ALPINE: Improved PFS, Fewer Cardiac Complications with Zanubrutinib for CLL

By Cameron Kelsall, MD /alert Contributor 

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Treatment with zanubrutinib led to significant improvements in progression-free survival when compared with ibrutinib in a cohort of patients with relapsed or refractory chronic lymphocytic leukemia, according to phase 3 study results published in The New England Journal of Medicine

The first-generation Bruton’s tyrosine kinase inhibitor has long been a standard of care for patients with CLL or small lymphocytic lymphoma. Zanubrutinib, a second-generation Bruton’s TKI, was developed with greater molecular specificity to reduce the risks for serious cardiac events that can be treatment-limiting. 

In a previous interim analysis of the ALPINE trial, Jennifer R. Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, and colleagues observed that patients treated with zanubrutinib demonstrated superior responses to those treated with ibrutinib. PFS served as the key endpoint of the final analysis. 

In the intent-to-treat population, 652 patients with relapsed or refractory CLL or SLL were randomly assigned to zanubrutinib (160 mg twice-daily; n = 327) or ibrutinib (420 mg once-daily; n = 325), with treatment continuing until disease progression or unacceptable toxicity. The median age of study participants was 67 years (range, 35-90), and the median number of prior therapy lines was 1 (range, 1-12). Chemoimmunotherapy was previously received by 80% of the zanubrutinib group and 76% of the ibrutinib group. At the time of reporting, 73% of patients assigned to zanubrutinib (n = 238) continued to receive treatment as did 58% (n = 190) of patients assigned to ibrutinib. 

The median follow-up for PFS was 29.6 months. The researchers observed 87 cases of disease progression or death among patients assigned to zanubrutinib, compared with 118 cases among patients assigned to ibrutinib (HR = 0.65; 95% CI, 0.49-0.86; P = .002). The median PFS for patients assigned to zanubrutinib was not reached, compared with 34.2 months (95% CI, 33.3-not estimable) for patients assigned to ibrutinib. 

The PFS benefit of zanubrutinib extended to a subgroup of patients with high-risk disease features, such as 17p deletion or TP53 mutation (HR = 0.53; 95% CI, 0.31-0.88). A greater percentage of high-risk patients assigned to zanubrutinib remained alive without evidence of disease progression at 24 months (72.6% vs 54.6%). 

The median OS had not been reached for either cohort at the time of reporting, although fewer deaths were observed among patients assigned to ibrutinib (48 vs 60). The overall response rate by independent assessment also favored assignment to zanubrutinib (86.2% vs 75.7%). 

Cardiac adverse events occurred at a lower rate among patients assigned to zanubrutinib (21.3% vs. 29.6%). In addition, zanubrutinib was associated with lower rates of treatment discontinuation due to cardiac disorders (0.3% vs 4.3%). Six patients assigned to ibrutinib died of cardiac disorders, with no cardiac-related deaths observed in the zanubrutinib arm. 

The incidence of atrial fibrillation or atrial flutter, which served as a key secondary outcome, was lower among patients assigned to zanubrutinib (any grade, 5.2% vs. 13.3%; grade 3 or higher, 2.5% vs. 4%). The researchers observed no new safety signals associated with zanubrutinib. Fewer patients assigned to zanubrutinib discontinued treatment due to any adverse events (15.4% vs 22.2%). 

“Monotherapy with a BTK inhibitor for CLL involves continuous treatment, so successful outcomes depend on the ability to deliver complete and sustained occupancy in tissues affected by disease, the ability to treat over a long-term period without unacceptable side effects, and a low incidence of treatment discontinuation,” Brown and colleagues wrote. “In the ALPINE trial, the incidence of treatment discontinuation for any reason was lower with zanubrutinib than with ibrutinib, including discontinuation due to both adverse events and progressive disease.” 


Disclosures: Brown declared financial ties to drugmakers. See full study for details. ALPINE is being supported by BeiGene. 

Photo Credit: Getty Images. 

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