LBA3, which was BRUIN CLL-313, was a phase III study of pirtobrutinib versus bendamustine/rituximab in patients with newly-diagnosed CLL/SLL. The study looked to evaluate the efficacy of the third-generation BTK inhibitor pirtobrutinib. This agent is a non-covalent BTK inhibitor which differs from the other two generations of BTK inhibitors which are covalent drugs, speaking of ibrutinib, acalabrutinib and zanubrutinib. Pirtobrutinib has been evaluated in the relapsed/refractory setting showing efficacy and safety in a CLL/SLL patient population and several studies have been evaluating this agent in earlier lines of therapy due to the perceived improved safety benefit of pirtobrutinib over some of the earlier generation BTK inhibitors.
In CLL-313 again these patients were randomised to either pirtobrutinib or bendamustine/rituximab. The study met its primary endpoint, delivering an improvement in progression free survival, 93.4% versus 70.7%, for pirtobrutinib with a trend towards overall survival but not yet reaching any statistically significant difference in overall survival.
Consistent with what we see in other situations, pirtobrutinib had a very appreciable safety benefit with fewer grade 3 or higher treatment-emergent adverse events, lower rates of neutropenia infection compared to bendamustine/rituximab. Duration of response also favoured pirtobrutinib, consistent with what we see with the progression free survival.
What does this mean for an overall patient population? It’s hard to say for sure. In some situations this fits with the theme that we’ve seen with all of the approved BTK inhibitors in front-line CLL in that most of them have shown a benefit over chemoimmunotherapy in most situations. The question we have to have in the context of where to place pirtobrutinib is how does it compare to the other covalent BTK inhibitors? The use of ibrutinib, which is a first-generation covalent BTK inhibitor, has been decreasing due to increased toxicity compared to some of the newer generation medications but with acalabrutinib and zanubrutinib now having an approval in CLL the question is would you place pirtobrutinib above these two agents? It’s tough to say at this point because while we know pirtobrutinib will work after patients have been exposed to a covalent BTK inhibitor, we don’t necessarily know if the inverse is the same. So if we start a patient with pirtobrutinib we don’t know if we will still get benefit with acalabrutinib or zanubrutinib. So pirtobrutinib maybe if it’s in the first-line setting may be the only drug in its class that we can use before moving to other treatment lines or other treatment modalities which would limit the amount of treatment options for patients with CLL.
So I do know there are ongoing front-line studies comparing pirtobrutinib to the second-generation BTK inhibitors. In the end it will be important to see how these studies read out. Additionally, it will be important to figure out if we can sequence these other covalent BTK inhibitors after pirtobrutinib if we are to move pirtobrutinib into the front-line setting.
