ASH 2025 | Pirtobrutinib versus ibrutinib in treatment-naïve and R/R CLL: findings from BRUIN-CLL-314

At ASH this year, we presented results from this BRUIN-CLL314 study, and this is a head-to-head randomized Phase III trial of the non-covalent BTK inhibitor pirtobrutinib compared with the covalent BTK inhibitor ibrutinib in patients with treatment-naive and relapsed/refractory CLL. So this study is the first clinical trial to directly compare a non-covalent to a covalent BTK inhibitor, and the first head-to-head comparison of any BTK inhibitors in the frontline setting. So in this study, patients with either treatment-naive or relapsed/refractory disease were randomized one-to-one to these two medications, which were both continued until disease progression. The primary objective of the study was looking at overall response rate and specifically non-inferiority of response of pirtobrutinib as compared with ibrutinib. Key secondary objectives were looking at response rate superiority in different subgroups, as well as progression-free survival in the entire intention to treat or ITT patient population, as well as in those with relapsed/refractory disease. And exploratory objectives were to look at outcomes in patients with treatment-naive CLL. So at this point, we are presenting the final results of the overall response rate analysis, so the primary objective, and some descriptive initial results of progression-free survival. So we saw that, in fact, pirtobrutinib was non-inferior to ibrutinib in the entire intention-to-treat patient population and actually was superior to ibrutinib across the entire cohort and in patients with both treatment-naive and relapsed/refractory CLL. When looking at progression-free survival, again, kind of an early look, we see a trend toward improvement of pirtobrutinib as compared with ibrutinib in the entire patient population in relapsed/refractory CLL, and actually most strikingly in patients with treatment-naive disease. And we also looked at the safety profile of the two drugs. Importantly, there were really very few drug discontinuations in either arm. The number of dose delays or dose reductions was significantly higher with ibrutinib as compared with pirtobrutinib, kind of underscoring the safety profile of pirtobrutinib, and especially when compared with the older BTK inhibitor ibrutinib. Specifically, cardiac toxicity, hypertension, and atrial fibrillation were much lower with pirtobrutinib as compared with ibrutinib. So overall, these data are showing us, again, response rate superiority and trend toward an improvement in progression-free survival for pirtobrutinib as compared with ibrutinib in all patients and specifically both relapsed/refractory and treatment-naive CLL.

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