Sonrotoclax: In Search of a Less Toxic BTK + BCL2 Inhibitor Combo for CLL

Patients with chronic lymphocytic leukemia (CLL) taking a next-generation combination of a Bruton tyrosine kinase (BTK) inhibitor and a therapy to target the BCL2 protein had 100% progression-free survival (PFS) after 9.7 months, signaling what may be a treatment shift for this population, according to results reported Saturday at the 65th American Society of Hematology Annual Meeting and Exposition in San Diego, California.

Lead investigator Constantine Tam, MD, PhD, of St. Vincent’s Hospital, Melbourne, Australia, reported on results involving zanubrutinib, the second-generation BTK inhibitor sold as Brukinsa, and sonrotoclax, the investigational BCL2 inhibitor now being studied in several blood disorders. Both are made by BeiGene.

Advancing treatment options for patients with CLL or small lymphocytic lymphoma (SLL) is not just about finding new therapies for patients who relapse, but also keeping patients on therapy in the first place—and that may mean creating better, less toxic versions of what works.

Combing the BTK inhibitor ibrutinib with venetoclax, the BCL2 inhibitor, has been effective in clinical trials for patients with treatment naive CLL, but toxicity rates are high. A 2019 phase 2 study published in the New England Journal of Medicine showed high remission rates; however, 60% of the patients had grade 3 adverse events (AEs). In the 2022 CAPTIVATE trial, the grade 3 AEs for patients receiving a fixed-duration regimen ibrutinib and venetoclax were lower, but investigators reported that rates of diarrhea and neutropenia were “somewhat higher than expected with ibrutinib alone.”

Since then, the second-generation BTK inhibitor, zanubrutinib, has been approved for treatment of CLL, having demonstrated superior efficacy to ibrutinib in the head-to-head ALPINE trial with fewer cardiac effects. Now, a next-generation BCL2 inhibitor, sonrotoclax, is being studied with zanubrutinib in CLL, with preliminary results.

The ALPINE results make zanubrutinib "the natural partner to be chosen to be paired with the second-generation BCL2 inhibitor," Tam said.

Sonrotoclax is described as a BH3 mimetic with greater than 10-fold potency compared with venetoclax, with higher selectivity. Tam said it also has a shorter half-life than venetoclax, which makes it easier to develop a rapid dose escalation schedule.

The phase 1/2 BGB-11417-101 trial (NCT04277637) involves patients with treatment-naive CLL or small lymphocytic lymphoma; it is evaluating sonrotoclax as a monotherapy and in various combinations to determine efficacy and appropriate dosing for further study.

Based on the positive phase 1/2 results, BeiGene officials have said the 320 mg dose of sonrotoclax will be evaluated in a global phase 3 trial (NCT06073821).

Constantine Tam, MBBS, MD

Tam reported on the study arm involving 107 patients who were treated with the combination of sonrotoclax and zanubrutinib. In this arm, patients were treated with zanubrutinib monotherapy for 8 to 12 weeks before receiving sonrotoclax dosing; sonrotoclax was dosed orally, 30 minutes after a low-fat meal. A ramp-up schedule was used to reach a target dose.

In this arm, 51 patients received 160 mg and 56 received 320 mg of sonrotoclax, plus zanubrutinib. Slightly more than a third of the group were age 65 or older (39% of the 160 mg group, 34% of the 320 mg group). Roughly a quarter had high-risk clinical features, namely 17p deletion and/or TP53 mutation status (24% of the 160 mg group, 27% of the 320 mg group).

Results were as follows:

• At a median follow-up of 9.7 months, no patient had experienced disease progression or died at either dose level of sonrotoclax.
• 75 patients were response-evaluable at the data cutoff.
• All patients responded, with 32% achieving a complete remission (CR) or complete remission with incomplete count recovery (CRi); the CR rate rose over time at both the 160 mg and the 320 mg doses. Tam noted these data are not yet mature.

Selected AEs were as follows:

• There was 1 dose reduction and no dose holds.
• 43 patients (40%) had treatment-related adverse events (AEs) of grade 3 or higher; of these, 15 were serious AEs (14%).
• 18 patients (17%) required granulocyte colony-stimulating factor, with a median duration of 10 days, which Tam described as "transient."
• 2 patients (2%) experienced febrile neutropenia at the 160 mg dose level; 1 did not need antibiotics, the events resolved.
• 8% of patients infections of grade 3 or higher.
• Pneumonia (4 patients) was the only recurring grade 3 infection; no deaths took place due to infection.

Investigators measured minimal residual disease (MRD), which showed a deepening response over time. By week 48, 100% of patients in the 320 mg group and 75% of patients in the 160 mg group had achieved undetectable MRD levels.

Reference

Tam CS, Anderson MA, Lasica M, et al. Combination treatment with sonrotoclax (BGB-11417), a second-generation BCL2 inhibitor, and zanubrutinib, a Bruton tyrosine kinase Inhibitor, is well tolerated and achieves deep responses in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma: data from an ongoing phase 1/2 study. Presented at: 65th American Society of Hematology Annual Meeting & Exposition; December 9-12, 2023; San Diego, California; Paper No. 0327. https://doi.org/10.1182/blood-2023-179541