Acalabrutinib Shows Better Exposure-Adjusted Tolerability in R/R CLL


John F. Seymour, MBBS, PhD, discusses the results of a post-hoc analysis of adverse events in the phase 3 ELEVATE-RR trial comparing acalabrutinib and ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.

John F. Seymour, M​BBS, PhD, director of the integrated hematology department, clinical hematologist, and associate director of clinical research at Peter MacCallum Cancer Centre and the Royal Melbourne Hospital in Victoria, Australia, discusses the results of a post-hoc analysis of adverse events (AEs) in the phase 3 ELEVATE-RR trial (NCT02477696) comparing acalabrutinib (Calquence) and ibrutinib (Imbruvica) in patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL).

Seymour explains that the analysis accounted for the overall toxicity burden of each Bruton tyrosine kinase (BTK) inhibitor by examining exposure-adjusted incidence rates. The median treatment exposures were 38.3 months for patients who received acalabrutinib and 35.5 months for those who received ibrutinib.

For cardiovascular toxicities, the rate of AEs in the trial was 24% with acalabrutinib and 30% with ibrutinib, but the exposure-adjusted time of patients experiencing these events was 7.1 months per 100 patient-months with acalabrutinib versus 13.0 months with ibrutinib. Those with ibrutinib had an even higher exposure-adjusted time with atrial fibrillation and hypertension of 3.8 months and 15.0 months, respectively, versus 1.3 months and 4.1 months with acalabrutinib.

Several other AEs such as diarrhea, arthralgias, back pain, muscle spasm, and dyspepsia showed greater exposure-adjusted time with ibrutinib. While muscle spasms occurred about twice as frequently (13% with ibrutinib versus 6% with acalabrutinib), exposure-adjusted time was over 10 times as much: 10 months with ibrutinib versus only 0.8 months with acalabrutinib.

The only AEs where ibrutinib was better tolerated in the analysis were headache and cough; these were higher with acalabrutinib in both the initial incidence rate and the exposure-adjusted time.


0:08 | In general, the exposure-adjusted time with events for these cardiovascular toxicities were, on average, 2- to 4-fold higher with the ibrutinib than with acalabrutinib, particularly for hypertension and atrial fibrillation. And this was regardless of the age of the patient or the number of prior therapies, as well as in patients without a prior history of these events.

0:40 | Some of the other generally lower-grade AEs such as diarrhea, arthralgias, back pain, muscle spasm, dyspepsia, for example, were 1.4- to 13-fold higher in their exposure-adjusted incidence in exposure-adjusted time with these events with ibrutinib compared [with] acalabrutinib, and I think the muscle [spasm] is probably the one that best illustrates the utility of this method of analysis. The overall incidence was 6% versus 13%, the higher rate with ibrutinib. That is moderately different. Yet, if we factor in the time with these events, that was actually 0.8 with ibrutinib per 100 patient months of treatment. An average of an expectation of less than 1 per 100 months of treatment versus 10.0 with ibrutinib, we have roughly 10% of the time that typical patient would be expected to have some of that toxicity. So that illustrates the greater precision that we get by factoring in this exposure adjustment.

1:59 | There were 2 toxicities with this adjustment that were more frequent, and with a greater time with acalabrutinib. They were headache and cough that had a 1.1- to 1.6-fold higher exposure-adjusted incidence then with ibrutinib.

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