Acalabrutinib Shows Noninferior PFS, Less Atrial Fibrillation Versus Ibrutinib in High-Risk CLL

The second-generation BTK inhibitor acalabrutinib (Calquence) demonstrated noninferiority with regard to progression-free survival (PFS) and a significantly lower incidence of atrial fibrillation compared with ibrutinib (Imbruvica) in previously treated patients with high-risk chronic lymphocytic leukemia (CLL), meeting the primary and secondary end points of the phase 3 ELEVATE-RR trial (NCT02477696).¹

No difference for grade 3 or higher infections or Richter’s transformation was demonstrated by additional hierarchical testing. Investigators also noted a descriptive trend for numerically favorable overall survival (OS).

Regarding safety, the data with acalabrutinib was found to be consistent with what has previously been reported with the agent.

Further findings will be shared with health authorities and presented at an upcoming medical conference, according to AstraZeneca.

“With over 40 months of follow-up, today’s results confirm that [acalabrutinib], a selective BTK inhibitor, displays superior safety in atrial fibrillation without compromising efficacy,” José Baselga, executive vice president of Oncology R&D of AstraZeneca, stated in a press release. “The totality of the data confirm our confidence in the favorable benefit-risk profile of [acalabrutinib].”

For the phase 3 trial, investigators set out to evaluate PFS benefit with acalabrutinib versus ibrutinib in previously treated patients with high-risk CLL.² Notably, ELEVATE-RR is the first phase 3 trial to compare 2 BTK inhibitors in patients with CLL.

To be eligible for enrollment, patients had to be at least 18 years of age, have CLL, have an ECOG performance status of 0-2, and have at least 1 high-risk prognostic factor, such as the presence of del(17p) or del(11q). Moreover, they had to have active disease, have received at least 1 previous therapy for CLL, and meet all of the laboratory parameter criteria for the trial.

If patients had known central nervous system lymphoma or leukemia, prolymphocytic leukemia or a history of Richter’s syndrome, uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura, they could not participate. Additionally, if patients were previously exposed to ibrutinib or a BCR or BCL-2 inhibitor; received any chemotherapy, external beam radiotherapy, anticancer antibodies, or an investigational drug within 30 days before the administration of the study drug; or had previously undergone an allogeneic or autologous transplant, they were excluded from the research.

In the trial, a total of 533 patients were randomized 1:1 to receive oral acalabrutinib at a twice-daily dose of 100 mg versus oral ibrutinib at a once-daily dose of 420 mg. Treatment was given until either progressive disease or intolerable toxicity.

The primary end point of the trial was PFS per independent review committee assessment and noninferiority was evaluated after 250 events were reported. Key secondary end points included incidence of atrial fibrillation, incidence of treatment-emergent infections that were grade 3 or higher in severity, incidence of Richter’s transformation, and OS.

References

1. CALQUENCE met primary efficacy endpoint in head-to-head trial against ibrutinib in chronic lymphocytic leukemia. News release. AstraZeneca. January 25, 2021. Accessed January 26, 2021. http://bit.ly/3ooJ7hE.
2. Study of acalabrutinib (ACP-196) versus ibrutinib in previously treated subjects with high risk CLL. ClinicalTrials.gov. Updated December 5, 2019. Accessed January 26, 2021. https://www.clinicaltrials.gov/ct2/show/NCT02477696.