Dr Opat on the Unique Mechanism of Action of Sonrotoclax in R/R CLL

“[Sonrotoclax] also targets BCL-2 like venetoclax; [however], what’s different about sonrotoclax is it is much more potent. In vitro, it [demonstrates] up to 10 times the potency of venetoclax.”

Stephen Opat, MBBS, the director of Clinical Hematology at Monash Health, Monash University; founder and chair of the Australasian Lymphoma and Related Diseases Registry; and lead investigator of the Melbourne Genomics Health Alliance Lymphoma Flagship, detailed the unique mechanism of action of sonrotoclax (BGB-11417) for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The novel, oral, selective BCL-2 inhibitor sonrotoclax has been shown to work similarly to venetoclax (Venclexta); however, it has shown stronger potency, Opat began. He emphasized that in vitro, the novel agent has up to 10 times the potency of venetoclax, with a short half-life of approximately 4 hours compared with 26 hours for venetoclax.

Sonrotoclax was evaluated in combination with zanubrutinib (Brukinsa) in patients with relapsed/refractory CLL or SLL in the phase 1 BGB-11417 study (NCT04277637). The study assessed sonrotoclax monotherapy or as a combination with zanubrutinib and/or obinutuzumab (Gazyva) in patients with B-cell malignancies that included relapsed/refractory CLL or SLL.

Data from the study demonstrated that the regimen led to durable responses with a tolerable safety profile. Specifically, the regimen produced a 97% overall response rate (ORR), including a complete response (CR)/CR with incomplete hematologic recovery (CRi) rate of 57% across all dose levels. Of note, the maximum tolerated dose was not reached, and the recommended phase 2 dose (RP2D) of sonrotoclax was chosen at 320 mg. Patients treated with the RP2D experienced an ORR of 100% and a CR/CRi rate of 73%.

With daily dosing, the agent won’t accumulate, which is important as the accumulation of venetoclax could be associated with adverse effects (AEs), including neutropenia and gastrointestinal intolerance, Opat continued.

In the study, any-grade treatment-emergent AEs (TEAEs) occurred in 94% of patients, with grade 3 or greater TEAEs reported in 51% and serious TEAEs in 28%. Furthermore, only 1 patient experienced TEAEs that led to discontinuation. The 5 most common TEAEs observed in the whole patient population included contusion (grade 1/2, 32%; grade ≥3, 0%), neutropenia (6%; 21%), COVID-19 (26%; 2%), diarrhea (28%; 0%), and fatigue (26%; 0%). Notably, no patients receiving sonrotoclax experienced TEAEs leading to a dose reduction of the agent, and no deaths were observed.