First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukaemia

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Published: 21 Jun 2021
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Dr John Byrd - The Ohio State University, Columbus, USA

Dr John Byrd speaks to ecancer about the first results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukaemia. Initially, he explains the rationale of the study.

Dr Byrd then talks about the methodology and results of this study. In this first head-to-head trial of bruton tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated non-inferior progression-free survival with less cardiotoxicity and fewer discontinuations due to AEs vs Ib.

In the end, he mentions the impact these results can have on the future treatment of CLL.

The rationale of the ELEVATE relapsed/refractory study was to compare a first generation BTK inhibitor that was very, very impactful in terms of improving CLL outcome but which had adverse events that occur from alternative targets that ibrutinib hits and comparing this to a more selective BTK inhibitor that hits less targets irreversibly and is also showing efficacy in CLL and that drug would be acalabrutinib. This study was an equivalence study to show that acalabrutinib was at least as good as ibrutinib. Often studies that look at equivalence look for another advantage to the new drug and specifically this study targeted adverse events that had been fairly significant with ibrutinib, such as atrial fibrillation and hypertension.

What was the methodology of the study?

This was a randomised phase III study. It was not blinded so the doctors and the patients knew what therapy they received. The patients came from a high risk group with deletion 17p and 11q in relapsed disease. The patients were not eligible if they had received a BCL-2 inhibitor or another B-cell receptor signalling agent, so it was a representative population of CLL patients. The study’s primary endpoint was IRC progression free survival.

What were the key findings?

The key findings with the absolute refractory ELEVATE study were that acalabrutinib was equivalent to ibrutinib with a hazard ratio of 1.0. Because equivalence was shown we were able to go on and look at other endpoints in a predetermined way. One was atrial fibrillation which was significantly higher with ibrutinib as compared to acalabrutinib. Other secondary endpoints overall survival, infections and Richter’s transformation were similar although overall survival favoured acalabrutinib with a hazard ratio of 0.82 although it overlapped with 1.0.

What was notable as well was that in addition to atrial fibrillation and atrial flutter there were many more adverse events on the ibrutinib arm that required patients to go off therapy as compared to acalabrutinib. The frequency of grade 3 or greater hypertension, pneumonitis, diarrhoea, bruising, all were more common with ibrutinib than acalabrutinib. Really the only adverse event that was seen more with acalabrutinib was headache and cough. The cough often would follow upper respiratory tract infections.

So what we’ve learned from this study is that a second generation BTK inhibitor, acalabrutinib, is at least as good as ibrutinib, as I said, survival was favourable, and it’s much better tolerated by patients. This enables potentially better combination approaches for CLL patients with this second generation molecule.

How can these results impact the future treatment of CLL?

The fact that a second generation BTK inhibitor in this study was shown to be as good provides evidence that in other settings of CLL, the upfront setting, patients with low risk disease who relapse, that this might be a better choice, particularly for patients who have cardiac problems, hypertension, a history of atrial fibrillation. I would say as well, though, that ibrutinib is still appropriate for some patients or zanubrutinib, another second generation BTK inhibitor, particularly patients who require protein pump inhibitors where acalabrutinib is problematic to give because of its absorption.

These types of studies are really ,really important. They’re a win-win for the patients, everybody that participated in this study in terms of the patients receiving great therapy but they also help the field move forward. Investigators are very grateful to the patients and their families that supported them during their participation on the study.