Final results from the head-to-head ELEVATE-RR Phase III trial of acalabrutinib demonstrated non-inferior progression-free survival (PFS) and statistically significantly fewer events of atrial fibrillation versus ibrutinib in adults with previously treated chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults.

Separately, updated results at four years of follow-up from the ELEVATE-TN Phase III trial continued to show a strong PFS benefit for acalabrutinib as combination therapy or as monotherapy in previously untreated patients with CLL.

Because increased selectivity of the Bruton tyrosine kinase (BTK) inhibitor may improve treatment tolerability, the study team conducted an open-label, randomized, noninferiority, phase 3 trial to compare acalabrutinib vs ibrutinib in patients patients with CLL.

At a median follow-up of 40.9 months, the ELEVATE-RR trial met its primary endpoint of PFS non-inferiority versus ibrutinib with a median PFS of 38.4 months in both arms (based on a hazard ratio [HR] of 1.0, 95% confidence interval [CI] 0.79-1.27). Patients treated with acalabrutinib had a statistically significantly lower incidence of all-grade atrial fibrillation compared with patients treated with ibrutinib (9.4% versus 16.0%), a key secondary endpoint. Atrial fibrillation is an irregular heart rate that can increase the risk of stroke, heart failure and other heart-related complications.

John C. Byrd, MD, Distinguished University Professor, The Ohio State University, and lead investigator of the ELEVATE-RR trial, said: “Cardiac adverse events are an important consideration for treating chronic lymphocytic leukemia patients with Bruton’s tyrosine kinase inhibitors because they can produce significant morbidity in some cases and also lead patients to discontinue treatment. These data provide compelling evidence that acalabrutinib is a more tolerable option with reduced cardiovascular toxicity and overall fewer discontinuations due to adverse events, giving clinicians further reassurance when prescribing this medicine that patients can stay on treatment while maintaining ongoing control of their disease.”

The results of both trials were presented during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting on June 7, 2021.

ELEVATE-RR (ACE-CL-006) ELEVATE-RR is the first Phase III trial to compare two BTK inhibitors in patients with previously treated CLL with presence of 17p deletion or presence of 11q deletion. The trial met the non-inferiority endpoint for PFS defined by the trial for acalabrutinib (n=268) versus ibrutinib (n=265) in patients with previously treated CLL with certain high-risk prognostic factors.

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Patients treated with acalabrutinib had statistically significantly lower incidence of all-grade atrial fibrillation, a key secondary endpoint, compared with patients treated with ibrutinib (9.4% [n=25/266] versus 16.0% [n=42/263]; p=0.02). A lower frequency of adverse events (AEs) was observed with acalabrutinib versus ibrutinib including lower common AEs, Grade 3 or higher AEs, serious AEs, treatment discontinuations due to AEs and overall cardiac events. The safety and tolerability of acalabrutinib in ELEVATE-RR was consistent with the known profile of acalabrutinib .

Adverse events led to treatment discontinuation in 14.7% of patients on acalabrutinib and 21.3% of patients on ibrutinib. AEs of clinical interest for acalabrutinib versus ibrutinib included cardiac events (all grade, 24.1%, and 30.0%, respectively), bleeding events (all grade, 38.0% and 51.3%, respectively), hypertension (all grade, 9.4% and 23.2%, respectively), infections (all grade, 78.2% and 81.4%, respectively), interstitial lung disease/pneumonitis (all grade, 2.6% and 6.5%, respectively) and second primary malignancies excluding non-melanoma skin cancer (all-grade, 9.0% and 7.6%, respectively). Serious AEs (any grade) occurred in 53.8% of patients on acalabrutinib versus 58.6% of patients receiving ibrutinib.

Median overall survival (OS) was not reached in either arm, with 63 (23.5%) patients in the acalabrutinib arm and 73 (27.5%) patients in the ibrutinib arm experiencing an event (HR of 0.82, 95% CI 0.59-1.15).

ELEVATE-TN: Four-Year Follow-Up in Untreated CLL

ELEVATE-TN, a randomized, multicenter, open-label Phase III trial, evaluated the safety and efficacy of acalabrutinib in combination with obinutuzumab or alone versus chlorambucil in combination with obinutuzumab in previously untreated patients with CLL. The trial met its primary endpoint (IRC-assessed PFS with acalabrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab) at the data cut-off for the interim analysis after a median follow-up of 28.3 months.

After a median follow-up of 46.9 months, the ELEVATE-TN Phase III trial showed acalabrutinib plus obinutuzumab reduced the risk of disease progression or death by 90% (HR 0.10, 95% CI 0.07-0.17) and as a monotherapy by 81% (HR 0.19, 95% CI 0.13-0.28) compared with chlorambucil plus obinutuzumab. Estimated PFS rates at 48 months for acalabrutinib plus obinutuzumab or as monotherapy were 87% and 78%, respectively, versus 25% for chlorambucil plus obinutuzumab. PFS findings were consistent across high-risk subgroups. Median PFS was not yet reached for either acalabrutinib arm at four years of follow up. Median OS was not reached in any treatment arm with a trend toward significance in the acalabrutinib plus obinutuzumab group (p=0.0604).