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Zanubrutinib Plus Venetoclax and Obinutuzumab Yields Deep Remissions in Patients With Chronic Lymphocytic Leukemia
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Key Takeaways
- Zanubrutinib, venetoclax, and obinutuzumab achieved significant uMRD rates and deep remissions in relapsed/refractory CLL patients.
- The triplet regimen resulted in a PFS of 96% and OS of 96.8% at 18 months, indicating durable efficacy.
Undetectable minimal residual disease rates improved with ongoing therapy.
Zanubrutinib (Brukinsa; BeiGene), venetoclax (Venclexta; AbbVie Inc), and obinutuzumab (Gazyva; Genentech) demonstrated significant improved undetectable minimal residual disease (uMRD)-negativity and yielded deep remissions in patients with chronic lymphocytic leukemia (CLL) in the phase 2 CLL2-BZAG trial (NCT04515238). The data were published in Blood.1,2
Cancer cells in the blood stream | Image Credit: © freshidea - stock.adobe.com
Although there has been significant progress in treating patients with CLL and other cancers, resistance and less than ideal treatment outcomes still exist. Chemotherapy is now part of the standard of care treatment, coupled with new immunotherapies or targeted medicines in frontline and relapsed settings. Bruton's tyrosine kinase (BTK) inhibitors have significantly increased therapy efficacy and tolerability, displacing more traditional therapies.3
Zanabrutinib is a potent BTK inhibitor designed to bind to BTK proteins with greater precision for longer durations and persist at high concentrations during treatment. In 2019, it was approved by the FDA for CLL and small lymphocytic leukemia based on results from the SEQUOIA trial (NCT03336333).3,4
In the prospective, open-label, multicenter phase 2 trial, investigators explored the efficacy and safety of bendamustine (Bendeka; Teva Pharmaceuticals) followed by obinutuzumab, zanubrutinib, and venetoclax in patients with relapsed/refractory CLL. They assessed a total of 42 patients who previously received a median of 1 prior line of therapy (range 1 to 5), of which 45% were treated with BTK inhibitors, 17.5% received venetoclax, and 12.5% previously received both. The population had a median age of about 64 years, and 67.5% were male.2
The primary end point of the analysis is the uMRD rates, with other key end points including safety, progression-free survival (PFS), and overall survival (OS). Patients treated with obinutuzumab, zanubrutinib, and venetoclax achieved significant uMRD rates with remissions deepening over time. The combination regimen resulted in a uMRD rate in the peripheral blood of 52.5% (23) at the end of induction treatment. With ongoing therapy, uMRD rates increased, the best being 85%. At 18 months, the triplet yielded a PFS of 96% and an OS of 96.8%.2
The safety profile, separate from COVID-19-related adverse events (AEs), was favorable, and the triplet was well-tolerated. The most common AEs were COVID-19 (n = 26 patients), diarrhea (n = 15), infusion-related reactions (n = 15), thrombocytopenia (n = 14), nausea (n = 12), fatigue (n = 12), and neutropenia (n = 12). Of the population, 2 experienced fatal AEs of COVID-19 and fungal pneumonia secondary to COVID-19.2
Overall, findings from the CLL2-BZAG trial suggest that the combination of zanubrutinib, venetoclax, and obinutuzumab offers a promising, chemotherapy-free treatment option for patients with relapsed/refractory CLL, demonstrating high rates of undetectable MRD, deep and durable remissions, and a manageable safety profile. These results support further investigation of this triplet regimen in larger, randomized studies.
