Jennifer R. Brown, MD, PhD
As reported in The New England Journal of Medicine by Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute and Harvard University, and colleagues, the phase III ALPINE trial has shown significantly better progression-free survival with zanubrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor with increased specificity, vs ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1
Interim analysis of overall response rate in the trial2 (the primary endpoint) supported the January 2023 approval by the U.S. Food and Drug Administration of zanubrutinib for treatment of CLL or SLL.
In the open-label trial, 652 patients with at least one prior course of therapy from sites in 15 countries in North America, Europe, and the Asia-Pacific region were randomly assigned between November 2018 and December 2020 to receive zanubrutinib at 160 mg twice daily (n = 327) or ibrutinib at 420 mg once daily (n = 325) until the occurrence of disease progression or unacceptable toxic effects. Randomization was stratified by age, geographic region, refractory status, and 17p deletion/TP53 mutation status. The primary endpoint was investigator-assessed overall response. Investigator-assessed progression-free survival was a key secondary endpoint; it was tested hierarchically, with analysis of superiority occurring if noninferiority was established. The current report presents findings of the final progression-free survival analysis.
At a median follow-up of 29.6 months, zanubrutinib was found to be noninferior and superior to ibrutinib in progression-free survival; investigator-assessed progression-free survival events occurred in 87 patients (26.6%) vs 118 patients (36.3%), yielding a hazard ratio of 0.65 (95% confidence interval [CI] = 0.49–0.86, P = .002). Progression-free survival rates were 83.3% (95% CI = 78.7%–87.0%) in the zanubrutinib group vs 75.0% (95% CI = 69.8%–79.4%) in the ibrutinib group at 18 months and 78.4% (95% CI = 73.3%–82.7%) vs 65.9% (95% CI = 60.1%–71.1%) at 24 months. On independent review committee assessment, progression-free survival events occurred in 26.9% of the zanubrutinib group vs 36.9% of the ibrutinib group, yielding a hazard ratio of 0.65 (95% CI = 0.49–0.86, P = .0024); progression-free survival rate at 24 months was 79.5% vs 67.3%.
Among 75 patients in each treatment group with 17p deletion, TP53 mutation, or both, progression-free survival events occurred in 32% vs 48% of patients on investigator assessment, yielding a hazard ratio of 0.53 (95% CI = 0.31–0.88). Progression-free survival rate was 72.6% (95% CI = 60.3%–81.7%) vs 54.6% (95% CI = 40.7%–66.4%) at 24 months. On independent review committee assessment, events occurred in 30.7% vs 45.3% of patients, yielding a hazard ratio of 0.52 (95% CI = 0.30–0.88); progression-free survival rate at 24 months was 77.6% vs 55.7%.
In other progression-free survival subgroup analyses, hazard ratios favored zanubrutinib in most subgroups on investigator assessment: they were 0.72 (95% CI = 0.52–1.01) among patients aged 65 or older (n = 401) and 0.53 (95% CI = 0.32–0.86) among those aged up to 65; 0.39 (95% CI = 0.18–0.36) among 94 patients from Asia, 1.46 (95% CI = 0.59–3.61) among 58 from Australia/New Zealand, 0.72 (95% CI = 0.51–1.03) among 389 from Europe, and 0.42 (95% CI = 0.20–0.86) among 111 from North America; 0.85 (95% CI = 0.45–1.65) among 149 with mutated IGHV at baseline and 0.60 (95% CI = 44%–82%) among 479 unmutated IGHV; and 0.72 (95% CI = 0.54–0.97) among 598 with one to three prior lines of therapy and 0.24 (95% CI = 0.09–0.65) among 54 with more than three prior lines.
One investigator assessment, the proportion of patients free of treatment failure at 24 months was 79.9% (95% CI = 75.1%–83.9%) vs 65.0% (95% CI = 59.5%–70.0%). At the time of analysis, death had occurred in 48 patients (14.7%) in the zanubrutinib group vs 60 patients (18.5%) in the ibrutinib group (hazard ratio = 0.76, 95% CI = 0.51–1.11).
In the safety population of 324 patients in each group, grade ≥ 3 adverse events occurred in 67.3% of the zanubrutinib group vs 70.4% of the ibrutinib group, with the most common in both groups being neutropenia (16.0% vs 13.9%) and hypertension (14.8% vs 11.1%). Serious adverse events occurred in 42% vs 50% of patients and led to treatment discontinuation in 15.4% vs 22.2%. Cardiac disorders of any grade occurred in 21.3% of the zanubrutinib group vs 29.6% of the ibrutinib group and led to treatment discontinuation in 0.3% vs 4.3%; cardiac events led to death in six patients, all in the ibrutinib group. Atrial fibrillation or flutter (a key secondary endpoint) of any grade occurred in 5.2% vs 13.3% of patients and was grade ≥ 3 in 2.5% vs 4.0%.
Adverse events led to death in 33 patients (10.2%) in the zanubrutinib group and 36 patients (11.1%) in the ibrutinib group. Among the 69 patients, death was attributed to infections in 44 patients, with involvement of COVID-19 in many. Overall, adverse events related to COVID-19 occurred in 28.7% vs 21.6% of patients, were grade ≥ 3 in 12.3% vs 8.6%, led to discontinuation of treatment in 3.7% vs 4.9%, and led to death in 3.7% vs 4.6%.
The investigators concluded: “In patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib than among those who received ibrutinib, and zanubrutinib was associated with fewer cardiac adverse events.”
DISCLOSURE: The study was funded by BeiGene, the developer of zanubrutinib. Dr. Brown has served as a consultant to AbbVie, Acerta/AstraZeneca, BeiGene, Bristol Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, MorphoSys AG, Novartis, Pfizer, Rigel, Grifols Worldwide Operations, Hutchmed, iOnctura, and Pharmacyclics; and has received research funding from BeiGene, MEI Pharma, Gilead Sciences, Loxo/Lilly, Verastem/SecuraBio, TG Therapeutics, and iOnctura.
1. Brown JR, Eichhorst B, Hillmen P, et al: Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 388:319-332, 2023.
2. Hillmen P, Eichhorst B, Brown JR, et al: Zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: Interim analysis of a randomized phase III trial. J Clin Oncol 41:1035-1045, 2023.