UK’s MHRA Approves Zanubrutinib for CLL and MZL

Chronic Lymphocytic Leukemia

The Medicines and Healthcare Products Regulatory Agency (MHRA) has approved zanubrutinib (Brukinsa) in Great Britain for both the treatment of adult patients with chronic lymphocytic leukemia (CLL) and the treatment of adult patients with marginal zone lymphoma (MZL) who have received at least one prior anti-CD20–based therapy.¹

The approval for CLL is based on findings from the phase 3 SEQUOIA (NCT03336333) and ALPINE (NCT03734016) trials. SEQUOIA evaluated zanubrutinib vs bendamustine (Bendeka) plus rituximab (Rituxan; BR) in patients with previously untreated CLL. ALPINE examined zanubrutinib vs ibrutinib (Imbruvica) in patients with relapsed/refractory CLL.

The MHRA authorization for MZL is supported by findings from the phase 2 MAGNOLIA trial (NCT03846427) that evaluated zanubrutinib in patients with relapsed/refractory MZL who received at least one anti-CD20–based regimen.

“[Zanubrutinib] is a highly selective BTK inhibitor that has demonstrated clinically meaningful improvements over the first generation of BTK inhibitor in relapsed CLL,” Renata Walewska, PhD, MRCP, FRCPath, of the department of Hematology at University Hospitals Dorset, stated in a news release. “The authorization of [zanubrutinib] for MZL and CLL in Great Britain is a significant step forward for eligible patients and their physicians as there is no targeted treatment currently authorized for MZL patients other than chemoimmunotherapy, and it represents an alternative to current BTK inhibitor treatments for patients with CLL.”

Interim findings from SEQUOIA showed that at a median follow-up of 26.2 months, the BTK inhibitor significantly improved independent review committee (IRC)–assessed progression-free survival (PFS) vs BR (HR, 0.42; 95% CI, 0.27-0.63; 2-sided P <.0001).² Investigator-assessed PFS also demonstrated a benefit for zanubrutinib (HR, 0.42; 95% CI, 0.27-0.66; 1-sided P <.0001, 2-sided P = .0001). The estimated 24-month IRC-assessed PFS rates were 85.5% (95% CI, 80.1%-89.5%) for the zanubrutinib arm and 69.5% (95% CI, 62.4%-75.5%) for the BR arm.

Data from an interim analysis of the ALPINE trial demonstrated that zanubrutinib elicited an overall response rate (ORR) of 78.3% (95% CI, 72%-83.7%) compared with 62.5% (95% CI, 55.5%-69.1%) for ibrutinib.³ Patients given zanubrutinib also achieved a 12-month PFS rate of 94.9%) vs 84% for those administered ibrutinib (HR, 0.4; 95% CI, 0.23-0.69; P = .0007). The 12-month overall survival (OS) rates were 97% vs 92.7%, respectively (HR, 0.54; 95% CI, 0.25-1.16; P = .1081).

Patients with relapsed/refractory MZL who received zanubrutinib during the MAGNOLIA trial achieved an ORR of 56% (95% CI, 43%-68%), including a complete response rate of 20% based on CT scan assessment. In September 2021, these data led to FDA accelerated approval of zanubrutinib for the treatment of adult patients with relapsed or refractory MZL who received at least 1 anti–CD20-based regimen.⁴

SEQUOIA enrolled patients who were at least 65 years of age or who were not candidates to receive fludarabine, cyclophosphamide, and rituximab. In cohort 1, patients with treatment-naïve CLL/SLL without del(17p) were randomly assigned to 160 mg of zanubrutinib twice per day or 90 mg/m² of bendamustine on days 1 and 2 plus 375 mg/m² of rituximab in cycle 1 and 500 mg/m² in cycles 2 to 6 for six 28-day cycles.

The primary end point of the trial was PFS per IRC assessment. Key secondary end points included investigator-assessed PFS, IRC- and investigator-assessed ORR, OS, and safety.

Any-grade adverse effects (AEs) of interest with zanubrutinib vs BR, respectively, included atrial fibrillation (3.3% vs 2.6%), bleeding (45.0% vs 11.0%), hypertension (14.2% vs 10.6%), infection (62.1% vs 55.9%), and neutropenia (15.8% vs 56.8%). Grade 3 or higher AEs included bleeding (3.8% vs 1.8%, respectively), infection (16.3% vs 18.9%), and neutropenia (11.7% vs 51.1%).

Updated findings from SEQUOIA presented at the 2022 Pan Pacific Lymphoma Conference showed that among all patients treated in cohort 1, those given zanubrutinib (n = 241) experienced a reduced risk of disease progression or death of 58% compared with those treated with BR (n = 238; HR, 0.42; 95% CI, 0.28-0.63).⁵

Additionally, in the high-risk subgroup of patients with unmutated IGHV, zanubrutinib (n = 125) reduced the risk of disease progression or death by 76% vs BR (n = 121; HR, 0.24; 95% CI, 0.13-0.43). In the subgroup of patients with del(11q), zanubrutinib (n = 43) reduced the risk of disease progression or death by 79% compared with BR (n = 46; HR, 0.21; 95% CI, 0.09-0.50).

ALPINE enrolled patients with relapsed/refractory CLL or small lymphocytic lymphoma who previously received at least 1 systemic therapy. Patients were randomly assigned to 160 mg of zanubrutinib twice daily or 420 mg of ibrutinib once daily.

The primary end point of the trial was investigator-assessed ORR. Other end points included duration of response (DOR), PFS, OS, time to treatment failure, patient-reported outcomes, and safety.

AEs of special interest included cardiac disorders, atrial fibrillation and flutter, hemorrhage, and hypertension. The rate of any-grade atrial fibrillation and flutter was 2.5% for zanubrutinib compared with 10.1% for ibrutinib.

Updated results from a preplanned interim analysis of ALPINE presented at the 10th Annual Meeting of the Society of Hematologic Oncology showed that patients administered zanubrutinib (n = 207) experienced an ORR of 78.3% (95% CI, 72.0%-83.7%) vs 62.5% (95% CI, 55.5%-69.1%) for those treated with ibrutinib (n = 208; 2-sided P = .0006; pre-specified α = .0099).⁶

MAGNOLIA enrolled 66 patients with relapsed/refractory MZL who received at least 1 anti–CD20-based regimen, including 26 patients with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and 4 with unknown subtype. Patients received 160 mg of zanubrutinib twice daily until disease progression or intolerable toxicity. Long-term treatment with antiplatelet and anticoagulation agents was permitted.

The primary end point of the trial was ORR per IRC and Lugano classification. Secondary end points consisted of investigator-assessed ORR, DOR, PFS, and safety.

The most common AEs reported included decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain.

References

1. Brukinsa® (zanubrutinib) receives marketing authorization for chronic lymphocytic leukemia (CLL) and marginal zone lymphoma (MZL) in Great Britain by MHRA. News release. BeiGene, Ltd. January 19, 2023. Accessed January 19, 2023. http://bit.ly/3ZLemHD
2. 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
3. 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.
4. US FDA grants Brukinsa (zanubrutinib) accelerated approval in relapsed or refractory marginal zone lymphoma. News release. BeiGene, Ltd. September 15, 2021. Accessed September 15, 2021. https://bit.ly/3zbzB6X
5. Kahl BS, Giannopoulos K, Jurczak W, et al. SEQUOIA: results of a phase 3 randomized study of zanubrutinib versus bendamustine + rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 2022 Pan Pacific Lymphoma Conference; July 18-22, 2022; Koloa, Hawaii.
6. Brown JR, Hillmen P, Eichhorst B, 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: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Poster CLL-115.