Acalabrutinib confers equal PFS with less toxicity vs. ibrutinib in previously treated CLL
Click Here to Manage Email Alerts
Acalabrutinib proved noninferior to ibrutinib in terms of PFS and resulted in less cardiotoxicity and fewer discontinuations due to adverse effects in a head-to-head trial among patients with previously treated chronic lymphocytic leukemia.
Researchers presented results of the open-label, randomized, phase 3 noninferiority trial, which directly compared the Bruton tyrosine kinase (BTK) inhibitors among this patient population, during the virtual ASCO Annual Meeting.
“Acalabrutinib [Calquence, AstraZeneca] is more selective for BTK and, in the phase 2 study, appeared at least as good and also with fewer side effects, such as atrial fibrillation and hypertension,” Jonathan C. Byrd, MD, Dr. Warren Brown chair of leukemia research, distinguished university professor of medicine, medicinal chemistry and veterinary biosciences, and senior advisor for cancer experimental therapeutics at The James Cancer Hospital and Solove Research Institute at The Ohio State University’s Comprehensive Cancer Center, as well as a HemOnc Today Editorial Board Member, told Healio. “This study was initiated to test if a more selective BTK inhibitor, such as acalabrutinib, maintained the superior efficacy seen with ibrutinib [Imbruvica; Pharmacyclics, Janssen] and a lower adverse event profile.”
Byrd and colleagues randomly assigned 533 previously treated patients with CLL and 17p deletion or 11q deletion to either 100 mg twice-daily oral acalabrutinib (n = 268; median age, 66 years; range, 41-89; 69% men) or 420 mg once-daily oral ibrutinib (n = 265; median age, 65 years; range, 28-88; 73.2% men).
Treatment continued until disease progression or unacceptable toxicity. Researchers stratified patients by 17p deletion status, ECOG performance status (2 vs. 0-1) and the number of previous therapies (1-3 vs. 4).
Independent review committee-assessed PFS served as the primary endpoint. If noninferiority was met, researchers would test superiority of acalabrutinib on secondary endpoints hierarchically in the following order: any-grade atrial fibrillation, incidence of grade 3 or greater infection, incidence of Richter transformation and OS. If noninferiority on the primary endpoint was not met, or superiority on a secondary endpoint was not met, the P values for all subsequent endpoints would be presented descriptively, Byrd said.
Median follow-up was 40.9 months (range, 0-59.1), with a data cutoff date of Sept. 15, 2020.
At median follow-up, acalabrutinib demonstrated noninferiority to ibrutinib with regard to PFS (median, 38.4 months in both groups; HR = 1; 95%, CI, 0.79-1.27), with comparable results across prespecified subgroups.
However, any-grade atrial fibrillation incidence was significantly lower with acalabrutinib vs. ibrutinib (9.4% vs. 16%; P = .02).
“I was a bit surprised that atrial fibrillation was so high even in the acalabrutinib arm, although it had a different pattern, including late development vs. earlier in the ibrutinib arm,” Byrd told Healio.
Incidence of other secondary endpoints appeared comparable, including grade 3 or greater infection (30.8% vs. 30%) and Richter transformation (3.8% vs. 4.9%).
The acalabrutinib and ibrutinib groups had similar rates of any-grade adverse events (97.7% vs. 93.3%), but the acalabrutinib group had numerically fewer grade 3 or greater adverse events (n = 183 vs. 197), adverse events leading to treatment discontinuation (n = 39 vs. 56), serious adverse events (n = 143 vs. 154) and deaths due to adverse events (17 vs. 25).
Among the most common adverse events, the acalabrutinib group demonstrated lower incidence of arthralgia (any grade, 15.8% vs, 22.8%; grade 3, 0% vs. 0.8%) and diarrhea (any grade, 34.6% vs. 46%; grade 3; 1.1% vs. 4.9%), but a higher incidence of headache (any grade, 34.6% vs. 20.2%; grade 3, 1.5% vs. 0%) and cough (any grade, 28.9% vs. 21.3%; grade 3, 0.8 vs. 0.4).
Researchers observed fewer adverse events of clinical interest in the acalabrutinib group, including cardiac events (any grade, 24.1% vs. 30%; grade 3, 8.6% vs. 9.5%), hypertension (any grade, 9.4% vs. 23.2%; grade 3, 4.1% vs. 9.1%) and major bleeding events (any grade, 4.5% vs. 5.3%; grade 3, 3.8% vs. 4.6%).
Median OS was not reached in either group, with an HR favoring acalabrutinib (HR = 0.82; 95% CI 0.59–1.15). Sixty-three deaths occurred in the acalabrutinib group compared with 73 in the ibrutinib group.
“This study shows acalabrutinib is safer than ibrutinib and has similar therapeutic efficacy,” Byrd said. “Given similar efficacy and improved safety of acalabrutinib, even more justification can be directed toward using this agent as the BTK inhibitor of choice for [patients with CLL] requiring therapy.”
In terms of future research, Byrd said efforts should try to improve the formulation of acalabrutinib so it can be used with proton pump inhibitors.
“The need to omit these with acalabrutinib therapy can be problematic for some,” he said. “In addition, the entire field, including myself, is interested in strategies to get [patients with CLL] off therapy with new combination-based therapies.”
Perspective
Back to Top
Andrew Gillis-Smith, MD
This report by Byrd and colleagues is very helpful to physicians who treat CLL, who until now have relied on indirect comparisons to inform decisions as to which BTK inhibitor would be best for a given patient. Reassuringly, PFS with acalabrutinib was noninferior to that of ibrutinib; clinicians can now choose between these two agents based on considerations of safety, comorbidities and dosing schedule. Acalabrutinib is more selective for BTK than ibrutinib, thus leading to the differences in adverse event profiles.
Overall, this trial demonstrates that treatment with acalabrutinib achieves comparable outcomes but with fewer adverse events than ibrutinib, arguably making acalabrutinib the preferred choice for most patients. Ibrutinib may still be preferable for patients who prefer daily dosing, require concomitant proton pump inhibitor therapy, or value its longer follow-up data and clinical experience.
Median PFS was only 38.4 months with both agents, demonstrating that further strategies are needed to improve the outcomes of patients with high-risk CLL. Indeed, combinations of BTK and BCL2, with or without an anti-CD20 antibody, have yielded promising results. Given its more favorable safety profile, acalabrutinib may prove to be a better fit in combination therapies.
Collapse
Byrd JC, et al. Abstract 7500. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
Click Here to Manage Email Alerts