Zanubrutinib Applications for CLL and MZL Accepted for Review in Europe

The European Medicines Agency has accepted for review 2 new indication applications for zanubrutinib (Brukinsa) as a therapeutic option for patients with chronic lymphocytic leukemia (CLL) and for those with marginal zone lymphoma (MZL).¹

The application for CLL is based on findings from 2 phase 3 trials: ALPINE (NCT03734016) and SEQUOIA (NCT03336333). The application for MZL is supported by findings from 2 single-arm clinical trials: MAGNOLIA (NCT03846427) and BGB-3111-AU-003 (NCT02343120).

In ALPINE, zanubrutinib (n = 207) elicited an objective response rate (ORR) of 78.3% (95% CI, 72.0%-83.7%) vs 62.5% (95% CI, 55.5%-69.1%) with ibrutinib (Imbruvica; n = 208) in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL).² In SEQUOIA, zanubrutinib (n = 241) resulted in a 58% reduction in the risk of disease progression or death per independent review committee (IRC) assessment vs bendamustine plus rituximab (Rituxan; n = 238) in treatment-naïve patients with CLL/SLL without del(17p) (HR, 0.42; 95% CI, 0.27-0.63; 2-sided P < .0001).³

Results from the phase 2 MAGNOLIA trial showed that the BTK inhibitor produced an ORR of 56% (95% CI, 43%-68%) based on assessment using CT scan, with a complete response (CR) rate of 20% in 66 patients with relapsed or refractory MZL who have previously received at least 1 anti–CD20-based regimen.⁴ Based on assessment prioritizing PET CT scan, the ORR with the agent was 67% (95% CI, 54%-78%), with a CR rate of 26%. In the phase 1/2 BGB-3111-AU-003 trial, zanubrutinib produced an ORR of 80% (95% CI, 56%-94%) based on assessment using CT scan, with a CR rate of 20% in 20 patients with MZL.

“Following [zanubrutinib’s] recent European Union approval in Waldenström macroglobulinemia, we are pleased that [zanubrutinib] is now under review for 2 more indications—CLL and MZL,” Jane Huang, MD, chief medical officer of hematology at BeiGene, stated in a press release. “We are confident in the broad clinical evidence from its global clinical development program and hope to bring this next-generation BTK inhibitor to CLL and MZL patients in the European Union.”

The ALPINE trial randomized 415 patients to receive zanubrutinib at 160 mg twice daily (n = 207) or ibrutinib at 420 mg once daily (n = 208). The primary end point of the trial was investigator-assessed ORR, and other end points comprised duration of response (DOR), PFS, overall survival (OS), time to treatment failure, patient-reported outcomes, and safety.

Additional data from the trial presented during the 2021 EHA Congress indicated that the 12-month PFS rates achieved with zanubrutinib and ibrutinib were 94.9% and 84.0%, respectively (HR, 0.40; 95% CI, 0.23-0.69; P = .0007); the 12-month OS rates were 97.0% and 92.7%, respectively (HR, 0.54; 95% CI, 0.25-1.16; P = .1081).

Notably, zanubrutinib was found to drastically reduce the rate of any-grade atrial fibrillation and flutter compared with ibrutinib, at 2.5% and 10.1%, respectively. Other toxicities of special interest included cardiac disorders, hemorrhage, and hypertension.

SEQUOIA was comprised of 3 cohorts. The first cohort included treatment-naïve patients with CLL/SLL without del(17p), who were randomized to receive either zanubrutinib at 160 mg twice daily or bendamustine at 90 mg/m² on days 1 and 2 in combination with rituximab at 375 mg/m² in cycle 1 and at 500 mg/m² in cycles 2 through 6 for the duration of 6 cycles comprised of 28 days. Those in cohort 2 had del(17p) and were given zanubrutinib, as those in cohort 3 had del(17p) and TP53 mutations and were given zanubrutinib plus venetoclax (Venclexta).

Among those in cohort 1 (n = 479), 241 patients received zanubrutinib and 238 were given BR. The primary end point of the trial was IRC-assessed PFS, and secondary end points included investigator (INV)-assessed PFS, IRC- and INV-assessed ORR, OS, and safety.

Additional data from the trial presented during the 2021 ASH Annual Meeting showed that at a median follow-up of 26.2 months, zanubrutinib reduced the risk of disease progression or death by 58% per INV assessment compared with BR (HR, 0.42; 95% CI, 0.26-0.66; 1-sided P < .0001, 2-sided P = .0001). The estimated 24-month PFS rate with zanubrutinib was 85.5% (95% CI, 80.1%-89.5%) vs 69.5% (95% CI, 62.4%-75.5%) with BR.

The BTK inhibitor also produced an ORR of 94.6% (95% CI, 91.0%-97.1%) per IRC assessment vs 85.3% (95% CI, 80.1%-89.5%) with BR; the CR rates achieved in the investigative and control arms were 6.6% and 15.1%, respectively. The INV-assessed ORR was also found to be higher with zanubrutinib vs BR, at 97.5% (95% CI, 94.7%-99.1%) and 88.7% (95% CI, 83.9%-92.4%), respectively.

The estimated 24-month OS rates were similar between the zanubrutinib and BR arms, at 94.3% (95% CI, 90.4%-96.7%) and 94.6% (95% CI, 90.6%-96.9%), respectively.

“As a BTK inhibitor designed to maximize BTK occupancy and minimize off-target binding, [zanubrutinib] demonstrated improvements in ORR and advantages in overall cardiac safety compared with ibrutinib in the ALPINE study in patients with relapsed or refractory CLL,” Peter Hillmen, MBChB, PhD, professor of experimental hematology at University of Leeds, and principal investigator of ALPINE, stated in a press release. “Together, with results from the SEQUOIA study in frontline CLL, [zanubrutinib has the potential to become a preferred treatment option for patients with CLL and MZL in the European Union.”

MAGNOLIA enrolled 66 patients with relapsed or refractory MZL who had received at least 1 anti–CD20-based regimen; this included 26 patients with extranodal disease, 26 with nodal disease, 12 with splenic disease, and 4 with an unknown disease subtype. Patients received zanubrutinib at 160 mg twice daily until disease progression or unacceptable toxicity.

The primary end point of the trial was ORR per IRC and Lugano classification, and key secondary end points included INV-assessed ORR, DOR, PFS, and safety.

Additional data showed that at a median follow-up of 8.3 months, the median DOR had not yet been reached with the BTK inhibitor. Eighty-five percent of responders were still in remission at 12 months (95% CI, 67-93). Zanubrutinib produced responses in all MZL subtypes analyzed.

Findings from the 2020 ASH Annual Meeting showed that at a data cutoff of August 14, 2020, and with a median follow-up of 10.7 months, the INV-assessed ORR with zanubrutinib was 74.2% (95% CI, 62.0%-84.2%), and this included a CR rate of 24.2% and a partial response rate of 50.0%.⁵

Notably, the BTK inhibitor produced ORRs of 88.9% (95% CI, 65.3%-98.6%) in those aged 75 years and older (n = 18), of 64.7% (95% CI, 38.3%-85.8%) in those who received at least 3 prior lines of therapy (n = 17), of 71.0% (95% CI, 47.8%-88.7%) in those with refractory disease (n = 21), and of 84.0% (95% CI, 63.9%-95.5%) in those with nodal disease.

At a median follow-up of 9.13 months, the 6-month PFS rate with the BTK inhibitor was 80.0%; at 9 months, this rate was 67.0%. Seventy-nine percent of responders continued to respond at 6 months. The estimated OS rate at 12 months was 94.0%.

BGB-3111-AU-003 enrolled 20 patients, including 9 with extranodal disease, 5 with nodal disease, and 6 with splenic disease. Additional findings showed that at a median follow-up of 31.4 months, the median DOR had not yet been reached. Notably, 72% of responders were still in remission at 1 year (95% CI, 40%-88%).

In September 2021, the FDA granted an accelerated approval to zanubrutinib for use in adult patients with relapsed or refractory MZL who have received at least 1 anti–CD20-based regimen based on findings from MAGNOLIA and BGB-3111-AU-003.⁴ A supplemental new drug application for zanubrutinib in adult patients with CLL or SLL has also been accepted by the regulatory agency for review.⁶

In June 2020, China’s Medical Products Administration approved the NDA for zanubrutinib in adult patients with CLL and SLL who have received at least 1 prior therapy, and for adult patients with mantle cell lymphoma who received at least 1 previous therapy.⁷ The decision was based on findings from the phase 2 BGB-3111-205 trial (NCT03206918) and the phase 2 BGB-3111-206 trial (NCT03206970).

References

1. BeiGene announces European Medicines Agency acceptance of applications for BRUKINSA (zanubrutinib) in chronic lymphocytic leukemia and marginal zone lymphoma. News release. BeiGene; February 22, 2022. Accessed February 23, 2022. https://bit.ly/3JLNqyL
2. Hillmen P, Eichhorst B, Brown JR, et al. First interim analysis of ALPINE study: Results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 2021 European Hematology Association Congress; June 9-17, 2021; Virtual. Abstract LB190.
3. Tam CS, Giannopoulos K, Jurczak W, et al. SEQUOIA: Results of a phase 3 randomized study of zanubrutinib versus bendamustine + rituximab (BR) in patients with treatment-naïve (TN) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Blood. 2021;138(suppl 1):396. doi:10.1182/blood-2021-148457
4. US FDA grants BRUKINSA (zanubrutinib) accelerated approval in relapsed or refractory marginal zone lymphoma. News release. BeiGene, Ltd.; September 15, 2021. Accessed February 23, 2022. https://bit.ly/3zbzB6X
5. BeiGene announces data on BRUKINSA (zanubrutinib) from phase 2 trial in marginal zone lymphoma and phase 3 trial in chronic lymphocytic leukemia or small lymphocytic lymphoma at the 62nd ASH Annual Meeting. News release. BeiGene, Ltd.; December 6, 2020. Accessed February 23, 2022. https://bwnews.pr/3hCRyp1
6. BeiGene announces US FDA acceptance of supplemental new drug application for BRUKINSA (zanubrutinib) in chronic lymphocytic leukemia. News release. BeiGene; February 22, 2022. Accessed February 23, 2022. https://bit.ly/3s7MBKx
7. 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 February 23, 2022. https://yhoo.it/301qMyN