As reported in the Journal of Clinical Oncology by John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center, 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 chronic lymphocytic leukemia (CLL), along with a reduced risk of cardiovascular events.¹

According to the authors, the study 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.

John C. Byrd, MD

Study Details

In the open-label trial, 533 previously treated patients with centrally confirmed del(17)(p13.1) or del(11)(q22.3) from sites in 15 countries 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. Randomization was stratified by del(17)(p13.1) status, Eastern Cooperative Oncology Group (ECOG) performance status score (2 vs ≤ 1), and number of prior therapies (1–3 vs ≥ 4 or more). Patients with significant cardiovascular disease, concomitant warfarin or equivalent vitamin K antagonist treatment, prior BTK or BCL2 inhibitor treatment, or 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 two-sided 95% confidence interval was below 1.429. Secondary endpoints were overall survival and incidence of any-grade atrial fibrillation, grade ≥ 3 infection, and Richter’s transformation.

In the acalabrutinib vs ibrutinib groups, median age was 66 years (range = 41–89 years, 15% ≥ 75 years) vs 65 years (range = 28–88 years, 15% ≥ 75 years), and 69% vs 73% were male. ECOG performance status was 0 or 1 in 92% vs 92% and 2 in 8% vs 8%, Overall, 45% vs 45% had del(17)(p13.1) and 62% vs 66% had del(11)(q22.3), 37% vs 42% had TP53 mutation, and 16% vs 11% had IGHV mutation. The median number of prior therapies was two (range = 1–9) vs two (range = 1–12), with 87% vs 89% having one to three prior therapies and 12% vs 11% having at least four. The most common prior therapies were alkylators (90% vs 91%), anti-CD20 antibodies (85% vs 86%), and purine analogs (64% vs 60%).

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% confidence interval [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 (hazard ratio [HR] = 1.00, 95% CI = 0.79–1.27, thus meeting the noninferiority criterion).

In subgroup analyses, hazard ratios for progression-free survival for acalabrutinib vs ibrutinib were 1.00 (95% CI = 0.73–1.38) among 245 patients with and 1.00 (95% CI = 0.71–1.41) among 288 patients without del(17)(p13.1) and 1.08 (95% CI = 0.80–1.47) among 342 patients with and 0.86 (95% CI = 0.59–1.24) among 190 patients without del(11)(q22.3). Hazard ratios were 0.99 (95% CI = 0.77–1.27) among 477 patients having received one to three prior therapies and 1.07 (95% CI = 0.57–2.02) among 56 havined received at least four, and 1.03 (95% CI = 0.80–1.33) among 492 patients with an ECOG performance status of 0 or 1 and 0.64 (95% CI = 0.32–1.29) among 41 patients with an ECOG performance status of 2.

Median overall survival was not reached in either group; death occurred in 63 patients (23.5%) in the acalabrutinib group and 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. An objective response was observed in 81.0% vs 77.0%.

Any-grade atrial fibrillation (9.0% vs 15.6%) or atrial flutter (0.4% vs 0.8%) occurred in 9.4% vs 16.0% of patients (P = .02; HR for cumulative incidence = 0.52, 95% CI = 0.32–0.86). Events led to treatment discontinuation in no patients given acalabrutinib vs seven patients given ibrutinib. The median time to any-grade atrial fibrillation/flutter was 28.8 vs 16.0 months. With regard to other secondary endpoints, no significant differences were observed in the incidence of grade ≥ 3 infection (30.8% vs 30.0%) or Richter’s transformation (3.8% vs 4.9%).

Overall Adverse Events

Grade ≥ 3 adverse events occurred in 68.8% of the acalabrutinib group vs 74.9% of the ibrutinib group, with the most common in the acalabrutinib group being neutropenia (19.5% vs 22.8% in 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 (HR = 0.72, 95% CI = 0.52–1.00) and were grade ≥ 3 in 8.6% vs 9.5%. Hypertension of any grade occurred in 9.4% vs 23.2% (HR = 0.34, 95% CI = 0.21–0.54) and was grade ≥ 3 in 4.1% vs 9.1%. 

The most common serious adverse events in at least 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 Bruton’s tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior [progression-free survival] with fewer cardiovascular adverse events.” 

DISCLOSURE: The study was supported by the National Cancer Institute, Four Winds Foundation, Sullivan CLL Foundation, and D. Warren Brown Foundation and was sponsored by Acerta Pharma BV. Dr. Byrd holds stock or other ownership interests in Vincerx Pharma; has received honoraria from AstraZeneca, Novartis, Pharmacyclics, Syndex, and Trillium Therapeutics; has served as a consultant or advisor to Acerta Pharma, AstraZeneca, Janssen, Kura Oncology, Novartis, and Syndax; has received research funding from Zencor; has received institutional research funding from Acerta Pharma and Pharmacyclics; holds institutional intellectual property in The Ohio State University patents; and has been reimbursed for travel, accommodations, or other expenses by Gilead, Janssen, Novartis, Pharmacyclics, and TG Therapeutics.

REFERENCE

1. Byrd JC, Hillmen P, Ghia P, et al: Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized phase III trial. J Clin Oncol. July 26, 2021 (early release online).