Sonrotoclax/Zanubrutinib Leads to Durable Responses in R/R CLL/SLL

Stephen Opat

Early efficacy and safety data from the combination of sonrotoclax (BGB-11417) and zanubrutinib (Brukinsa) have pointed to its potential as another treatment option for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to Stephen Opat, MBBS.

Updated data from the phase 1/1b BGB-11417-101 study (NCT04277637) presented at the 2024 EHA Congress demonstrated that patients with relapsed/refractory CLL/SLL treated with any dose level of sonrotoclax in combination with zanubrutinib (n = 35) achieved an overall response rate (ORR) of 97%, including a complete response (CR)/CR with incomplete hematologic recovery (CRi) rate of 57%. Notably, at the recommended phase 2 dose (RP2D) of sonrotoclax at 320 mg in combination with zanubrutinib (n = 11), the ORR was 100%, and the CR/CRi rate was 73%. No dose-limiting toxicities were reported at any dose levels, and the maximum tolerated dose of sonrotoclax was not reached.

“If we look at the ORR rate at the RP2D, all patients had a response, and the majority of them were CRs. There were also high levels of minimal residual disease [MRD] negativity, which is likely to mean [patients] are having very durable responses to treatment,” Opat said in an interview with OncLive^®.

In the interview, Opat explained what differentiates sonrotoclax from other BCL2 inhibitors, expanded on data from the CLL/SLL cohort of the BGB-11417-101 trial, and detailed the next steps of research and potential clinical implications for this combination.

Opat is the director of Clinical Hematology at Monash Health in Melbourne, Australia.

OncLive: What was the rationale for investigating the combination of sonrotoclax and zanubrutinib in relapsed/refractory CLL/SLL?

Opat: This was a study looking at a new BCL2 inhibitor called sonrotoclax. This drug could be better than the prototype, venetoclax [Venclexta], because it has increased potency and selectivity, and a shorter half-life. [At EHA, we presented data from] an arm of the ongoing phase 1 trial looking at the activity of this drug in patients with relapsed or refractory CLL/SLL.

What makes the mechanism of sonrotoclax unique?

[Similar to venetoclax], this drug also targets BCL2; however [the difference with] sonrotoclax is that it is much more potent. In vitro, [sonrotoclax displayed] up to 10 times the potency of venetoclax. It also has a shorter half-life of only about 4 hours compared with 26 hours for venetoclax. This means that with daily dosing, the drug won't accumulate. We suspect that the accumulation of venetoclax could be one of the factors responsible for some of the adverse effects [AEs] such as neutropenia and gastrointestinal intolerance.

What was the phase 1 study’s methodology?

This was a phase 1/1b study. The phase 1 [portion] looked at sonrotoclax as a single agent in [patients with] a range of hematological malignancies to identify the RP2D for further development. The phase 1b [portion] looked at sonrotoclax in combination with other targeted agents and antibodies that are known to be effective in B-cell malignancies. [The goal of the phase 1b portion was] to work out what the [optimal] dose should be for [sonrotoclax] in combination [therapies].

In the whole study, there were patients with a range of B-cell malignancies. However, the data presented [at EHA focused on a] cohort of patients with relapsed/refractory CLL/SLL. CLL is the [most common] B-cell malignancy affecting adults.

What efficacy findings were presented at EHA for the CLL/SLL cohort?

The data have become more mature with a median follow-up of 19.3 months [range, 0.4-35.7]. What we have seen is how well tolerated the treatment is with 46 out of 47 patients remaining on the trial. We also identified a RP2D for sonrotoclax at 320 mg. [This dose of sonrotoclax plus zanubrutinib is now being evaluated in the] frontline [setting for patients with] CLL in the phase 3 CELESTIAL-TNCLL study [NCT06073821].

There is evidence that if you eliminate MRD, patients will have a prolonged progression-free survival. We had a look at MRD in patients at 2 time points: 24 weeks and 48 weeks. There were 2 things we identified. First, the MRD negativity [rate] increased [from week 24 to week 48]. Second, at the RP2D, all evaluable patients were MRD negative at week 48, so they had very deep responses, which is encouraging.

What did the updated safety data demonstrate?

The majority of AEs were mild. There was a small rate of grade 3 neutropenia [21%]; however, there was no consistent signal regarding toxicity. There was not any gastrointestinal intolerance, and there was no febrile neutropenia. Patients could stay on the study without [issues from AEs].

What implications of these findings for future research and, potentially, clinical practice?

What's great about this combination is that it's all oral, which means that patients don't have to come to the hospital for treatment. This is hopefully a treatment that can be widely applied in the clinic. There certainly would need to be some monitoring of blood tests; however, as opposed to other therapies that require intravenous infusions, this is potentially an important patient-focused study. [This combination is] something that [would] be easy to prescribe and deliver in community practice. It's highly effective, and we look forward to seeing this treatment combination compared with established treatments in phase 3 studies, which are in progress.

What are the next steps from this research?

The follow-up [for the phase 1/1b study] is still fairly short; therefore, we still need to see what happens with longer follow-up. It looks like a very promising combination, but with all new treatments, we require phase 3 data to show how they compare with existing therapies. I am fairly confident that this will be a useful treatment that we'll hopefully see in the clinic very soon.

Reference

Opat S, Anderson MA, Tedeschi A, et al. Results from the phase 1 study of the novel BCL2 inhibitor sonrotoclax in combination with zanubrutinib for relapsed/refractory (R/R) CLL/SLL show deep and durable responses. Presented at: 2024 EHA Congress; June 5-14, 2024; Madrid, Spain. Abstract P1053.