Final Response Analysis of ALPINE Finds Zanubrutinib Superior to Ibrutinib in R/R CLL

The results of the phase 3 ALPINE trial found zanubrutinib demonstrated superiority compared with ibrutinib in adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.

Zanubrutinib had achieved superiority in the primary end point of investigator-assessed overall response rate in the interim analysis. Zanubrutinib had a response rate of 80.4% compared with 72.9% for ibrutinib. A total of 652 patients who were enrolled in the trial across Europe, the United States, China, New Zealand, and Australia were followed for a median of 24.2 months.

Patients were randomized to receive either zanubrutinib 160 mg orally twice a day or ibrutinib 420 mg orally once a day.

Results were consistent with previous studies on zanubrutinib. The rate of atrial fibrillation or flutter continued to be lower in the zanubrutinib arm. The rate of atrial fibrillation or flutter at 24.2 months of median follow-up was 4.6% in the zanubrutinib arm and 12.0% in the ibrutinib arm.

Zanubrutinib is a second-generation Bruton tyrosine kinase inhibitor, which accounts for the lower rate of atrial fibrillation or flutter. Compared with ibrutinib, zanubrutinib minimizes off-target inhibition of TEC- and EGFR-family kinases.

Across both arms, 13.0% of patients who received zanubrutinib who discontinued treatment due to adverse events (AEs) compared with 17.6% of patients who received ibrutinib. The most common AEs for zanubrutinib versus ibrutinib respectively were neutropenia (14.2% vs 13.9%), hypertension (12.7% vs 10.2%), pneumonia (4.0% vs 7.4%), neutrophil count decreased (4.3% vs 4.0%), and COVID-19 pneumonia (4.3% vs 3.1%).

“We understand that for people living with CLL and their families, relapse and treatement resistance are especially devastating,” said Lai Wang, PhD, global head of research and development at BeiGene. "That’s why we are encouraged by this final response analysis, which adds to the growing body of clinical evidence for BRUKINSA as a potential treatment for CLL."

The interim results of ALPINE were presented at the European Hematology Association 2021 Virtual Congress in June 2021. In the interim results, the ORR was 78.3% (95% CI, 72.0%-83.7%) for zanubrutinib vs 62.5% (95% CI, 55.5%-69.1%) for ibrutinib. The 12-month progression-free survival was 94.9% for zanubrutinib vs 84.0% for ibrutinib, although the overall survival was similar: 97.0% for zanubrutinib vs 92.07% for ibrutinib.

In the interim results, 7.8% of patients receiving zanubrutinib discontinued treatment due to AEs compared with 13.0% of patients receiving ibrutinib. The zanubrutinib arm also reported a lower proportion of death due to AEs (3.9% vs 5.8%).

BeiGene has submitted the results from ALPINE to support applications for the approval of zanubrutinib in CLL in the United States, European Union, and other markets. The FDA and European Medicines Agency had previously accepted supplemental new drug applications for zanubrutinib in February 2022. The target action date for the Prescription Drug User Fee Act is October 22, 2022.

Zanubrutinib is already approved in the United States to treat adults with R/R marginal zone lymphoma who have received at least 1 anti–CD20-based regimen, adults with Waldenström macroglobulinemia, and adults with mantle cell lymphoma who have received at least 1 prior therapy.