EMA Accepts Application for Zanubrutinib in Waldenström Macroglobulinemia

The European Medicines Agency (EMA) has validated and accepted a marketing authorization application for zanubrutinib (Brukinsa) for the treatment of patients with Waldenström macroglobulinemia who have received at least 1 prior therapy or as frontline treatment for patients who are ineligible for chemoimmunotherapy, according to BeiGene, Ltd, the manufacturer of the BTK inhibitor. ¹

The application is based on data from the open-label, phase 3 randomized ASPEN trial, as well as pooled safety findings from 779 patients with B-cell malignancies who received zanubrutinib in 6 clinical trials.

“This is our first submission to the EMA and the first for Waldenström macroglobulinemia, marking a significant milestone for [zanubrutinib], which has demonstrated efficacy and clinically meaningful improvements in safety and tolerability in patients with [the disease] compared with the first-generation BTK inhibitor, ibrutinib (Imbruvica), in our head-to-head ASPEN trial,” Jane Huang, MD, chief medical officer of Hematology at BeiGene said in a press release issued by the company.

In the phase 3 ASPEN trial, patients with Waldenström macroglobuinemia and a MYD88 mutation (n = 201) were randomized 1:1 to receive either zanubrutinib at 160 mg twice daily (n = 102) or once daily ibrutinib at 420 mg (n = 99). Patients were stratified based on CXC4 mutational status and the number of prior therapies received. An additional cohort comprised of 28 patients without MYD88 mutations were also administered 160 mg daily.

Results from the trial presented at the 2020 ASCO Virtual Scientific Program showed that treatment with zanubrutinib was associated with a complete response (CR) and a very good partial response rate (VGPR) of 28.4% versus 19.2% with ibrutinib (P = .0921).²

Although the primary hypothesis of superiority in CR+VGPR via independent review committee was not met, a greater CR+VGPR response rate was observed by investigator assessment. At the August 2019 data cutoff, the CR+VGPR rate was 28.4% with zanubrutinib versus 17.2% with ibrutinib (P = .04). At the January 2020 data cutoff, the rates were 30.4% versus 18.2% with zanubrutinib and ibrutinib, respectively (P = .0302).

Regarding safety, treatment with zanubrutinib led to a reduction in the risk of atrial fibrillation/flutter versus ibrutinib, at 2.0% versus 15.3%, respectively. Those in the zanubrutinib also had lower rates of hypertension (10.9% vs 17.3%), major bleeding (5.9% vs 9.2%), grade 3 or higher adverse events (AEs; 58.4% vs 63.3%), AEs resulting in treatment discontinuation (4.0% vs 9.2%), and AE-related deaths (1.0% vs 4.1%) compared with ibrutinib.

Although the rate of grade 3 or higher infections was similar between the 2 arms (17.8%, zanubrutinib; 19.4%, ibrutinib), those in the zanubrutinib arm had a higher rate of neutropenia versus the comparator arm, at 29.7% versus 13.3%, respectively.

In November 2019, the FDA granted an accelerated approval to zanubrutinib for use in adult patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy following efficacy data from the phase 2 BGB-31110206 trial (NCT03206970) and the phase 1/2 BGB-2111-AU-003 trial (NCT02343120).³

Results from the BGB-3111-206 trial, for which FDG-PET scans were required, showed that the overall response rate (ORR) was 84% (95% CI, 74-91) and the complete response (CR) rate of 59% (95% CI, 48-70). The median duration of response (DOR) with the agent was 19.5 months (95% CI, 16.6-not estimable). Data for the BGB-3111-AU-003, for which FDG-PET scans were not required, the ORR was 84% (95% CI, 67-95), with a CR rate of 22% (95% CI, 9-40), and a median DOR of 18.5 months (95% CI, 12.6-not estimable).

In June 2020, zanubrutinib was also approved for use in China as a treatment for adult patients with MCL who have received at least 1 prior treatment, as well as patient with chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) who had received at least 1 prior treatment.

The agent is currently under investigation in several ongoing clinical trials. In the phase 3 SEQUOIA trial (NCT03336333), investigators are comparing zanubrutinib with bendamustine plus rituximab (Rituxan) in treatment-naïve patients with CLL and SLL. In the phase 3 ALPINE trial (NCT03734016, zanubrutinib is being compared with ibrutinib in relapsed/refractory CLL/SLL.

Other trials include the phase 2 MANGROVE trial (NCT04002297) comparing zanubrutinib with rituximab (Rituxan) in untreated mantle cell lymphoma; the phase 2 MAGNOLIA trial (NCT03846427) examining the agent in marginal zone lymphoma; the phase 2 ROSEWOOD trial (NCT03332017) in China examining zanubrutinib in comparison with obinutuzumab (Gazyva) in relapsed/refractory follicular lymphoma; and more.

References

1. BeiGene announces European Medicines Agency acceptance of its marketing authorization application for Brukinsa (zanubrutinib) for the treatment of patients with Waldenström’s macroglobulinemia. News release. BeiGene. June 18, 2020. Accessed June 18, 2020. bit.ly/2BhhMLw.
2. Tam CSL, Opat S, D’Sa S, et al. ASPEN: results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). J Clin Oncol. 2020;38(suppl 15):8007. doi:10.1200/JCO.2020.38.15_suppl.8007
3. FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma. News release. FDA. November 14, 2019. Accessed June 18, 2020. bit.ly/37FQt9X.