ASH 2025 | BRUIN CLL-313 results: pirtobrutinib versus BR in patients with treatment-naive CLL/SLL

Thank you for this question, but perhaps first I will say that ASH 2025 is extremely good for pirtobrutinib and for non-covalent BTK inhibitors. In fact, we are presenting two studies with pirtobrutinib in early CLL, which means either entirely in treatment-naive as in a randomized comparison of BRUIN-313 study which is pirtrobrutinib versus BR or a study where a good proportion is treatment-naive but we also include a relapsed and refractory and this was a randomized comparison of pirtobrutinib versus ibrutinib. What is important is that in both studies we reach the primary targets. Both studies are positive. In both studies, progression-free survival is significantly better than the comparator arm. 

Perhaps I will start with bendamustine-rituximab comparison. Nobody uses bendamustine-rituximab nowadays, but at the time we started the protocol, it was one possible standard of care. Now, bendamustine-rituximab arm did equally well as in other comparisons, like with ibrutinib and with zanubrutinib. Now, what we achieved, we achieved an ultimate victory with a hazard ratio of 0.19, which means that it’s a reduction of progression or mortality by 80%. And that’s jolly good, because if we look at the similar comparisons with Ibrutinib or Zanubrutinib, the hazard ratio is anything between 0.35 and 0.40. 

More to it, in a secondary analysis, or a secondary endpoint, was overall survival. And although, for whatever the reasons, the statistician claimed the data to be immature, after the average observation time of 28 months, we have a significant difference with p less than whatever and it’s very likely that it will hold, and this overall survival difference where we had 98 versus 93 people alive for two years was despite the crossover. We allowed for the crossover and out of 34 patients who relapsed, 18, which means 54%, were actually subjected to pirtobrutinib in a second line. Despite that, overall survival difference is significant. Now talking more about progression-free survival, it’s the progression, the median progression-free survival in pirtobrutinib is not met. The median progression-free survival of BR is 34 months. Now at two years, we have 94% versus 70%, which is jolly good. Toxicity? What is toxicity? We didn’t observe it. But being more serious, pirtobrutinib was extremely well tolerated with grade 3 CTCA in less than a few patients. The toxicity we demonstrated in a time-adjusted manner, as the average time of pirtobrutinib therapy was much longer than the time-limited BR. And in fact, we could say that in all analyzed adverse events or treatment-emergent adverse events, pirtobrutinib was better except for the bleeding tendency which was mild, with just one patient having a CTCAE grade 3 event. If you’re looking at infections, indeed COVID infections were the most common adverse event of pirtobrutinib. However, we didn’t observe a lot of fatal outcomes. Literally, we lost one patient due to infections in the pirtobrutinib arm and four patients in BR. 

Therefore, we can conclude that it’s definitely deserving to be approved in earlier therapy lines although none of us believes that it will become a standard of care for the majority of patients, as nowadays we are more concentrated on fixed-duration regimens combining BTK inhibitors with anti-CD20s or BTK inhibitors with BCL2 inhibitors or BCL2 inhibitors with anti-CD20s.

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