Stephen Opat, MBBS, is 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 in Australia. 

Stephen Opat, MBBS, explains the unique mechanism of action of sonrotoclax and how it differs from venetoclax for the treatment of patients with relapsed/refractory CLL or SLL.

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.

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.

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Dr Opat on the Accessibility of Sonrotoclax Plus Zanubrutinib in R/R CLL/SLL

Stephen Opat, MBBS, director, Clinical Hematology, head, Department of Hematology, School of Clinical Sciences, Monash Health, Monash University; founder, chair, the Australasian Lymphoma and Related Diseases Registry, lead investigator, the Melbourne Genomics Health Alliance Lymphoma Flagship, discusses the accessibility and clinical implications of the combination of sonrotoclax (BGB-11417) and zanubrutinib (Brukinsa) in the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Updated findings from the phase 1 BGB-11417-101 study

 (NCT04277637), which were presented at the 

, showed that across all dose levels, patients treated with the combination therapy experienced an overall response rate (ORR) of 97% across all dose levels, including a complete response (CR) or CR with incomplete hematologic recovery rate (CRi) of 57%. Notably, patients treated with the recommended phase 2 dose of sonrotoclax at 320 mg, the ORR was 100%, and the CR/CRi rate was 73%. Regarding safety, no dose-limiting toxicities were reported, and the maximum tolerated dose of sonrotoclax was not reached.

One of the significant benefits of this combination is its oral administration, eliminating the need for frequent hospital visits for intravenous (IV) infusions, Opat explains. This level of convenience can enhances patient compliance and quality of life, making it a more accessible treatment option for patients who might face logistical challenges or have limited travel access to treatment centers, he continues.

Opat emphasizes that this regimen could be beneficial in clinical practice, particularly in community settings where access to hospital-based treatments might be limited. Monitoring blood tests is also necessary to ensure patient safety and manage potential adverse effects, Opat notes. However, the simplicity of this regimen compared with IV therapies could facilitate its integration into routine clinical practice, he says.

Opat explains that ongoing phase 3 trials will provide further insights into the effectiveness of the combination compared with current standard-of-care treatments for patients with CLL/SLL. An ongoing phase 3 trial (NCT06073821) is evaluating sonrotoclax plus zanubrutinib vs venetoclax (Venclexta) plus obinutuzumab (Gazya) in patients with treatment-naive CLL/SLL.

Stephen Opat, MBBS, discusses the accessibility of sonrotoclax plus zanubrutinib in relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.  

Dr Opat on Sonrotoclax With Zanubrutinib in Relapsed/Refractory CLL and SLL

Stephen Opat, MBBS, director, Clinical Hematology, head, Department of Hematology, School of Clinical Sciences, Monash Health, Monash University; founder, chair, the Australasian Lymphoma and Related Diseases Registry, lead investigator, the Melbourne Genomics Health Alliance Lymphoma Flagship, discusses the combination of sonrotoclax (BGB-11417) and zanubrutinib (Brukinsa) for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

, showcase the efficacy of this combination therapy.

With a median follow-up of 19.3 months (range, 0.4-35.7), the study reported no dose-limiting toxicities, indicating a tolerable safety profile for patients receiving the combination. The maximum tolerated dose (MTD) was not reached, and 320 mg was established as the recommended phase 2 dose (RP2D) for sonrotoclax, Opat states. These findings support the potential for higher doses of sonrotoclax to be safely administered in future studies.

The efficacy of the combination therapy was notable according to Opat, with an overall response rate (ORR) of 97% across all dose levels. This includes a complete response (CR) or CR with incomplete hematologic recovery rate (CRi) of 57%. Notably, in the 320 mg cohort, the ORR was 100%, and the CR/CRi rate was 73%, he explains. These high response rates suggest that the combination of sonrotoclax and zanubrutinib may be highly effective for patients with relapsed/refractory CLL/SLL, Opat reports.

A lack of dose-limiting toxicities and the achievement of deep and durable responses underscore the combination's utility in CLL/SLL. The establishment of 320 mg as the RP2D for sonrotoclax sets the stage for further clinical investigations, including phase 2 studies, to confirm these findings and to explore the long-term benefits and safety of this therapeutic regimen, he imparts.

Opat concludes that the combination of sonrotoclax and zanubrutinib has demonstrated a favorable safety profile and robust efficacy in patients with relapsed/refractory CLL/SLL. These results from the BGB-11417-101 study suggest that this combination could become an important addition to the treatment landscape, pending further validation in subsequent trials, such as the ongoing phase 3, CELESTIAL-TNCLL (NCT06073821), which seeks to assess the combination of sonrotoclax and zanubrutinib vs venetoclax and obinutuzumab for treatment-naïve (TN) CLL, Opat closes.

Stephen Opat, MBBS, discusses sonrotoclax plus zanubrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma.



Results From the Phase 1 Study of the Novel BCL2 Inhibitor Sonrotoclax in Combination with Zanubrutinib for Relapsed/Refractory CLL/SLL Show Deep and Durable Responses

BGB-11417-101 is a global phase 1/1b study evaluating sonrotoclax as monotherapy, or in combination ± zanubrutinib, and ± obinutuzumab in patients with B-cell malignancies. (NCT04277637) 

Stephen Opat, MBBS

Articles

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

Dr Opat on the Accessibility of Sonrotoclax Plus Zanubrutinib in R/R CLL/SLL

Dr Opat on Sonrotoclax With Zanubrutinib in Relapsed/Refractory CLL and SLL

Results From the Phase 1 Study of the Novel BCL2 Inhibitor Sonrotoclax in Combination with Zanubrutinib for Relapsed/Refractory CLL/SLL Show Deep and Durable Responses