BeiGene announces results of Zanubrutinib in Mantle Cell Lymphoma

BeiGene announced the presentation of clinical data from two ongoing trials of its investigational Bruton’s tyrosine kinase inhibitor, zanubrutinib, in patients with mantle cell lymphoma. The presentations were made at the 60th Annual Meeting of the American Society of Hematology. Results from the pivotal Phase 2 trial of zanubrutinib in Chinese patients with relapsed or refractory MCL were featured in an oral presentation, while updated results from the global Phase 1 trial of zanubrutinib in patients with multiple subtypes of B-cell malignancies, including treatment naive and R/R MCL, were featured in a poster presentation. Zanubrutinib is being studied in several clinical trials as part of a broad development program and was granted Fast Track Designation by the U.S. Food and Drug Administration for the treatment of patients with Waldenstrom macroglobulinemia. BeiGene plans to submit an initial NDA to the FDA for zanubrutinib in 2019 or early 2020. The NDAs in China for R/R MCL and R/R chronic lymphocytic leukemia/small lymphocytic lymphoma have been accepted by the National Medical Products Administration and the MCL filing has been granted priority review. The single arm, open-label, multi-center, pivotal Phase 2 trial of zanubrutinib as a monotherapy in Chinese patients with R/R MCL enrolled 86 patients who had received a median of two prior lines of therapy. Patients were treated with zanubrutinib, dosed at 160 mg orally twice-daily. The primary endpoint of the trial was overall response rate assessed by independent review committee using PET-based imaging according to the Lugano Classification 2014. As of March 27, 2018, 85 patients with R/R MCL were evaluable for efficacy and 65 patients remained on study treatment. The median follow-up time for patients enrolled in the trial was 35.9 weeks. Results included: The ORR by IRC was 83.5%; the complete response rate was 58.8% and the partial response rate was 24.7%; The 24-week progression-free survival was estimated at 82%. The median PFS had not yet been reached; With 24.1 weeks median follow-up, the median duration of response had not yet been reached and 90% of responders were still in response at 24 weeks; Zanubrutinib tolerability was generally consistent with previous reports in patients with various B-cell malignancies and the majority of adverse events were grade 1 or 2 in severity. The most frequent AEs of any attribution were neutrophil count decreased, rash, upper respiratory tract infection, and platelet count decreased; The most frequently reported grade 3 or higher AEs were neutrophil count decreased and lung infection; Four patients had treatment emergent adverse events leading to death; and among events of special interest for BTK inhibitors, diarrhea was observed in nine patients, all grade 1-2. Major hemorrhage was observed in 1 patient with blastoid variant of MCL who had intra-parenchymal CNS bleeding. No cases of atrial fibrillation/flutter were reported in this trial. Meanwhile, the open-label Phase 1 trial of zanubrutinib as a monotherapy in patients with different subtypes of B-cell malignancies, including MCL, is being conducted in Australia, New Zealand, the U.S, Italy, and South Korea. As of July 24, 2018, 48 patients with TN or R/R MCL have been enrolled in the trial and the median follow-up time was 12.7 months. 45 patients including six with TN and 39 with R/R MCL, were evaluable for efficacy in this analysis, per the Lugano 2014 classification. At the time of the data cutoff, 26 patients remained on study treatment. Updated results included: The ORR by investigator was 88.9%; the CR rate was 26.7% and the PR rate was 62.2%. The majority of patients were assessed via CT-scan; PET scans were optional per trial protocol; The median DOR was 16.2 months and the median PFS for R/R patients was 18.0 months; Zanubrutinib tolerability was generally consistent with previous reports in patients with various B-cell malignancies and the majority of AEs were grade 1 or 2 in severity. Grade 3-5 AEs occurred in 56.3% of patients. Grade 3-5 AEs of any attribution reported in greater than three patients included anemia, major hemorrhage, cellulitis, myalgia, neutropenia, pneumonia; and thrombocytopenia; Discontinuation due to AEs occurred in 18.8% of patients with all but one event determined to be unrelated to study drug; and there were four deaths due to AEs, which were all determined by the investigators to be unrelated to zanubrutinib treatment.
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