Zanubrutinib Receives NICE Recommendation for Treatment of CLL

The United Kingdom’s National Institute for Health and Care Excellence (NICE) has issued a final draft guidance recommending the approval of zanubrutinib (Brukinsa) for the treatment of adult patients with untreated, high-risk chronic lymphocytic leukemia (CLL) harboring a 17p deletion or TP53 mutation; those with untreated CLL who do not have a 17p deletion or TP53 mutation and are unsuitable for fludarabine plus cyclophosphamide and rituximab (Rituxan; FCR) or bendamustine plus rituximab (BR); and those with relapsed or refractory CLL.¹

“We are delighted that NICE has recognized the clinical and economic benefit of [zanubrutinib] for patients with CLL,” Dr Robert Mulrooney, general manager of United Kingdom and Ireland at BeiGene, stated in a news release. “This follows the previous approval of [zanubrutinib] by NICE in July 2022 as the only cost-effective treatment for patients with Waldenström macroglobulinemia. Although we are a relatively new player in the UK market, we are rapidly establishing ourselves as a company that can make innovative cancer medicines accessible and affordable for UK patients.”

In January 2023, the FDA approved zanubrutinib for the treatment of patients with CLL or small lymphocytic lymphoma (SLL), based on data from the phase 3 SEQUOIA (NCT03336333) and ALPINE (NCT03734016) trials.²

Findings from SEQUOIA showed that at a median follow-up of 25.0 months, patients with treatment-naïve CLL/SLL who were randomly assigned to receive zanubrutinib experienced a median progression-free survival (PFS) that was not reached (95% CI, not estimable [NE]-NE) per independent review committee (IRC) assessment compared with 33.7 months (95% CI, 28.1-NE) for those treated with BR (HR, 0.42; 95% CI, 0.28-0.63; P ≤ .0001).

Furthermore, previously untreated patients with CLL/SLL harboring 17p deletions (n = 110) who were administered zanubrutinib in a non-randomized cohort of SEQUOIA achieved an overall response rate (ORR) of 88% (95% CI, 81%-94%) per IRC assessment. The median duration of response (DOR) was not reached at a median follow-up of 25.1 months.

ALPINE data demonstrated that at a median follow-up of 14.1 months, patients with relapsed/refractory CLL/SLL treated with zanubrutinib achieved an ORR of 80% (95% CI, 76%-85%) compared with 73% (95% CI, 68%-78%) for those who received ibrutinib (response rate ratio, 1.10; 95% CI, 1.01-1.20; P = .0264). The median DOR was not reached in either arm.

SEQUOIA enrolled patients at least 18 years of age with CD20-positive CLL or SLL requiring treatment who were unsuitable for chemoimmunotherapy with FCR. Other key inclusion criteria included measurable disease by imaging, an ECOG performance status of 0 to 2, a life expectancy of at least 6 months, and adequate bone marrow, renal, and hepatic function.³

Patients were excluded if they received previous systemic treatment for CLL/SLL, required ongoing corticosteroids, had known prolymphocytic leukemia or a history of or suspected Richter's transformation, had clinically significant cardiovascular disease, had a history of severe bleeding disorder, had a history of stroke or intracranial hemorrhage within 6 months of study treatment, or had severe or debilitating pulmonary disease.

Patients without 17p deletions (n = 479) were randomly assigned 1:1 to receive 80 mg of oral zanubrutinib twice per day until disease progression or unacceptable toxicity or BR for 6 cycles.2,3 Patients with 17p deletions all received 80 mg of oral zanubrutinib twice per day until disease progression or unacceptable toxicity.

IRC-assessed PFS for the randomized arms served as the trial’s primary end point. Secondary end points included ORR, DOR, investigator-assessed PFS, quality of life (QOL), and safety.

ALPINE enrolled patients at least 18 years of age with a confirmed diagnosis of CLL or SLL per 2008 International Workshop on CLL criteria CLL/SLL that was relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL. Patients also needed to have measurable disease by imaging, an ECOG performance status of 0 to 2, a life expectancy of at least 6 months, and acceptable bone marrow, renal, and hepatic function.⁴

Key exclusion criteria included known prolymphocytic leukemia, or a history of or currently suspected Richter’s transformation; clinically significant cardiovascular disease; a history of a severe bleeding disorder or history of spontaneous bleeding requiring blood transfusion or other intervention; a history of stroke or intracranial hemorrhage within 180 days of enrollment; and severe or debilitating pulmonary disease.

Patients (n = 652) were randomly assigned to receive 160 mg of zanubrutinib twice per day or 420 mg of oral ibrutinib once per day.^2,4

ORR served as the trial’s primary end point. Secondary end points consisted of PFS, DOR, time to treatment failure, overall survival, QOL, and safety.

Regarding safety, pooled data from clinical trials evaluating zanubrutinib showed that the most common adverse effects reported in at least 30% of patients included decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%).²

Thirteen percent of patients developed second primary malignancies, including non-skin carcinomas. Additionally, 3.7% of patients experienced atrial fibrillation or flutter, and grade 3 or higher ventricular arrhythmias occurred 0.2% of patients.

“[The NICE recommendation] represents a significant milestone for patients in England and Wales with CLL, the most common form of leukemia in adults,” Nick York, a patient advocacy health-care liaison officer at UK Leukemia Care, added in the news release.¹ “Despite continued treatment advances, many patients with CLL will relapse and need additional treatment options. Furthermore, a proportion of patients have a disease which is refractory to initial treatment.”

References

1. Brukinsa receives positive recommendation from NICE in U.K. for adult patients with chronic lymphocytic leukemia. News release. BeiGene. October 20, 2023. Accessed October 20, 2023. https://ir.beigene.com/news/brukinsa-receives-positive-recommendation-from-nice-in-u-k-for-adult-patients-with-chronic-lymphocytic-leukemia/f6c8dafe-b903-4038-ac7f-f9729c80a1ca/
2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. January 19, 2023. Accessed October 20, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
3. A study comparing zanubrutinib with bendamustine plus rituximab in participants with previously untreated CLL or SLL (SEQUOIA). ClinicalTrials.gov. Updated March 8, 2023. Accessed October 20, 2023. https://clinicaltrials.gov/study/NCT03336333
4. A study of zanubrutinib (BGB-3111) versus ibrutinib in participants with relapsed/​refractory chronic lymphocytic leukemia (ALPINE). ClinicalTrials.gov. Updated August 25, 2023. Accessed October 20, 2023. https://www.clinicaltrials.gov/study/NCT03734016