FDA Greenlights BTK Inhibitor Zanubrutinib for CLL/SLL

The FDA has approved the Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa) for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Approval was based on results from the phase III SEQUOIA and ALPINE trials that demonstrated significant efficacy and a favorable safety profile for zanubrutinib in both the first-line and relapsed/refractory settings.

“We have seen striking data from the Brukinsa development program demonstrating significant and consistent efficacy across CLL patient subtypes, including the high-risk del17p/TP53-mutated population, and regardless of treatment setting,” said Jennifer Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston, who was an investigator in both trials, in a press release issued by BeiGene, the developer of zanubrutinib.

“With extensive follow-up across the CLL development program and the combined results from the SEQUOIA and ALPINE trials, Brukinsa is established as a new standard of care for CLL,” she added.

In the SEQUOIA trial, among 479 previously untreated patients, most with CLL and all without 17p deletion, progression-free survival (PFS) was significantly improved with zanubrutinib compared with bendamustine plus rituximab (HR 0.42, 95% CI 0.28-0.63, P<0.0001) at a median follow-up of about 2 years.

In a separate non-randomized cohort of SEQUOIA, zanubrutinib was evaluated in 110 patients with previously untreated CLL/SLL with 17p deletion — a group of patients with historically poor outcomes with chemoimmunotherapy — and demonstrated an overall response rate (ORR) per independent review of 88%.

In the ALPINE trial, among 652 patients with relapsed/refractory CLL/SLL, the ORR was 80% in the zanubrutinib arm and 73% in the ibrutinib (Imbruvica) arm (response rate ratio 1.10, 95% CI 1.01-1.20, P=0.0264).

A final PFS analysis of ALPINE, presented at the 2022 American Society of Hematology (ASH) annual meeting and published in the New England Journal of Medicine, showed that PFS was significantly longer with zanubrutinib compared with ibrutinib (HR 0.65, 95% CI 0.49-0.86, P=0.002) at a median follow-up of 29.6 months, with 2-year investigator-assessed PFS rates of 78.4% and 65.9%, respectively.

Importantly, the incidence of atrial fibrillation or flutter of any grade was lower in the zanubrutinib group versus the ibrutinib group (5.2% vs 13.3%).

The recommended zanubrutinib dosage is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.

Across clinical trials of zanubrutinib, the most common adverse reactions (≥30%) were neutrophil count decrease (42%), upper respiratory tract infection (39%), platelet count decrease (34%), hemorrhage (30%), and musculoskeletal pain (30%). Second primary malignancies, including non-skin carcinomas, developed in 13% of patients.

Atrial fibrillation or flutter were reported in 3.7% of patients, and ≥grade 3 ventricular arrhythmias were reported in 0.2% of patients.

“Thanks to research that has delivered innovative and effective medicines, people with CLL can remain on therapy for years, so tolerability is an important consideration,” said Brian Koffman, MD, chief medical officer and executive vice-president of the CLL Society, in the BeiGene release. “I’m pleased that the approval of zanubrutinib provides a new BTK inhibitor option for people with CLL/SLL, with demonstrated efficacy as well as being very well tolerated long-term.”