Phase 3 Study: Zanubrutinib Improves PFS Over Chemoimmunotherapy in Untreated CLL, SLL

Zanubrutinib may be a new potential frontline treatment option for patients with untreated chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), including among a subgroup of hard-to-treat patients, according to recent research.

The findings, coming from the phase 3 SEQUOIA study, found that the next-generation, selective Bruton tyrosine kinase inhibitor had superior efficacy versus chemoimmunotherapy and demonstrated an acceptable safety profile among 600 older patients with comorbidities.

“SEQUOIA is, to our knowledge, the first randomised, phase 3 study examining the efficacy and safety of zanubrutinib in patients with untreated CLL,” explained the researchers, adding, “The SEQUOIA study provides aggregate data supporting the potential use of zanubrutinib as a new treatment option for patients with untreated CLL or SLL.”

Compared with bendamustine-rituximab, zanubrutinib significantly improved progression-free survival (PFS) (HR, 0.42; 95% CI, 0.28-0.63) among patients without the high-risk genetic abnormality del(17)(p13.1), meeting the primary endpoint of the study.

At a median follow-up of 26.2 months, median PFS was not reached among either group. Estimated PFS at 24 months was 85% among patients receiving zanubrutinib and was 69.5% among patients receiving bendamustine-rituximab. According to the researchers, their findings are consistent with previous randomized trials, including of ibrutinib (Alliance A041202) and of acalabrutinib (ELEVATE­TN), among patients with comorbidities.

Patients receiving zanubrutinib also experienced a higher overall response rate (94.6% vs 85.3%) as determined by an independent review committee. The researchers noted that BTK inhibitors are uncommon within the first 3 years of treatment, resulting in a need for longer follow-up to determine if responses to zanubrutunib deepen over time.

The study also included a group of patients with del(17)(p13.1)—a group of patients who historically have poor outcomes with chemoimmunotherapy—who were treated with zanubrutinib and at 24 months had an estimated PFS of 88.9%.

Patients receiving zanubrutinib received the treatment orally twice a day at 160 mg for 28-day cycles and patients receiving bendamustine-rituximab received bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for 6 cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2–6.

Across all 3 groups of patients, the most common grade 3 or worse adverse event was neutropenia, occurring in 11% of patients without del(17)(p13.1) receiving zanubrutinib, 51% of patients without del(17)(p13.1) receiving bendamustine-rituximab, and in 15% of patients with del(17)(p13.1) receiving zanubrutinib.

“Consistent with the known class effects of BTK inhibitors, bleeding adverse events occurred more often in patients treated with zanubrutinib. Several patients who reported major bleeding adverse events were concurrently administered antithrombotic medications, which might have contributed to these events,” wrote the researchers. “Overall, rates of any­grade bleeding events were similar to those reported in studies of other BTK inhibitors. Alliance A041202 and ELEVATE­TN required stopping of anticoagulation before enrolment, whereas our study did not restrict anticoagulation use at study entry; differences in study conduct might confound comparison of bleeding rates between BTK inhibitors.”

Among patients with del(17)(p13.1), rates of infection were similar between both treatment groups. Patients receiving zanubrutinib were more likely to report worse COVID-19 infection than patients receiving bendamustine-rituximab. The group flagged limitations of the study brought on by the COVID-19 epidemic, including prevention of certain sites being able to complete all study assessments, including bone marrow examinations.

Reference

Tam C, Brown J, Kahl B, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. Published online July 7, 2022. doi: 10.1016/S1470-2045(22)00293-5