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FDA Gives Zanubrutinib Approval for First-line, R/R CLL/SLL


The broad approval, while expected, will likely signal a milestone in the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The FDA approved the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa; BeiGene) on January 19 for all patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), whether newly diagnosed or previously treated for the disease—including those who have received ibrutinib (Imbruvica).1

Ibrutinib, a first-generation BTK inhibitor, created a sea change in treating CLL when it was approved in 2014. Broad approval for zanubrutinib in CLL promises a new milestone in treating patients with the disease, which accounts for one-fourth of all US leukemia cases.2 In an email to The American Journal of Managed Care®, the lead investigator for the study that showed zanubrutinib’s superiority over ibrutinib said she expected a rapid shift to zanubrutinib, with no resistance from payers.

The approval could affect up to estimated 21,000 patients in the United States who will receive a diagnosis of CLL or SLL in 2023, according to the American Cancer Society.2 It follows the December 13, 2022, presentation of data from the phase 3 ALPINE trial (NCT03734016) at the 64th American Society of Hematology (ASH) Annual Meeting.3 The data also were published in the New England Journal of Medicine.4 Study results showed that after 2.5 years zanubrutinib offered a 35% benefit in progression-free survival (PFS) over ibrutinib among patients with relapsed/refractory (R/R) disease, and the edge widened among higher-risk patients (HR, 0.65; 95% CI, 0.49-0.86; P =.002).

In ALPINE, efficacy among 652 patients was evaluated based on overall response rate (ORR) and duration of response (DOR), as determined by an independent review committee. The ORR was 80% (95% CI, 76%-85%) in the zanubrutinib arm and 73% (95% CI, 68%-78% in the ibrutinib arm for a response rate ratio of 1.10 (95% CI, 1.01-1.20; P =.0264). The median DOR was not reached in either arm after a median follow-up of 14.1 months.

The FDA approval also covers patients previously untreated for CLL/SLL, based on results from the phase 3 SEQUOIA trial (NCT03336333), which were presented at the 2022 European Hematology Association Congress. In that study, the median PFS was not reached in the zanubrutinib arm, however patients receiving a combination bendamustine plus rituximab had a PFS of 33.7 months (HR, 0.42; 95% CI, 0.28-0.63, P <.0001).1

In SEQUOIA, a nonrandomized cohort of previously untreated patients with CLL/SLL and 17p deletion were also evaluated. The ORR was 88% (95% CI, 81%-94%), and the median DOR was not reached after a median follow-up of 25.1 months.

Zanubrutinib was previously approved in the United States to treat smaller patient groups with mantle cell lymphoma, marginal zone lymphoma, and those with Waldenström macroglobulinemia.

Jennifer R. Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute in Boston, Massachusetts, who presented the ALPINE data at ASH, had predicted that the FDA’s label would be broad.

In an emailed statement, Brown said ALPINE “found that zanubrutinib led to fewer [adverse] effects and adverse events than ibrutinib, leading to a better quality of life for patients. I am encouraged that zanubrutinib has been approved for adult patients with CLL and SLL and optimistic that many patients across the country will benefit from this approval.”

Zanubrutinib’s benefit over ibrutinib is seen as 2-fold. It offers superior responses and fewer adverse effects, because this second-generation therapy has “greater BTK specificity than ibrutinib,” Brown explained during her ASH presentation. Its higher concentration allows for more sustained BTK inhibition, and its improved mechanism reduces off-target cardiac effects, allowing patients to stay on therapy longer.

In fall 2022, the National Comprehensive Cancer Network (NCCN) listed zanubrutinib as a preferred agent over ibrutinib in CLL in its guidelines, based on zanubrutinib’s improved safety profile.5

During ASH, Brown told reporters she could not think of a patient group that should be prescribed ibrutinib instead of zanubrutinib. She repeated that recommendation in a follow-up email when asked if she expected rapid adoption of zanubrutinib.“I certainly hope that clinicians will move quickly to Brukinsa, given that it demonstrated improved efficacy and safety compared to Imbruvica,” Brown said. “There is no situation in which I would start a patient on ibrutinib anymore.”

Asked if she anticipated any payer resistance to coverage in in CLL, Brown said, “No, not with the approval and the NCCN listing. Payers are already quite adapted to BTK inhibitors in first-line CLL.”

This article has been updated with additional comments from Jennifer R. Brown, MD, PhD.


  1. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic leukemia. News release. FDA. January 19, 2023. Accessed January 19, 2023. http://bit.ly/3WrqH0A
  2. Key statistics for chronic lymphocytic leukemia. American Cancer Society. January 12, 2023. Accessed January 19, 2023. http://bit.ly/3uZtUJv
  3. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib demonstrates superior progression-free survival (PFS) compared with ibrutinib treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL): results from final analysis of ALPINE randomized phase 3 study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; New Orleans, LA; December 10-13, 2022; Abstract LBA-6.
  4. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. Published online December 13, 2022. doi:10.1056/NEJMoa2211582
  5. Caffrey M. NCCN update moves zanubrutinib ahead of ibrutinib in CLL/SLL based on toxicity profile. Am J Manag Care. 2022;28(supp 7):SP427.
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