Analyzing Mechanisms of Pirtobrutinib Resistance Among Patients With CLL Pre-Treated With a Covalent BTK Inhibitor

Results From the Phase 1/2 Bruin Study 

At the 2023 European Hematology Association (EHA) Congress, Jennifer Brown, MD, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, presented results from the phase 1/2 Bruin study on mechanisms of resistance to pirtobrutinib among patients with chronic lymphocytic leukemia pre-treated with a covalent BTK inhibitor.

Transcript: 

Hello, I'm Dr. Jennifer Brown, director of the CLL Center and Institute Physician at Dana Farber Cancer Institute and Worthington and Margaret Collette professor of medicine in the field of hematologic oncology at Harvard Medical School.

I had the pleasure of presenting at the European Hematology Association on mechanisms of resistance to pirtobrutinib. As you know, pirtobrutinib is a novel non-covalent BTK inhibitor, that is highly specific for BTK and has demonstrated significant efficacy in patients previously treated with covalent BTK inhibitors. Pirtobrutinib is now approved for relapsed/refractory mantle cell lymphoma (MCL) in the United States. 

We have a cohort of 311 patients previously treated with covalent BTK inhibitors on the phase 1 Bruin Trial. And from among those patients, 49 had available a baseline and post-progression sample that could be used for targeted, next-generation sequencing on a panel of 74 genes.

The overall characteristics of these patients were very similar to the overall patient population. They had a median of 4 prior regimens and 1 prior covalent BTK inhibitor, which in most cases was ibrutinib, although there were 10 patients who'd had acalabrutinib.

The baseline genomics showed that half had a BTK mutation and about half had a P53 mutation. 10% or 5 patients had PLC gamma 2 mutations. Regardless of the baseline mutations, response to pirtobrutinib was similar and I should say that the primary BTK mutation seen at baseline was C481S, as we might imagine. There was only 1 non-C481 mutation present at baseline. At progression, 71% of patients had acquired a mutation and for 55% of them, this was a mutation in BTK. 29% of patients actually had not acquired any mutations in this panel, suggesting mechanisms of resistance that differ from the 74 genes evaluated in the panel.

If we look at the BTK mutations that were acquired specifically, T474, a gatekeeper residue, was the primary mutation, followed by L528W, which is a kinase-impaired mutation. Next most common were scattered other mutations across the kinase domain. We honed in more on the BTK mutations themselves, and notably, 92% of patients lost their BTK C481, usually S mutation, during the treatment. And what came up instead were T474 mutations, L528W, and those scattered mutations elsewhere in the kinase domain. And again, regardless of the baseline C481 mutation, patients responded well to pirtobrutinib.

We then looked actually at the baseline samples in patients who demonstrated acquisition of T474 L528W, or other kinase domain mutations, to see if they were present on manual review. And it turned out that 25% of the patients had evidence of the mutation seen at progression, also present at baseline at a variant allele frequency of 1% to 3%. At progression, the median variant allele frequency was 40% though, so there is a significant increase over time. 

But again, regardless of whether the mutation was present at baseline, the patients were able to respond to pirtobrutinib, and their time on drug was pretty similar at 11 months. So, in conclusion, pirtobrutinib is a potent, non-covalent BTK inhibitor. And during treatment, we see loss of C481 mutations with acquisition of T474 and L528W mutations in some cases. But half of patients did not acquire any mutations in BTK, and have currently unknown mechanisms of resistance.

Importantly, even if these mutations seen at progression were detected at lower allele frequencies of baseline, the patients still responded to therapy with pirtobrutinib. And ,we will be analyzing an expanded cohort of patients as there are now more samples available from patients on the trial. Thank you for your attention.

Source:

Brown J, Desikan S P, Nguyen B, et al. Genomic Evolution and Resistance to Pirtobrutinib in Covalent BTK-Inhibitor (CBTKI) Pre-Treated Chronic Lymphocytic Leukemia (CLL) Patients: Results From The Phase I/II Bruin Study. Presented at the EHA Congress; June 8-15, 2023; Frankfurt, Germany.