December 9, 2023
By Catlin Nalley
At a median follow-up of 3 years, data from the Phase III ALPINE study showed sustained progression-free survival (PFS) benefits of zanubrutinib when compared to ibrutinib among patients with relapsed/refractory chronic lymphocytic leukemia.>
The durable PFS benefits of this therapy were observed across major subgroups, according to Jennifer Brown, MD, PhD, Director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute, who presented these findings during the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 9-12 in San Diego (Abstract 202).
The randomized, multinational Phase III ALPINE study (NCT03734016) of patients with R/R CLL/SLL “established the statistical and clinically meaningful superiority of zanubrutinib over ibrutinib on progression-free survival and overall response rate (ORR) and confirmed the favorable safety/tolerability profile of zanubrutinib,” according to Brown and colleagues. The extended follow-up of this analysis is discussed below.
In this study, relapsed/refractory CLL/SLL patients with measurable disease who had received one or more prior therapies were randomized 1:1 to receive zanubrutinib (n=327; 160 mg BID) or ibrutinib (n=325; 420 mg QD).
Treatment is ongoing in 59 percent of patients in the zanubrutinib cohort versus 47 percent of patients in the ibrutinib group. Brown reported that 130 patients who were treated with zanubrutinib and 172 of those who received ibrutinib discontinued treatment.
The most common reason for treatment discontinuation was adverse events in both treatment arms (n=69, zanubrutinib; n=88, ibrutinib) and progressive disease (n=51, zanubrutinib; n=62, ibrutinib).
With this extended median follow-up of 39 months, zanubrutinib sustains progression-free survival benefit over ibrutinib, with a 3-year landmark estimate of 64.9 percent PFS versus 54.8 percent, according to Brown, who also noted that progression-free survival favored zanubrutinib across all subgroups, including in patients with del(17p)/TP53 mutations with 36-month PFS rates of 58.6 percent and 41.3 percent, respectively.
The zanubrutinib PFS benefit was also confirmed in a sensitivity analysis that included only progression and death events that occurred on active treatment, Brown and colleagues reported.
Data revealed that ORR remained higher with zanubrutinib compared with ibrutinib (90.2% vs. 82.8%). Responses deepened in both arms with CR/CRi rates of 10.4 percent for zanubrutinib and 7.1 percent for ibrutinib. Overall survival showed fewer deaths with zanubrutinib. However, Brown noted that this did not reach statistical significance.
The safety profile of zanubrutinib remained favorable when compared with ibrutinib. The median treatment duration was 38.3 months and 35 months for zanubrutinib and ibrutinib, respectively. There were fewer Grade 3-5 adverse events as well as serious adverse events among patients treated with zanubrutinib versus ibrutinib.
“Zanubrutinib also has a safer cardiac profile than ibrutinib with significantly lower rates of atrial fibrillation, serious cardiac events, cardiac events leading to treatment discontinuation, and no fatal cardiac events,” Brown said.
Additionally, the study authors reported adverse events leading to dose reduction, treatment discontinuation, and hospitalization were all lower with zanubrutinib compared with ibrutinib. The most common adverse events of any grade with zanubrutinib and ibrutinib were COVID-19, diarrhea, and upper respiratory tract infection.
“In conclusion, ALPINE is the only study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors,” Brown said. “Zanubrutinib demonstrated sustained PFS benefit over ibrutinib in patients with relapsed/refractory CLL/SLL with a median follow-up of 39 months.”
PFS benefit is consistent across multiple sensitivity analyses, she added, while noting that this demonstrates that PFS advantage for zanubrutinib was primarily driven by efficacy and not tolerability.
“With over 3 years of follow-up, these data reconfirm that zanubrutinib improved efficacy over ibrutinib and has a more favorable safety profile in patients with relapsed/refractory CLL/SLL,” Brown noted during her presentation.
Catlin Nalley is a contributing writer.