As reported in the Journal of Clinical Oncology by John C. Byrd, MD, and colleagues, the phase III ELEVATE-RR trial has shown noninferior progression-free survival with the more selective Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib vs the less selective inhibitor ibrutinib in previously treated patients with chronic lymphocytic leukemia (CLL), along with a reduced risk of cardiovascular events.

According to the authors, the trial is the first phase III trial comparing more- vs less-selective BTK inhibitors in this setting. They hypothesized that the greater selectivity might improve tolerance of continuous therapy.

In this first direct comparison of less vs more selective BTK inhibitors in CLL, acalabrutinib demonstrated noninferior progression-free survival with fewer cardiovascular adverse events.

— John C. Byrd, MD, and colleagues

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Study Details

The open-label trial included 533 previously treated patients with CLL and centrally confirmed del(17)(p13.1) or del(11)(q22.3) from sites in 15 countries. They were randomly assigned between October 2015 and November 2017 to receive acalabrutinib at 100 mg twice daily (n = 268) or ibrutinib at 420 mg once daily (n = 265) until disease progression or unacceptable toxicity. Patients with significant cardiovascular disease, concomitant warfarin or equivalent vitamin K antagonist treatment, prior BTK or BCL2 inhibitor treatment, or those requiring treatment with proton-pump inhibitors were excluded.

The primary endpoint was independent review committee–assessed noninferiority of acalabrutinib for progression-free survival; noninferiority was shown if the upper bound of the hazard ratio (HR) two-sided 95% confidence interval (CI) was below 1.429. Secondary endpoints were overall survival and incidence of any-grade atrial fibrillation, grade ≥ 3 infection, and Richter transformation.  

Progression-Free Survival and Secondary Endpoints

At data cutoff for the final analysis (September 2020), median follow-up was 40.9 months (range = 0.0–59.1 months). Median progression-free survival was 38.4 months (95% CI = 33.0–38.6 months) in the acalabrutinib group vs 38.4 months (95% CI = 33.0–41.6 moths) in the ibrutinib group (HR = 1.00, 95% CI = 0.79–1.27, thus meeting the noninferiority criterion).

Median overall survival was not reached in either group. Death occurred in 63 patients (23.5%) in the acalabrutinib group and in 73 patients (27.5%) in the ibrutinib group (HR = 0.82, 95% CI = 0.59–1.15). Median event-free survival was 33.2 vs 33.0 months. Objective response was observed in 81.0% vs 77.0%.  

Any-grade atrial fibrillation/atrial flutter occurred in 9.4% vs 16.0% of patients (P = .02; HR for cumulative incidence = 0.52, 95% CI = 0.32–0.86). No significant differences were observed in incidence of grade ≥ 3 infection (30.8% vs 30.0%) or Richter transformation (3.8% vs 4.9%).

Overall Rates of Adverse Events

Grade ≥ 3 adverse events occurred in 68.8% of patients in the acalabrutinib group vs 74.9% of those in the ibrutinib group, with the most common in the acalabrutinib group being neutropenia (19.5% vs 22.8% in the ibrutinib group), anemia (11.7% vs 12.9%), and pneumonia (10.5% vs 8.7%). Cardiac events of any grade occurred in 24.1% vs 30.0% of patients, and hypertension of any grade occurred in 9.4% vs 23.2% (HR for cumulative incidence = 0.34, 95% CI = 0.21–0.54), with grade ≥ 3 hypertension being reported in 4.1% vs 9.1%.

The most common serious adverse events in ≥ 5% of either group were pneumonia (10.2% vs 9.9%), anemia (5.3% vs 4.9%), and atrial fibrillation (2.3% vs 5.3%). Adverse events led to discontinuation of treatment in 14.7% vs 21.3% of patients.

The investigators concluded, “In this first direct comparison of less vs more selective BTK inhibitors in CLL, acalabrutinib demonstrated noninferior progression-free survival with fewer cardiovascular adverse events.”

Dr. Byrd, of The Ohio State University Comprehensive Cancer Center, Columbus, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute, Four Winds Foundation, Sullivan CLL Foundation, and D. Warren Brown Foundation. For full disclosures of the study authors, visit ascopubs.org.