FDA Accepts sNDA for Zanubrutinib to Treat CLL/SLL

The supplemental new drug application (sNDA) filing includes data from 2 pivotal randomized phase 3 global studies, ALPINE and SEQUOIA, of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). The target action date is October 22, 2022.

The FDA has accepted a supplemental new drug application for zanubrutinib (Brukinsa, BeiGene) for the treatment of adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. The target action date is October 22, 2022.

The filing includes data from 2 pivotal randomized phase 3 studies: ALPINE comparing zanubrutinib to ibrutinib in patients with relapsed or refractory (R/R) disease and SEQUOIA comparing zanubrutinib to bendamustine and rituximab (BR) in treatment-naïve patients. The filing also included data from 8 supportive studies in B-cell malignancies.

Zanubrutinib is already approved by the FDA for the treatment of adults with R/R marginal zone lymphoma (MZL) who have received at least 1 anti–CD20-based regimen, for adults with Waldenström macroglobulinemia (WM), and for adults with mantle cell lymphoma who have received at least 1 prior therapy.

ALPINE and SEQUOIA were global studies with patients from 17 countries. The results of ALPINE were reported at the 26th European Hematology Association (EHA21) Virtual Congress in June 2021, and results from SEQUOIA were reported at the 63rd American Society of Hematology (ASH) Annual Meeting in December 2021.

“With superiority in investigator-assessed [objective response rate] over ibrutinib in ALPINE for relapsed or refractory patients and in PFS [progression-free survival] over chemoimmunotherapy in the SEQUOIA study for treatment-naïve patients, Brukinsa has demonstrated its potential to improve treatment outcomes for CLL patients,” Jane Huang, MD, chief medical officer of hematology at BeiGene, said in a statement.

Zanubrutinib is a next-generation Bruton tyrosine kinase (BTK) inhibitor that minimizes the off-target inhibition of TEC- and EGFR-family kinases seen with ibrutinib, which has been the standard of care in CLL. This more targeted treatment improves outcomes and reduces toxicity, Peter Hillmen, PhD, MB ChB, professor at the University of Leeds and honorary consultant hematologist at Leeds Teaching Hospitals NHS Trust, explained while presenting interim results of ALPINE at EHA21.

SEQUOIA found zanubrutinib produced prolonged PFS compared with BR. The estimated 24-month PFS was 85.5% for zanubrutinib vs 69.5% for BR, and the estimated overall survival was 94.3% vs 94.6%.

Constantine S. Tam, MBBS, MD, consulting hematologist and associate professor, Peter MacCallum Cancer Centre, and lead author on a SEQUOIA abstract presented at ASH 2021, noted zanubrutinib had better tolerance with reduced adverse events compared with the BR arm.

“I think this really confirms the highly tolerable nature of BTK inhibitors in general,” he said in an interview with The American Journal of Managed Care®. In addition, although BTK inhibitors are associated with atrial fibrillation, in SEQUOIA, the rates of atrial fibrillation were the same as the comparator arm. “I think this confirms earlier data that zanubrutinib is less cardiotoxic than other BTK inhibitors, and in particular, less cardiotoxic than ibrutinib,” Tam said.

Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute and a principal investigator of ALPINE and SEQUOIA, echoed in a statement the safety and efficacy benefits of zanubrutinib.

“While previously approved BTK inhibitors have been transformational for some patients with CLL, there continues to be unmet need as not all patients achieve a favorable clinical response while others are unable to tolerate currently approved BTKi therapies,” she said. “As demonstrated in both the ALPINE AND SEQUOIA studies, Brukinsa was generally well tolerated in CLL patients with low rates of atrial fibrillation and showed strong efficacy compared to ibrutinib and chemo-immunotherapy, respectively.”

The European Medicines Agency also accepted applications for zanubrutinib in CLL and MZL. The therapy is currently approved for patients with WM who have received at least 1 prior therapy or for first-line treatment of patients unsuitable for chemo-immunotherapy.