In an interim analysis of the phase III ALPINE trial reported in the Journal of Clinical Oncology, Peter Hillmen, MBChB, PhD, and colleagues found that zanubrutinib produced a significantly higher objective response rate vs ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.

“[Patients treated with] zanubrutinib had a significantly higher objective response rate, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile vs ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.”

— Peter Hillmen, MBChB, PhD, and colleagues

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Study Details

In the open-label trial, 652 patients were enrolled from sites in 15 countries between November 2018 and December 2020. An interim analysis of investigator-assessed objective response rate was scheduled for approximately 12 months after the first 415 patients were enrolled. The 415 patients were randomly assigned to receive zanubrutinib at 160 mg twice daily (n = 207) or ibrutinib at 420 mg once daily (n = 208) until disease progression or unacceptable toxicity.

Responses

At a median follow-up of 15 months (range = 0.1–26.0 months), objective response (partial response/nodular partial response or better) was observed in 162 patients (78.3%, 95% confidence interval [CI] = 72.0%–83.7%) in the zanubrutinib group vs 132 patients (62.5%, 95% CI = 55.5%–69.1%) in the ibrutinib group (P < .001). Complete response/complete response with incomplete marrow recovery was observed in four (1.9%) vs three (1.4%) patients. The estimated proportion of responses lasting ≥ 12 months was 89.8% vs 77.9%.

Among 41 and 38 patients with del(17p) and/or TP53 mutation, objective response rates were 80.5% with zanubrutinib vs 50.0% with ibrutinib. Among 61 and 55 patients with del(11q), objective response rates were 83.6% with zanubrutinib vs 69.1% ibrutinib.

Progression-free survival at 12 months was 94.9% (95% CI = 90.7%–97.2%) in the zanubrutinib group vs 84.0% (95% CI = 78.1%–88.5%) in the ibrutinib group (HR = 0.40, 95% CI = 0.23–0.69). Overall survival at 12 months was 97.0% vs 92.7% (HR = 0.54, 95% CI = 0.25–1.16).

Adverse Events

Grade ≥ 3 adverse events occurred in 55.9% of patients in the zanubrutinib group vs 51.2% of those in the ibrutinib group; the most common events in both groups were neutropenia (13.7% vs 10.6%) and hypertension (10.3% vs 7.2%). Grade ≥ 3 infections occurred in 12.7% vs 17.9% of patients, including pneumonia in 3.9% vs 4.8%. Serious adverse events occurred in 27.5% vs 32.4% of patients. Adverse events led to discontinuation of treatment in 7.8% vs 13.0%. Atrial fibrillation/flutter of any grade—a key secondary endpoint—occurred in 2.5% vs 10.1% of patients (P = .001). Cardiac disorder adverse events of any grade occurred in 13.7% vs 25.1% and major hemorrhage occurred in 2.9% vs 3.9%. Second primary malignancies occurred in 8.3% vs 6.3% of patients, including nonmelanoma skin cancers in 3.4% vs 4.8%. Adverse events led to death in 8 patients (3.9%) vs 12 patients (5.8%).

The investigators concluded, “[Patients treated with] zanubrutinib had a significantly higher objective response rate, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile vs ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.”

Dr. Hillmen, of St James’s University Hospital, Leeds, United Kingdom, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by BeiGene. For full disclosures of the study authors, visit ascopubs.org.