Fixed-Duration Zanubrutinib/Venetoclax Shows Efficacy in R/R Chronic Lymphocytic Leukemia

The fixed-duration combination of zanubrutinib (Brukinsa) and venetoclax (Venclexta) demonstrated activity with acceptable tolerability in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to data from an interim analysis of a phase 2 study (NCT05168930) presented during the 2024 ASH Annual Meeting & Exposition.

At a median follow-up of 8 months, at best response, the doublet elicited an overall response rate of 95% in evaluable patients (n = 22); this comprised a complete response (CR) rate of 17% and a partial response (PR) rate of 78%. Of note, a PR was noted in a patient who had prior exposure to a BTK inhibitor and a BCL2 inhibitor, as well as another patient who had prior exposure to acalabrutinib (Calquence).

Depth of response with the combination improved over time. Of the 6 patients who reached end of treatment and had available minimal residual disease (MRD) data, 1 achieved undetectability in the peripheral blood and bone marrow.

“Fixed-duration combination therapy with zanubrutinib/venetoclax is effective and well tolerated in relapsed/refractory CLL, including patients who had prior treatment with targeted agents,” Inhye E. Ahn, MD, of the Department of Medical Oncology, Dana-Farber Cancer Institute, in Boston, MA, said in a poster presentation of the data. “The study is actively accruing. A larger number of patients, and longer follow-up, will help further improve our understanding of this regimen in CLL.”

Ahn noted that CLL is an incurable cancer of mature B cells, the survival of which is driven by the activation of the B-cell receptor–signaling pathway and overexpression of prosurvival proteins. She added that “standard of care leverages these cellular mechanisms by targeting the BCR-signaling pathway with a BTK inhibitor such as zanubrutinib, or promoting apoptosis with a BCL2 inhibitor, such as venetoclax.”

The investigator-sponsored, multicenter, phase 2 study enrolled patients to 1 of 3 nonrandomized cohorts based on prior treatment status or disease progression status. Those who did not have prior exposure to a BTK or BCL2 inhibitor were enrolled in cohort A (n = 13), those who were exposed to BTK or BCL2 inhibition and stopped therapy due to reasons beyond disease progression were enrolled in cohort B (n = 12), and those who had progressed on a BTK inhibitor were enrolled in cohort C (n = 1). Those with a known BTK C481 mutation were excluded.

All patients received up to 15 cycles of zanubrutinib plus venetoclax, and each cycle was comprised of 28 days. Zanubrutinib was given at 160 mg twice daily beginning on day 1 of cycle 1, followed by a standard 5-week ramp-up of venetoclax on day 1 of cycle 4 for cohorts A and B and on day 1 of cycle 2 for cohort C. All pts stopped receiving the doublet after cycle 15 irrespective of clinical response or MRD status at end of treatment. For those with detectable MRD at this time point, retreatment with 12 cycles of the combination was permitted at time of progression. For those with undetectable MRD at that time point, retreatment was permitted at time of MRD recurrence.

The primary end point of the study was rate of uMRD at end of therapy in the bone marrow based on central multicolor flow cytometry at 10-4. Response assessment was performed in accordance with 2018 International Workshop for CLL criteria and safety assessment was based on National Cancer Institute CTCAE v. 5 criteria.

A total of 26 patients have been enrolled to the trial, to date. “A higher proportion of patients in cohort B had high-risk prognostic markers than other cohorts,” Ahn noted; these included unmutated IGHV, found in 75.0% of the those in cohort B vs 30.8% of those in cohort A, and complex karyotype, found in 33.3% of cohort B vs 25.0% of cohort A. The driver gene mutations, such as NOTCH1, SF3B1, and TP53, were also found more frequently in cohort B. In cohorts A and C, patients received a median of 1 prior line of therapy; in cohort B, a median of 2 prior lines was received.

A total of 9 patients completed the planned 15 cycles of the doublet; this included 1 patient who began retreatment per protocol because of progressive disease following the initial 15 cycles. Seventeen patients were on active therapy with the initial 15 cycles of the combination. A total of 22 patients were determined to be response evaluable as they had received at least 3 cycles of study treatment.

No differences in response were observed across the cohorts. The respective ORRs in cohorts A and B/C were 91% and 100%; the respective CR rates were 18% and 18%.

The most common treatment-emergent adverse effects (TEAEs) experienced by at least 20% of patients included bruising (57.7%), diarrhea (42.3%), thrombocytopenia (38.5%), neutropenia (34.6%), constipation (30.8%), fatigue (30.8%), headache (30.8%), increased creatinine (26.9%), hypertension (26.9%), nausea (26.9%), anemia (23.1%), arthralgia (23.1%), epistaxis (23.1%), and hyperhidrosis (23.1%).

Neutropenia was the most common grade 3 or higher AE, occurring in 19% of patients. Moreover, febrile neutropenia and sepsis were not found to be common, occurring in 4% of patients each. “Two patients, or 8%, developed atrial fibrillation,” Ahn said. “The patient with grade 3 atrial fibrillation when off study during the first cycle of zanubrutinib; the other patient with grade 2 atrial fibrillation continued study therapy and completed 15 cycles of zanubrutinib/venetoclax.” No patients experienced tumor lysis syndrome.

No dose reductions were required.

Disclosures: Dr Ahn served in a consultancy role for or research funding from Eli Lilly and BeiGene, and a consultancy role for AstraZeneca.

Reference

Ahn IE, Ren Y, Fisher DC, et al. A phase 2 study of zanubrutinib and venetoclax (ZV) in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL). Blood. 2024;144(suppl 1):1874. doi:10.1182/blood-2024-201668