Zanubrutinib Gains Approval in China for Relapsed/Refractory CLL/SLL and MCL

John V. Oyler

China's National Medical Products Administration (NMPA) has approved new drug applications (NDAs) for zanubrutinib (Brukinsa) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) who have received at least 1 prior therapy, as well as for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.¹

Both applications had been previously granted priority review status by the Center for Drug Evaluation of the NMPA. The recommended dose of zanubrutinib, as described in the Chinese Package Insert, is 160 mg twice daily orally.

"The concurrent approvals of Brukinsa in relapsed/refractory CLL/SLL and relapsed/refractory MCL are a tribute to the collective expertise and hard work of the BeiGene team. With two product approvals covering 4 indications in China and 1 in the United States in merely 7 months, we continue to focus on execution in advancing our broad portfolio,” John V. Oyler, co-founder, chief executive officer, and chairman of BeiGene, the developer of zanubrutinib, stated in a press release.

Zanubrutinib is a small molecule BTK inhibitor that has been investigated as a single agent and in combination with other agents to treat patients with a wide range of B-cell malignancies.

The Chinese approval of zanubrutinib in patients with relapsed/refractory CLL/SLL is based on single-arm, phase 2 findings of the BGB-3111-205 study (NCT03206918), which enrolled 91 patients in China, 82 of whom had CLL and 9 with SLL; all patients had relapsed/refractory disease. Patients were treated with zanubrutinib at 160 mg twice daily.

Results showed that the overall response rate (ORR) was 62.6%, including a complete response (CR) rate of 3.3%, a partial response (PR) rate of 59.3%, and a PR with lymphocytosis (PR-L) rate of 22%; responses were assessed by an independent review committee (IRC) per International Workshop 2008 criteria for CLL and Lugano Classification 2014 for SLL.

Regarding safety, the most common adverse events (AEs) reported in the Chinese label (10% or higher) were neutropenia (68.1%), thrombocytopenia (40.7%), hematuria (35.2%), purpura (34.1%), anemia (23.1%), leukopenia (18.7%), pneumonia (18.7%), upper respiratory tract infection (15.4%), hemorrhage (14.3%), and rash (12.1%). Grade 3 or higher AEs occurred in 69.2% of patients; the incidence of serious AEs was 19.8%, the most common of which was pneumonia (11.0%).

“The approval of Brukinsa will provide an important treatment option for Chinese patients with relapsed/refractory CLL/SLL," Jianyong Li, MD, professor and director of the Department of Hematology and Director of the Pukou CLL Center at the First Affiliated Hospital of Nanjing Medical University, stated in the press release. "In addition to Brukinsa's significant antitumor activity evidenced by an ORR of more than 60%, the drug demonstrated a favorable safety and tolerability profile."

The Chinese approval of zanubrutinib in relapsed/refractory MCL is based on results from the single-arm, phase 2 BGB-3111-206 trial (NCT03206970) that enrolled 86 patients in China who had received 1 to 4 prior treatment regimens. Patients were treated with 160 mg twice daily of zanubrutinib until disease progression or unacceptable toxicity.² The primary endpoint was ORR by an independent review committee using PET-based imaging, according to the Lugano classification.

Regarding patient characteristics, the median age was 60.5 years (range, 34-75), 78% of patients were male, and the disease status was refractory in 52.3% and relapsed in 47.7% of patients. Seventy-eight patients (90.7%) had stage III/IV disease and 58%, 29%, and 13% were low, intermediate, and high risk, respectively, by the Mantle Cell Lymphoma International Prognostic Index Combined Biologic Index. Moreover, 7 patients (8.1%) had bulky disease >10 cm and 37 (43%) had disease >5 cm, and 12 patients (14%) had the blastoid variant of MCL; 71% of patients had extranodal disease. The median number of prior therapies was 2; the most common prior regimens included CHOP-based (91%) and rituximab (Rituxan)-based (74%).

Findings showed that, in the label and as assessed by an independent review committee per Lugano Classification 2014, the ORR was 83.7%, which included a CR rate of 68.6% and a partial response PR rate of 15.1%. Previously, results showed that the ORR was 84% (95% CI, 74%-91%), which included a 59% complete response (CR) rate and a 24% partial response (PR) rate at a median follow-up of 18.4 months. The median duration of response (DOR) was 19.5 months (95% CI, 16.6—not estimated [NE]).

Regarding safety, the most common AEs reported in the label in China were neutropenia (47.7%), rash (32.6%), leukopenia (31.4%), thrombocytopenia (30.2%), and anemia (11.6%). The incidence of serious AEs was 15.1%, and common serious adverse reactions (≥2%) included pneumonia (8.1%), hemorrhage (2.3%), and thrombocytopenia (2.3%).

"Brukinsa has shown promise in hematologic malignancies including in patients with relapsed/refractory MCL. With robust results including a 68.6% CR rate in the MCL trial, we are optimistic and excited about the clinical benefits Brukinsa can bring to these patients,” Jun Zhu, MD, PhD, professor and director of the Department of Internal Medicine and Lymphoma, Peking University Cancer Hospital, stated in the press release.

In November 2019, the FDA granted an accelerated approval to zanubrutinib capsules for the treatment of adult patients with MCL who have received ≥1 prior therapy. The decision was based on findings from two single-arm studies, one of which included BGB-3111-206, in which zanubrutinib elicited an ORR of 84% in patients with MCL who received ≥1 prior treatment.^3,4

References

1. BeiGene announces the approval of Brukinsa (zanubrutinib) in China for patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed/refractory mantle cell lymphoma [news release]: Beijing, China and Cambridge, Mass. BeiGene. Published June 3, 2020. Accessed June 3, 2020. https://yhoo.it/301qMyN.
2. Song Y, Zhou K, Zou D, et al. Safety and activity of the investigational Bruton tyrosine kinase inhibitor zanubrutinib (BGB-3111) in patients with mantle cell lymphoma from a phase 2 trial. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 148.
3. FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage. FDA. Published November 14, 2019. https://bit.ly/375KElo. Accessed November 14, 2019.
4. U.S. FDA Grants BeiGene’s BRUKINSATM (zanubrutinib) Accelerated Approval to Treat Adult Patients with Mantle Cell Lymphoma Who Received at Least One Prior Therapy. BeiGene. Published November 14, 2019. https://bit.ly/2NLovB7. Accessed November 14, 2019.