FDA Accepts sNDA for Zanubrutinib in Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

The FDA has accepted for review a supplemental new drug application for zanubrutinib for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

Jennifer R. Brown, MD, PhD

Jennifer R. Brown, MD, PhD

The FDA has accepted for review a supplemental new drug application (sNDA) for zanubrutinib (Brukinsa) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1

The application is supported by findings from 2 phase 3 trials, ALPINE (NCT03734016) and SEQUOIA (NCT03336333), which showed that zanubrutinib produced superior response and progression-free survival (PFS) rates vs ibrutinib (Imbruvica) in those with CLL/SLL and a statistically significant improvement in PFS vs bendamustine plus rituximab (Rituxan; BR) in treatment-naïve patients with CLL/SLL, respectively.2,3 The sNDA is also based on data from 8 supportive studies that were conducted in patients with B-cell malignancies.

Under the Prescription Drug User Fee Act, the regulatory agency will decide on the application by October 22, 2022.

“We are pleased with the FDA’s acceptance of [zanubrutinib’s] filing in CLL. This is an important milestone in [zanubrutinib’s] global registration program,” Jane Huang, MD, chief medical officer of hematology at BeiGene, stated in a press release. “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.”

In the ALPINE trial, investigators evaluated the safety and efficacy of zanubrutinib vs ibrutinib in patients with relapsed/refractory CLL/SLL who previously received at least 1 systemic therapy. A total of 415 patients were randomized to receive either zanubrutinib at a twice-daily dose of 160 mg (n = 207) or ibrutinib at a once-daily dose of 420 mg (n = 208).

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

Baseline characteristics were well balanced between the treatment arms. The median age in both arms was 67 years, and the majority were male.

At a data cutoff of approximately 1 year, zanubrutinib elicited an ORR of 78.3% (95% CI, 72.0%-83.7%) vs 62.5% (95% CI, 55.5%-69.1%) with ibrutinib. Considering partial response/lymphocytosis, the ORRs in the investigative and control arms were 88.4% and 81.3%, respectively.

The 12-month PFS rate achieved with zanubrutinib was 94.9% vs 84.0% with ibrutinib (hazard ratio [HR], 0.40; 95% CI, 0.23-0.69; P = .0007). However, the OS rate at 12 months were relatively similar between the 2 arms, at 97.0% and 92.7%, respectively (HR, 0.54; 95% CI, 0.25-1.16; P = .1081).

Adverse effects of special interest included cardiac disorders, atrial fibrillation and flutter, hemorrhage, and hypertension. The rate of any-grade atrial fibrillation and flutter was drastically reduced with zanubrutinib vs ibrutinib, at 2.5% vs 10.1%, respectively.

The SEQUOIA trial set out to compare the efficacy of zanubrutinib with that of BR in patients with previously untreated CLL/SLL. The trial enrolled those who were at least 65 years of age or who were not candidates to receive fludarabine, cyclophosphamide, and rituximab. Additionally, del(17p) status had to be centrally verified by fluorescence in situ hybridization.

In cohort 1 of the study, patients with treatment-naïve CLL/SLL without del(17p) were randomized to receive zanubrutinib at a twice-daily dose of 160 mg vs bendamustine at 90 mg/m2 on day 1 and 2 plus rituximab at 375 mg/m2 in cycle 1 and 500 mg/m2 in cycles 2 to 6 for six 28-day cycles. Cohort 2 of the trial, which was comprised of those with del(17p), were given zanubrutinib, and cohort 3, which included those with del(17p) and TP53 mutations, received zanubrutinib plus venetoclax (Venclexta).

A total of 479 patients were randomized to receive zanubrutinib (n = 241) or BR (n = 238). Participants were stratified by age (younger than 65 years vs 65 years or older), Binet Stage (C vs A/B), IGHV mutational status, and geographic region.

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

The median age was 70.0 years in both treatment arms. Moreover, 53.4% (n = 125/234) of patients who received zanubrutinib had unmutated IGHV vs 52.4% (n = 121/231) of those who were given BR. Additionally, 17.8% and 19.3% of patients in the investigative and control arms, respectively, had del(11q).

At a median follow-up of 26.2 months, zanubrutinib significantly improved IRC-assessed PFS vs BR, with a HR of 0.42 (95% CI, 0.27-0.63; 2-sided P < .0001). A similar PFS benefit was observed via investigator assessment, with a HR of 0.42 (95% CI, 0.27-0.66; 1-sided P < .0001, 2-sided P = .0001). The estimated IRC-assessed PFS rates at 24 months in the investigative and control arms were 85.5% (95% CI, 80.1%-89.5%) and 69.5% (95% CI, 62.4%-75.5%), respectively.

The PFS benefit achieved with zanubrutinib was observed across all key subsets, including age, Binet stage, bulky disease, and del(11q) status.

Zanubrutinib elicited an IRC-assessed ORR of 94.6% (95% CI, 91.0%-97.1%) vs 85.3% (95% CI, 80.1%-89.5%) with BR; the complete response rates in these arms were 6.6% and 15.1%, respectively. Additionally, the INV-assessed ORR with zanubrutinib was 97.5% (95% CI, 94.7%-99.1%) vs 88.7% (95% CI, 83.9%-92.4%) with BR.

The estimated OS 24-month OS rate with zanubrutinib was 94.3% (95% CI, 90.4%-96.7%) vs 94.6% (95% CI, 90.6%-96.9%) with BR.

Any-grade toxicities of interest with zanubrutinib vs BR, respectively, were 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 adverse effects (AEs) included bleeding (3.8% vs 1.8%, respectively), infection (16.3% vs 18.9%), and neutropenia (11.7% vs 51.1%).

Moreover, 8.3% of patients discontinued treatment with zanubrutinib because of AEs vs 13.7% of those who received BR. The majority of patients (85.5%) receiving zanubrutinib remained on treatment at the time of the data presentation at the 2021 ASH Annual Meeting. Toxicities resulting in death occurred in 4.6% of those who received zanubrutinib vs 5.3% of those who were given BR. No sudden deaths occurred.

“While previously approved BTK inhibitors have been transformational for some patients with CLL, there continues to be 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 principal investigator in the 2 studies, added in the press release. “As demonstrated in both the ALPINE and SEQUOIA studies, [zanubrutinib] was generally well tolerated in [patients with] CLL with low rates of atrial fibrillation and showed strong efficacy compared with ibrutinib and chemoimmunotherapy, respectively.”


  1. 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 22, 2022. https://bit.ly/3s7MBKx
  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
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