FDA Accepts sNDA for Zanubrutinib in Adults With CLL/SLL

The FDA had accepted the supplemental new drug application (sNDA) for the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa) as a potential treatment option for adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), according to a press release by BeiGene.¹

Data from two phase 3 randomized studies supported the sNDA, including the ALPINE study (NCT03734016) of zanubrutinib versus ibrutinib (Imbruvica) in a relapsed/refractory CLL population, and the SEQUOIA study (NCT03336333) of zanubrutinib versus bendamustine and rituximab (Rituxan) for the treatment of treatment-naïve patients with CLL. The FDA has set a Prescription Drug User Fee Act date of October 22, 2022.^1-3

“While previously approved BTK inhibitors have been transformational for some patients with CLL, there continues to be an unmet need as not all patients achieve a favorable clinical response while others are unable to tolerate currently approved BTK [inhibitor] therapies,” Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute, and a principal investigator in the 2 studies, stated in a press release.¹ “As demonstrated in both the ALPINE AND SEQUOIA studies, Brukinsa was generally well-tolerated in CLL patients with low rates of atrial fibrillation and showed strong efficacy compared to ibrutinib and chemoimmunotherapy, respectively.”

In ALPINE, zanubrutinib was found to be noninferior to ibrutinib in patients with relapsed/refractory CLL. In the 415 patients evaluated, the objective response rate (ORR) observed with zanubrutinib was 78.3% compared with 62.5% in the ibrutinib arm (P = .0006). The 12-month progression-free survival (PFS) rate observed with zanubrutinib was 94.9% versus 84.0% in the ibrutinib arm, and the overall survival (OS) rate was 97.0% versus 92.7%, respectively.²

Similarly, in the SEQUOIA study, 479 patients with treatment-naïve CLL were administered zanubrutinib and the ORR was 94.6% (95% C,I 91.0%-97.1%) with zanubrutinib compared with 85.3% (95% CI, 80.1%-89.5%) with bendamustine and rituximab. Further, complete responses were observed in 6.6% of the zanubrutinib population compared with 15.1% of the bendamustine/rituximab arm.³

The estimated OS rate with zanubrutinib in SEQUOIA was 94.3% compared with 94.6% in the control arm. Improvement with PFS was statistically significant for the zanubrutinib arm compared with the bendamustine/rituximab arm (HR, 0.42; 95% CI, 0.28-0.63; 1-sided and 2-sided P < .0001). The estimated PFS at 24 months was 85.5% in the zanubrutinib group versus 69.5% in the control group.

Patients in the ALPINE and SEQUOIA studies have a similar age range and disease characteristics.

The ALPINE study primarily assessed ORR, with PFS, duration of response (DOR), time to treatment failure, OS, patient-reported outcomes, and the incidence of adverse events (AEs) as secondary end points. In SEQUOIA, the primary end point was PFS, and secondary end points included ORR, OS, DOR, patient-reported outcomes, rate of minimal residual disease undetectability, and the incidence of patients with AEs or serious AEs.^2-5

Zanubrutinib is approved in the United States for 3 indications, including mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom macroglobulinemia. The agent has been investigated in 3,900 patients across 35 clinical trials worldwide. It is approved for 20 indications in 40 different countries.

The label warning for zanubrutinib mentions hemorrhage, infection, cytopenia, secondary primary malignancies, cardiac arrhythmias, and embryo-fetal toxicity. AEs commonly observed with the agent include decreased neutrophil count (54%), upper respiratory tract infection (47%), decreased platelet count (41%), hemorrhage (35%), decreased lymphocyte count (31%), rash (31%), and musculoskeletal pain (30%), according to research from 847 patients.

“We are pleased with the FDA’s acceptance of Brukinsa’s filing in CLL. This is an important milestone in Brukinsa’s global registration program. With superiority in investigator-assessed ORR over ibrutinib in ALPINE for relapsed or refractory patients and in PFS over chemoimmunotherapy in the SEQUOIA study for treatment-naïve patients, Brukinsa has demonstrated its potential to improve treatment outcomes for CLL patients,” said Jane Huang, MD, chief medical officer of Hematology at BeiGene, in the press release.1 “We look forward to furthering our discussions with the FDA on this filing and the potential to bring this important treatment option to the CLL community in the United States.”

_References

_{1. BeiGene announces U.S. FDA acceptance of supplemental new drug application for Brukinsa (zanubrutinib) in chronic lymphocytic leukemia. News release. BeiGene. February 22, 2022. Accessed February 23, 2022.}

_{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: European Society of Hematology Congress; June 9-17, 2021. Virtual. Accessed June 11, 2021. Abstract LB1900.}

_{3. Tam CS, Giannopoulos K, Jurczak W, et al. 396 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. A study of zanubrutinib (BGB-3111) versus ibrutinib in participants with relapsed/refractory chronic lymphocytic leukemia (ALPINE). Clinicaltrials.gov. Accessed February 23, 2022. https://bit.ly/3HdGybC}

_{5. A study comparing zanubrutinib with bendamustine plus rituximab in participants with previously untreated CLL or SLL (SEQUOIA). Clinicaltrials.gov. Accessed February 23, 2022. https://bit.ly/3vcu55x}