China Approves Zanubrutinib in Previously Untreated CLL/SLL and Waldenström Macroglobulinemia

China’s National Medical Products Administration (NMPA) has approved 2 supplemental new drug applications of zanubrutinib (Brukinsa) for use in treatment-naïve adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and Waldenström macroglobulinemia.¹

Additionally, the NMPA approved 2 supplemental applications, converting conditional approvals for zanubrutinib to regular approvals for the treatment of adult patients with CLL/SLL and mantle cell lymphoma who have received at least 1 prior therapy, and for the treatment of adult patients with Waldenström macroglobulinemia who have received at least 1 prior therapy.

“[Patients with] CLL/SLL and Waldenström macroglobulinemia are predominantly [older], and there are increasing needs for improved efficacy and safety in CLL/SLL and Waldenström macroglobulinemia treatments,” Professor Ma Jun, director of the Harbin Institute of Hematology & Oncology, and chief supervisor of the Supervisory Committee at the Chinese Society of Clinical Oncology, stated in a news release. “[Zanubrutinib] has been recommended as the preferred regimen of multiple subtypes of lymphoma in both national and international guidelines. With these important approvals, [zanubrutinib] now becomes the only approved new-generation BTK inhibitor in China for the first-line treatment of adult [patients with] CLL/SLL and Waldenström macroglobulinemia, bringing healthcare providers in China a new standard of care for their patients.”

The approval of zanubrutinib for previously untreated patients with CLL/SLL was supported by data from the phase 3 SEQUOIA trial (NCT03336333), and the approval of the BTK inhibitor for patients with Waldenström macroglobulinemia was based on findings from the phase 3 ASPEN trial (NCT03053440).

Findings from SEQUOIA showed that at a median follow-up of 25.0 months, patients with treatment-naïve CLL/SLL without 17p deletion enrolled in a randomized cohort achieved a median progression-free survival (PFS) that was not yet reached (95% CI, not estimable [NE]-NE) with zanubrutinib vs 33.7 months (95% CI, 28.1-NE) with bendamustine and rituximab (Rituxan; BR; HR, 0.42; 95% CI, 0.28-0.63; P < .0001).2 In this group, zanubrutinib elicited an overall response rate (ORR) of 93% (95% CI, 89%-96), which included a complete response (CR) rate of 7%.

Previously untreated patients with CLL/SLL with 17p deletion (n = 110) enrolled in a separate non-randomized cohort of SEQUOIA who were treated with zanubrutinib experienced an ORR of 88% (95% CI, 81%-94%), which comprised a CR rate of 6%. At an estimated median follow-up of 25.1 months, the median duration of response (DOR) was NE (95% CI, NE-NE). The median time to response was 2.9 months (range, 1.9-13.9)

To be eligible for enrollment, patients must have been unsuitable for treatment with fludarabine, cyclophosphamide and rituximab, which was defined as being either at least 65 years of age, or 18 to 64 years of age with a total Cumulative Illness Rating Scale of more than 6, a creatinine clearance 30 to 69 mL/min, or history of serious or recurrent infection.

Patients without 17p del were randomly assigned to receive 160 mg of zanubrutinib twice daily until disease progression or unacceptable toxicity (n = 241) or 6 cycles of BR (n = 238), consisting of 90 mg/m2 of bendamustine per day for the first 2 days of each 28-day cycle, plus 375 mg/m2 of rituximab on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 to 6. All patients with 17p del received 160 mg of zanubrutinib twice daily until disease progression or unacceptable toxicity.

Regarding safety, serious adverse effects (AEs) occurred in 36% of patients given zanubrutinib. Serious AEs that were observed in at least 5% of patients consisted of COVID-19, pneumonia, and second primary malignancy (5% each). Fatal AEs were reported in 4.6% patients, and the leading cause of death was COVID-19 (2.1%).

In ASPEN, patients with Waldenström macroglobulinemia treated with zanubrutinib (n = 102) experienced an ORR of 77.5% (95% CI, 68.1%-85.1%) compared with 77.8% (95% CI, 68.3%-85.5%) with ibrutinib (Imbruvica; n = 99). No patients in either arm achieved a CR; 28.4% of patients in the zanubrutinib arm had a very good partial response vs 19.2% of those in the ibrutinib arm. The estimated 12-month DOR rate was 94.4% (95% CI, 85.8%-97.9%) in the zanubrutinib arm vs 87.9% (95% CI, 77.0%-93.8%) in the ibrutinib arm.

Patients in cohort 1 (n = 201) were randomly assigned 1:1 to receive 160 mg of zanubrutinib twice daily or 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity.

The trial’s primary end point was response rate, which was defined as achieving a partial response or better by independent review committee based on International Workshop on Waldenström’s Macroglobulinemia-6 criteria. DOR served as another key efficacy end point.

Safety findings from cohort 1 of ASPEN showed that serious AEs occurred in 44% of patients treated with zanubrutinib. Serious AEs reported in more than 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).

In January 2023, the FDA approved zanubrutinib for the treatment of patients with CLL/SLL, and the regulatory decision was supported by data from SEQUOIA and the phase 3 ALPINE (NCT03734016) trial.3 The FDA approved zanubrutinib for the treatment of adult patients with Waldenström macroglobulinemia in September 2021, based on data from ASPEN.⁴

References

1. BeiGene receives new approvals for BRUKINSA® (zanubrutinib) in China. News release. BeiGene. May 6, 2023. Accessed May 8, 2023. https://ir.beigene.com/news/beigene-receives-new-approvals-for-brukinsa-zanubrutinib-in-china
2. Zanubrutinib. Prescribing information. 2023. Accessed May 8, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213217s007lbl.pdf
3. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. January 19, 2023. Accessed May 8, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
4. FDA approves zanubrutinib for Waldenström’s macroglobulinemia. News release. FDA. August 31, 2021. Accessed May 8, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-waldenstroms-macroglobulinemia