EHA 2023 | BRUIN study update: analysis of the mechanisms of resistance to pirtobrutinib in CLL

So the Phase I/II BRUIN study is a very large study of pirtobrutinib which is a non-covalent BTK inhibitor and a novel mechanism of BTK inhibition that potentially works in patients with previous progression on covalent BTK inhibitors. And the results have been extensively presented and published showing a high overall response rate of about 80% and a median PFS of about 19 months in this very heavily pretreated sick population.

So the data that I presented at EHA actually focuses on mechanisms of resistance in the largest cohort available to date. It includes 49 patients who are enrolled in BRUIN with CLL who had pre- and post-progression samples available for study by next-generation sequencing. We used a targeted panel of 74 genes, all exons, and then looked in more detail at patients with acquired BTK mutations to see if they were present at lower variant allele frequency at baseline. At baseline, about half of the patients had BTK mutations or P53 mutations, 10% had PLCγ2 mutations and three out of five of those responded to pirtobrutinib. Across the board, regardless of mutations, the response rate was 80%, which was comparable to the general population. When we did the analysis of the progression events, 71% of patients had acquired mutations, 55% in BTK, 16% in other genes. And then there were fully 29% had no acquired mutations, suggesting other mechanisms of resistance. We focused particularly on the BTK mutations where, even though you see primarily C481 mutations at baseline, these actually declined during therapy with pirtobrutinib overall, and are replaced by mutations in the T474 gatekeeper mutation and L528W kinase impaired mutation as well as scattered other mutations in the kinase site. And when we looked at whether those new mutations have been present at baseline, about a quarter of them were present at baseline at low varying allele frequency, suggesting they were actually acquired during the prior covalent BTK inhibitor therapy.

And so I think this work is very important for establishing the primary mechanisms to pirtobrutinib in the relapsed refractory setting in CLL. And more work will be required to evaluate the emergence of these various mutations during covalent and non-covalent BTK inhibitor therapy and whether having them at baseline impacts on disease response to a given drug.