the next-generation BTK inhibitor zanubrutinib are being evaluated in the ongoing, first-in-human, phase 1/1b BGB-11417-101 (NCT04277637) study. The safety and efficacy data of sonrotoclax plus zanubrutinib from the treatment-naïve CLL/SLL cohort were presented at the 2023 American Society of Hematology annual meeting and summarized here.

Eligible patients received zanubrutinib (320 mg daily or 160 mg twice daily; for 8-12 weeks before sonrotoclax start) plus sonrotoclax (administered using a ramp-up schedule starting from 1 mg to the intended target dosage of 160 mg or 320 mg once daily [QD]) until progression or unacceptable toxicity. Primary end point was safety; secondary end point was overall response rate (ORR); exploratory end point was minimal residual disease assessed in blood every 24 weeks (uMRD4; <1 CLL cell per 10,000 leukocytes, or <0.01%). Date of data cut-off was May 21, 2023.

A total of 107 eligible patients were enrolled; of these, 51 received sonrotoclax 160 mg QD and 56 received 320 mg QD, plus zanubrutinib. Median follow-up was 9.7 months for all patients; 160 mg, 7.2 months; 320 mg, 9.8 months. No deaths have occurred, and all patients remain on study.

Any grade adverse events occurred in 89.7% of all patients; 92.2% with sonrotoclax 160 mg and 87.5% with sonrotoclax 320 mg. The most common treatment-emergent adverse events (TEAEs) were contusion, neutropenia, and low-grade gastrointestinal toxicity; neutropenia was the most common grade ≥3 TEAE in 18% of patients with sonrotoclax 160 mg and 25% of patients with sonrotoclax 320 mg. In both ramp-up schedules, there were no cases of clinical or laboratory tumor lysis syndrome or atrial fibrillation. Treatment discontinuation due to TEAE was reported in 1 patient (cryptococcal meningitis at 11 weeks). Sonrotoclax dose holds occurred in 21 patients (22.3%) for a median duration of 11 days; dose reductions were reported in 5 patients (5.3%).

A total of 75 patients were assessed for response. An ORR of 100% was achieved, including 32% with a complete response in all patients. High rates of blood uMRD4 occurred early, with 48% at Week 24 in 160 mg cohort and 78% in 320 mg cohort. The blood uMRD4 rates increased with time, with Week 48 uMRD4 rates of 74% in 160 mg and 100% in 320 mg. At a median follow-up of 9.7 months, there were no PFS events in either cohort.

Based on these results, it was concluded that the combination therapy of sonrotoclax (160 mg and 320 mg) plus zanubrutinib was well tolerated and achieves deep remissions in patients with treatment-naive CLL/SLL. Based on this data, sonrotoclax 320 mg was selected for a phase 3 study in combination with zanubrutinib in patients with treatment-naive CLL.

Source:

Tam C, Anderson M A, Lasica M, et al. Combination treatment with sonrotoclax (BGB-11417), a second-generation BCL2 inhibitor, and zanubrutinib, a Bruton tyrosine kinase (BTK) inhibitor, is well tolerated and achieves deep responses in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma (TN-CLL/SLL): data from an ongoing phase 1/2 study. Presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, December 9-12, 2023; San Diego, CA: Abstract 327.