Acalabrutinib as Frontline Therapy for CLL

William Wierda, MD, PhD: Let’s talk about second-generation and subsequent-generation BTK [Bruton tyrosine kinase] inhibitors. Ibrutinib [Imbruvica], first generation. We have a second generation which is acalabrutinib [Calquence®], also an irreversible inhibitor or BTK. Callie, can you introduce us to the drug and some of the features of acalabrutinib, which differentiates it from ibrutinib, and are particular factors that we think about before we start a patient on acalabrutinib?

Catherine Callaghan Coombs, MD: Sure. Acalabrutinib is a second-generation BTK inhibitor, also irreversible. Some of the main distinguishing features about it are that number 1, it is a bit more selective for BTK and appears to have less off-target activity. And that potentially gives it a better adverse effect profile. Some of the other distinguishing features are that it is given as a twice daily [BID] drug, and one of the reasons that I may not use it is if a patient needs a PPI [proton pump inhibitor], given that concurrent PPI use can affect absorption. We saw a few updates on acala [acalabrutinib] data in this past year, and one of them that was important is, of course, we finally saw the head-to-head data with ibrutinib in the relapsed setting. And so that was presented at ASCO [American Society of Clinical Oncology annual meeting] in 2021 and was published in JCO [Journal of Clinical Oncology].

It’s great to see head-to-head data on these 2 drugs, and what we can see is that acalabrutinib has a lower rate of all-grade atrial fibrillation when compared to ibrutinib. The acala [acalabrutinib] rate was 9% and ibrutinib was around 15%. The other advantage of acala [acalabrutinib], as far as adverse effect profile, is that it has lower rates of hypertension which of course is a particularly bothersome adverse effect of these drugs as a class, but the rate seems lower. Then there’s also some improvement in other low-grade toxicities, such as these myalgias and arthralgias that have already been mentioned. Acala [acalbrutinib] does have 1 kind of unique adverse effect that’s more commonly seen than ibrutinib [and] that’s specifically headaches. Fortunately, headaches don’t appear to be a longstanding issue. Usually, they occur early on over the patient’s treatment in the first month or 2 and often resolve with caffeine.

The other data that we saw at ASH [American Society of Hematology annual meeting] was some longer-term follow-up from the ASCEND trial. This trial you may remember was our first novel agent to novel agent comparator. One arm, this again was a relapsed trial, 1 arm was acalabrutinib monotherapy and then the other arm was the investigator’s choice of either idelalisib [Zydelig®] with rituximab [Rituxan®] or bendamustine [Treanda®] and rituximab. The oral presentation discussed now we have 3 years of follow-up on this trial, and we see continued improvement in the progression-free survival [PFS] rate of acala [acalabrutinib] compared to that investigator choice regimen, which was mostly the idela [idelalisib]. Though there were some patients that got BR [bendamustine, rituximab], but those were the minority. Interestingly, the response rates are similar, and all these agents are active, but the big difference is that the toxicity and the rates of discontinuation appear quite a bit higher for the idela [idelalisib]-treated patients. The PFS with more follow-up now out at 3 years continues to favor acalabrutinib in this study.

Transcript edited for clarity.