Toxicity Burden Decreased With Acalabrutinib Vs Ibrutinib in CLL

John F. Seymour, AM

Acalabrutinib (Calquence) demonstrated a lower incidence of cardiovascular-related toxicities and a lower overall toxicity burden compared with ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL), according to the results of a post-hoc analysis of the phase 3 ELEVATE-RR study (NCT02477696) that were presented during the 2021 ASH Annual Meeting and Exposition.1

This analysis aimed to further evaluate Bruton tyrosine kinase (BTK) inhibitor–associated adverse events (AEs) and the toxicity profile of ibrutinib and acalabrutinib in the multicenter, open-label study. This trial demonstrated noninferiority and tolerable safety after randomizing previously treated patients with CLL 1:1 to acalabrutinib at 100 mg by mouth twice daily or ibrutinib at 420 mg by mouth once daily.2

The primary end point of ELEVATE-RR was noninferiority by independent review committee–assessed progression-free survival, and secondary end points included incidence of any-grade atrial fibrillation (afib)/flutter, grade 3 or higher infection, Richter transformation, and overall survival.

“Event-based analyses demonstrated a higher BTK inhibitor­–related toxicity burden with ibrutinib in this head-to-head trial,” John F. Seymour, AM, from the Peter MacCallum Centre and the Royal Melbourne Hospital in Melbourne, Australia, said in his presentation. “Exposure-adjusted assessments of afib/flutter, hypertension, and bleeding events demonstrated a lower cardiovascular-related toxicity burden with acalabrutinib compared to ibrutinib. Cumulative incidences of hypertension and afib/flutter were also lower with acalabrutinib in patients without a prior history of these events.”

After a median follow-up of 41 months, investigators assessed events of clinical interest in 268 patients receiving acalabrutinib and 265 patients receiving ibrutinib. Of these events, any-grade afib/flutter, hypertension, and bleeding were statistically higher with ibrutinib. Exposure-adjusted incidence and exposure-adjusted time with these events were about 1.5 to 4.1 times higher with ibrutinib.

Other common BTK–related AEs noted for being significantly higher with ibrutinib in this analysis were any-grade diarrhea (46% vs 35%), arthralgia (23% vs 16%), back pain (13% vs 8%), muscle spasms (13% vs 6%), and dyspnea (12% vs 4%). Incidence of any-grade contusion and urinary tract infection (UTI) were also higher with ibrutinib. Besides UTI, exposure-adjusted incidence and exposure-adjusted time with events were about 1.4 to 13.1 times higher with ibrutinib.

The only AEs with statistically higher incidence with acalabrutinib were any-grade headache and cough, which occurred at rates of 35% and 29%, respectively, with acalabrutinib versus 20% and 21% with ibrutinib. Headache with acalabrutinib was associated with 1.6 times higher exposure-adjusted incidence and exposure-adjusted time with events, and cough was associated with 1.2 times higher exposure-adjusted incidence and exposure-adjusted time with events.

Investigators observed a longer median time to onset of any-grade afib/flutter with acalabrutinib versus ibrutinib, at 28.8 months and 16.0 months, respectively. Any-grade hypertension had a similar median time to onset for both therapies. Concomitant medication use for afib/flutter or hypertension for all patients was less common with acalabrutinib.

The cumulative incidence of any-grade afib/flutter and hypertension were consistently lower with acalabrutinib up to 36 months, according to Seymour. Additionally, incidence of these 2 AEs was lower in patient subgroups regardless of the number of prior therapies, age, and having no prior history of afib/flutter and hypertension. For patients with no prior history of afib/flutter or hypertension, there was a lower cumulative incidence in patients receiving acalabrutinib compared with ibrutinib (afib/flutter HR, 0.37; 95% CI, 0.20-0.67; hypertension HR, 0.23; 95% CI, 0.11-0.48).

With any-grade bleeding events, there was a similar time to onset for acalabrutinib and ibrutinib. Incidence was lower for the acalabrutinib arm regardless of age and in patients with 1 to 3 prior lines of therapy. Few patients in either treatment arm required dose modification due to bleeding events. Also, fewer patients given acalabrutinib used concomitant medication for bleeding events than patients given ibrutinib. The cumulative incidence of any-grade bleeding over 36 months was lower with acalabrutinib.

At the data cutoff, 43% of patients on the ELEVATE-RR trial were still receiving treatment. Patients on ELEVATE-RR had previously been treated for CLL with 1 or more prior lines of therapy, presence of deletion 17p and/or 11q, and an ECOG performance status of 2 or less. Those enrolled were stratified by their deletion 17p status, ECOG performance status, and number of prior therapies.

References

1. Seymour JF, Byrd JC, Hillmen P, et al. Characterization of Bruton tyrosine kinase inhibitor (BTKi)-related adverse events in a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia (CLL). Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 3721.
2. 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. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210