Acalabrutinib was equally efficacious with less toxicity when compared directly with ibrutinib in patients with previously treated relapsed or refractory chronic lymphocytic leukemia (CLL), according to the results of an open-label, randomized, noninferiority phase III trial presented at the 2021 ASCO Annual Meeting.¹ The study also reported fewer discontinuations in treatment due to toxicity in patients given acalabrutinib.

The ELEVATE-RR trial compared the first-generation Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib with the next-generation agent acalabrutinib. At a median follow-up of 40.9 months, acalabrutinib and ibrutinib were similarly effective in preventing disease progression. However, the incidence of cardiac events such as atrial fibrillation and hypertension was significantly lower with acalabrutinib.

“These results demonstrate that acalabrutinib is better tolerated and has similar efficacy to ibrutinib in patients with previously treated CLL,” said lead author John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center, Columbus. “Acalabrutinib demonstrated lower frequencies of common adverse events (grade 3 or higher), serious adverse events, and treatment discontinuations due to adverse events overall.”

These results demonstrate that acalabrutinib is better tolerated and has similar efficacy to ibrutinib in patients with previously treated CLL.

— John C. Byrd, MD

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Ibrutinib was the first BTK inhibitor to be approved in the treatment of patients with CLL or small lymphocytic leukemia (SLL). Although ibrutinib was effective, cardiovascular toxicity leading to treatment discontinuation has been a concern. The second-generation BTK inhibitor acalabrutinib was associated with fewer cardiac side effects in single-arm studies compared with ibrutinib. Acalabrutinib was approved 2 years ago for adults with CLL or SLL, based on results from the ELEVATE-TN and ASCEND trials.

“When compared across trials, acalabrutinib has fewer side effects, particularly cardiovascular effects. ELEVATE-RR is the first head-to-head trial comparing the safety and efficacy of acalabrutinib vs ibrutinib in patients with previously treated CLL and del(17p) or del(11q),” Dr. Byrd noted.

Study Details

The randomized, open-label, noninferiority trial enrolled 533 patients with CLL and del(17p) or del(11q) treated with one or more prior lines of therapy. They were randomly assigned 1:1 to receive acalabrutinib at 100 mg twice a day (n = 268) or ibrutinib at 420 mg/d (n = 265). Treatment was continued until disease progression or unacceptable toxicity.

Patients were stratified according to del(17p) status, Eastern Cooperative Oncology Group (ECOG) performance status (2 vs 1), and number of prior therapies (1–3 vs 4 or more). Key exclusion criteria included significant cardiovascular disease; concomitant treatment with warfarin or an equivalent vitamin K antagonist; and prior treatment with ibrutinib, a BCR inhibitor, or a BCL2 inhibitor (venetoclax).

At baseline, demographics and disease characteristics were similar in the two arms. Median age was 66 years; 16% were older than age 75; the median number of prior therapies was two; 45.2% had del(17p); and 64.2% had del(11q).

Key Findings

The primary endpoint was progression-free survival. Median progression-free survival was identical in both arms of the study—38.4%. “The hazard ratio suggested equivalency of efficacy,” Dr. Byrd stated.

Median overall survival was not reached in either arm, but the numerical trend favored acalabrutinib at this early time point. At data cutoff, there were 63 deaths in the acalabrutinib arm compared with 73 in the ibrutinib arm.

Acalabrutinib was associated with significantly fewer cardiac adverse events compared with ibrutinib, the former standard of care. The overall rate of cardiac events was 24.1% with acalabrutinib vs 30% with ibrutinib. Any-grade atrial fibrillation was reported in 9.4% of the acalabrutinib arm vs 16% of the ibrutinib arm. In patients without prior atrial fibrillation, the incidence of de novo atrial fibrillation was more than twice that of ibrutinib: 6.2% with acalabrutinib vs 14.9% with ibrutinib.

The time to development of atrial fibrillation was longer in the acalabrutinib arm: 28.8 months vs 16 months with ibrutinib. Treatment discontinuation attributed to atrial fibrillation occurred in no patients taking acalabrutinib vs 16.7% of those in the ibrutinib arm. Hypertension of any grade was reported in 9.4% vs 23.2%.

Furthermore, acalabrutinib was associated with a lower incidence of arthralgia (15.8% vs 22.8%) and diarrhea (34.6% vs 46%) but a higher incidence of headache (34.6% vs 20.2%) and cough (28.9% vs 21.3%). There were fewer cases of infections and pneumonitis with acalabrutinib as well. Both treatment arms had similar rates of grade 3 or greater adverse events, including Richter’s transformation.

Treatment Selection

During a discussion following the presentation, Dr. Byrd indicated that acalabrutinib would move to his first choice when a BTK inhibitor was needed. “With similar efficacy and diminished toxicity with acalabrutinib, that would likely be the first choice.”

Both drugs, although related, have differences, so a switch from one to the other could be considered for side effects, he added. “In younger patients, there are fewer data [with acalabrutinib], and using ibrutinib based on the ECOG study with rituximab may be a consideration as well, based on established data,” he noted. 

DISCLOSURE: The study was funded by Acerta Pharma/AstraZeneca. 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 Xencor; has received institutional research funding from Acerta Pharma and Pharmacyclics; 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: First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. 2021 ASCO Annual Meeting. Abstract 7500. Presented June 5, 2021.