Acalabrutinib, a second-generation Bruton’s Tyrosine Kinase (BTK) inhibitor, was engineered to maximize its effect on BTK and minimize off-target activity on other kinases.

The first-generation BTK inhibitor, Ibrutinib (Imbruvica®), lacks this specificity, which appears to result in a higher incidence of adverse effects.

The chart to the left (above on mobile) shows that ibrutinib inhibits more kinases (proteins) on the cancer cell, and to a greater extent than acalabrutinib. Researchers believe that the lack of specificity of ibrutinib is responsible for many of the adverse effects or toxicities.

We know that in-vitro (outside the human body), acalabrutinib has greater selectivity for BTK than ibrutinib. This improved selectivity for BTK may result in an enhanced safety profile vs. ibrutinib. A head-to-head study of these two drugs under the same conditions is needed to show superior safety for acalabrutinib definitively. The randomized Phase III ACE-CL-006 clinical trial design includes comparisons of efficacy and the safety profiles of acalabrutinib vs. ibrutinib. This clinical trial will be available at 162 sites, making acalabrutinib and ibrutinib more available to more patients. Sites enrolled in ACE-CL-006 are in the U.S, Australia, Belgium, Denmark, France, Germany, Hungary, Isreal, Italy, Netherlands, New Zealand, Poland, Spain, Turkey, and the United Kingdom.

The investigator assessment of cardiac adverse events looked at:
• the incidence, seriousness, severity, and the relationship to acalabrutinib,
• time to onset of adverse event and duration,
• event management and resolution (for Grade 3 or higher cardiac adverse events), and
• incidence of adverse events within the first six months of treatment.

For hypertension events, investigators assessed the incidence rate and time of onset.

Investigators used past medical histories to determine the cardiovascular and hypertension risk of future events.

Also, investigators’ analysis of cardiovascular events includes looking at the time of onset of cardiac events, event duration, and resolution for Grade 3 or higher toxicities.

One hundred twenty-nine (129) patients (17%) experienced a cardiac adverse event (CAE) of any grade. Ninety-one (91) percent of patients who showed acalabrutinib-related cardiac adverse events had one or more cardiovascular risk factors before starting acalabrutinib, including 67% with pre-existing high blood pressure, 29% with pre-existing high cholesterol or triglycerides, and 22% with cardiac arrhythmias.

The table above (left on desktop) explains the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). This grading classifies adverse events both in treatment and research. Standard definitions are critical to evaluating safety data across institutions or when more than one investigator participates in a clinical trial.

We look forward to the results of ACE-CL-006 to better understand the differences in efficacy and safety when comparing the first-generation BTK inhibitor ibrutinib with the newer second-generation acalabrutinib.