Head-to-Head Trial Confirms Acalabrutinib’s Noninferiority to Ibrutinib in CLL

At EHA2021 Virtual, researchers presented results from the first head-to-head trial of Bruton tyrosine kinase (BTK) inhibitors in chronic lymphocytic leukemia (CLL), finding that acalabrutinib is noninferior to ibrutinib in terms of progression-free survival (PFS).

Treatment with the more selective BTK inhibitor acalabrutinib also was associated with lower incidence of common adverse events (AEs), such as atrial fibrillation, lead author Peter Hillmen, MD, PhD, reported.

Dr. Hillmen, from St. James University Hospital in Leeds, U.K, shared results of the phase III ELEVATE-RR trial, an open-label, randomized, noninferiority trial that compared the two BTK inhibitors in patients with previously treated CLL.

Patients were randomized to receive acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. Randomization was stratified by del17p status, Eastern Cooperative Oncology Group performance status (2 vs. ≤1), and number of prior therapies (1-3 vs. ≥4).

The primary endpoint was PFS as assessed by independent review committee; secondary endpoints of all-grade atrial fibrillation, grade ≥3 infection, Richter transformation, and overall survival were assessed in hierarchical order. Informed consent was obtained from all patients prior to trial enrollment.

A total of 533 patients were randomized: 268 to acalabrutinib and 265 to ibrutinib. Patients’ median age was 66 years and they had received a median of two prior therapies. Approximately half of patients (45.2%) had CLL with del17p, and 64.2% had del11q.

At a median follow-up of 40.9 months, acalabrutinib demonstrated noninferiority to ibrutinib in terms of PFS, which was 38.4 months in both arms (hazard ratio [HR] = 1.00; 95% CI 0.79-1.27). Median overall survival was not reached in either arm (HR=0.82; 95% CI 0.59-1.15); 63 patients died in the acalabrutinib arm (23.5%), compared with 73 (27.5%) in the ibrutinib arm.

Acalabrutinib was statistically superior to ibrutinib when looking at the incidence of all-grade atrial fibrillation (9.4% vs. 16.0%; p=0.023). Acalabrutinib also was associated with lower incidence of any-grade hypertension (9.4% vs. 23.2%), arthralgia (15.8% vs. 22.8%), and diarrhea (34.6% vs. 46.0%). However, the newer-generation BTK inhibitor was associated with a higher incidence of headache (34.6% vs. 20.2%) and cough (28.9% vs. 21.3%). AEs led to treatment discontinuation in 14.7% of acalabrutinib-treated patients compared with 21.3% of ibrutinib-treated patients.

Among the other secondary endpoints, incidences of grade ≥3 infection (30.8% with acalabrutinib vs. 30.0% with ibrutinib) and Richter transformation (3.8% vs. 4.9%) were comparable.

“These results demonstrated that acalabrutinib is better tolerated and has similar efficacy to ibrutinib in patients with previously treated CLL,” Dr. Hillmen concluded.

Study authors report relationships with Acerta Phama, which sponsored this trial.


Hillmen P, Byrd JC, Ghia P, et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. Abstract #S145. Presented at the EHA2021 Virtual Congress, June 9-17, 2021.