This was the first phase III trial to directly compare a covalent BTK inhibitor, in this case ibrutinib, with a non-covalent BTK inhibitor, in this case pirtobrutinib. This study was conducted in patients with either treatment-naïve or relapsed/refractory CLL who had not previously been exposed to a BTK inhibitor.
What was the study design?
This is a randomised trial in which patients were randomised 1:1 to receive either pirtobrutinib or ibrutinib. Both were continued until disease progression and patients were stratified by lines of prior therapy and presence or absence of TP53 abnormalities.
What were the key results?
What we’re presenting at ASH this year is the final results of the overall response rate, which is the primary endpoint of the study. The study was initially designed to detect non-inferiority of pirtobrutinib compared with ibrutinib in the intention to treat population which was both treatment naïve and relapsed/refractory. Pirtobrutinib was indeed non-inferior, and in fact superior, to ibrutinib in overall response rate. This was across the entire patient cohort, including both patients with treatment naïve and relapsed/refractory CLL.
The progression free survival is still a little bit immature at this time but trends towards an improvement in progression free survival for pirtobrutinib compared with ibrutinib. Most strikingly, this is actually seen in the treatment naïve patient population where we’re seeing a very significant trend towards improvement in PFS with pirtobrutinib compared with ibrutinib. Importantly, we also saw that pirtobrutinib was safer than ibrutinib, this is expected based upon prior studies.
Interestingly, the rates of discontinuation were pretty equivalent between the two arms but the rates of dose reduction were much higher for patients on ibrutinib compared to pirtobrutinib. The rates of most adverse events were lower with pirtobrutinib, especially the adverse events of special interest that we think about with BTK inhibitors – significantly atrial fibrillation was quite a bit lower with pirtobrutinib compared with ibrutinib.
What is the clinical significance of these results?
This is a very important clinical trial in CLL and it suggests that for some patients pirtobrutinib might be a better option than a covalent BTK inhibitor as their first BTK inhibitor. Significantly, with the data we’re seeing in treatment naïve CLL, especially where at this ASH we’re also seeing a frontline study of pirtobrutinib being presented, it suggests that for some patients with CLL, in my opinion specifically those that are older and potentially frailer, more frail, that they may benefit from a very safe and effective drug like pirtobrutinib as their frontline treatment as opposed to other CLL therapies that are currently available.
