Sonrotoclax With Zanubrutinib Yields Durable Responses in CLL/SLL

Microscopic images of red blood cells activated platelets as a result of leukemia: ©AkuAku - stock.adobe.com

The combination of sonrotoclax (BGB-11417) with zanubrutinib (Brukinsa) led to promising responses and tolerability in patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the phase 1 BGB-11417-101 study (NCT04277637).¹

At a median follow-up of 19.3 months (range, 0.4-35.7), the maximum tolerated dose (MTD) was not reached. The recommended phase 2 dose (RP2D) was set as 320 mg of sonrotoclax.

Treatment with sonrotoclax plus zanubrutinib led to a 97% overall response rate (ORR), with a complete response (CR)/CR with incomplete hematologic recovery (CRi) rate of 57% across all dose levels. Among those in the 320-mg cohort, the ORR was 100%, and the CR/CRi rate was 73%.

“We have a lot of experience combining [Bruton tyrosine kinase (BTK)] inhibitors with BCL2 inhibitors… In this study, we are comparing the combination of sonrotoclax and zanubrutinib to the standard –of care, venetoclax [Venclexta] and obinutuzumab [Gazyva],” Mazyar Shadman, MD, MPH, Innovators Network Endowed Chair; associate professor, Clinical Research Division, Fred Hutch Cancer Center; associate professor, Medical Oncology Division, University of Washington School of Medicine, told Targeted Oncology^TM in an interview.

BGB-11417-101 is an ongoing trial evaluating sonrotoclax either alone or in combination with zanubrutinib and/or obinutuzumab in patients with B-cell malignancies, including relapsed/refractory CLL/SLL, relapsed/refractory mantle cell lymphoma, or treatment-naive CLL/SLL. Experts are assessing the primary end points of safety per CTCAE v5.0 criteria, as well as the determination of the MTD and RP2D.²

Mazyar Shadman, MD, MPH

The first arm of the study was the sonrotoclax plus zanubrutinib dose-finding arm where patients with relapsed/refractory CLL/SLL (n = 47) were treated with 8 to 12 weeks of zanubrutinib lead-in therapy at a dose of 320 mg daily or 160 mg twice daily. This was followed by zanubrutinib plus sonrotoclax with weekly ramp-up to the target dose until disease progression.

Patients in the dose-expansion phase of the trial received daily or weekly ramp-up to the target sonrotoclax dose of 320 mg. In total, 4, 9, 6, 22, and 6 patients received sonrotoclax at 40 mg, 80 mg, 160 mg, 320 mg, and 640 mg, respectively, throughout the dose-finding and dose-expansion phases.

The median age of all patients was 65 years (range, 36-76). The majority of patients were male (75%) and had an ECOG performance status (PS) of 0 (60%). A total of 26% of evaluable patients had 17p deletions, 53% had 17p deletions and/or TP53 mutations, and 68% had unmutated IGHV.¹

The median number of prior lines of therapy was 1 (range, 1-3). Fifteen percent of patients had received prior BTK inhibitors, and the median duration of prior BTK inhibition was 34.2 months (range, 1.6-86.6).

Thirty-three patients were evaluable for minimal residual disease (MRD) status, and at the data cutoff, 85% had undetectable MRD. Six patients were evaluable in the 160-mg cohort and the best MRD outcomes by week 24 were MRD4-positive (17%), undetectable MRD4 (50%), and not available (NA; 33%). In the 320-mg cohort, 9 patients were evaluable. The best MRD outcomes by week 24 in this cohort consisted of MRD4-positive (22%), undetectable MRD4 (44%), and NA (33%). Additionally, all patients, including 6 in the 160-mg cohort and 5 in the 320-mg cohort, who received sonrotoclax at 160 mg, 320 mg, and 640 mg who reached week 48 achieved undetectable MRD.

There was 1 progression-free survival event observed, and this occurred in the 40-mg cohort.

Looking at safety, no dose-limiting toxicities were seen with the combination. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 94% of all patients, while grade 3 or higher TEAEs occurred in 51%. Serious TEAEs were seen in 28% of patients.

Two patients discontinued zanubrutinib due to their TEAEs, and 1 patient had to reduce their dose of zanubrutinib due to TEAEs. A total of 94% of patients received treatment with sonrotoclax, 1 of whom had TEAEs leading to discontinuation of the drug. No patients had to reduce their dose of sonrotoclax due to TEAEs, and there were no deaths observed in the study.

In the 320-mg cohort of patients given sonrotoclax, any-grade TEAEs occurred in 91%, grade 3 or higher TEAEs occurred in 59%, and serious TEAEs occurred in 32%. There were no TEAEs that led to discontinuation of zanubrutinib. One patient had to reduce their dose of zanubrutinib due to TEAEs. At this dose level, 86% of patients received treatment with sonrotoclax, and none of these patients had TEAEs leading to discontinuation or dose reductions of sonrotoclax.

Among the entire patient population, the most common TEAEs consisted of contusion (grade 1/2, 32%; grade ≥3, 0%), neutropenia (6%; 21%), COVID-19 (26%; 2%), diarrhea (28%; 0%), fatigue (26%; 0%), nausea (23%; 0%), upper respiratory tract infection (23%; 0%), cough (21%; 0%), constipation (15%; 2%), headache (17%; 0%), hypertension (4%; 9%), back pain (13%; 0%), sinusitis (11%; 0%), and thrombocytopenia (11%; 0%).

In the group of patients who were treated with sonrotoclax at 320 mg, the most common TEAEs consisted of neutropenia (grade 1/2, 5%; grade ≥3, 36%), upper respiratory tract infection (32%; 0%), contusion (23%; 0%), diarrhea (23%; 0%), and constipation (18%; 5%). There were also no cases of tumor lysis syndrome, atrial fibrillation, febrile neutropenia, or dose reductions due to diarrhea.

A total of 46 patients remain on study treatment, and follow-up is ongoing.

REFERENCES:

1. Opat S, Anderson MA, Tedeschi A, et al. Results from the phase 1 study of the novel BCL2 inhibitor sonrotoclax (sonro) in combination with zanubrutinib (zanu) for relapsed/refractory (R/R) CLL/SLL show deep and durable responses. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract S156.

2. Study of Bcl-2 inhibitor BGB-11417 in participants with mature B-cell malignancies. ClinicalTrials.gov. Updated June 6, 2024. Accessed August 20, 2024. https://clinicaltrials.gov/study/NCT04277637