Analysis Uncovers Mechanisms of Resistance to BTK Inhibitors in R/R CLL

On-target Bruton tyrosine kinase (BTK) mutations and downstream PLCγ2 mutations leading to escape of BTK inhibition may result in noncovalent BTK inhibitor resistance in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to results from a genomic analysis published in the New England Journal of Medicine.

In a population of patients with CLL (n = 55), 9 were identified who had acquired genetic resistance mechanisms following treatment with pirtobrutinib (LOXO-305). The mutations—including BTK V416L, A428D, M437R, T474I, and L528W—were found in the BTK domain and were associated with resistance to covalent and specific noncovalent BTK inhibitors. Moreover, BTK or PLCγ2 mutations were identified in all 9 patients. Transcriptional activation reflecting B-cell receptor signaling was observed even when noncovalent BTK inhibitor treatment continued.

“Overall, the development of noncovalent BTK inhibitors represents a promising therapeutic advance for patients with CLL and other B-cell cancers that have previously been treated with covalent BTK inhibitors. We have identified a series of genetic mechanisms for acquired resistance to this new class of agents. More analyses of larger samples are necessary to characterize the frequency of these genetic events and how they will influence treatment options,” investigators wrote.

Investigators took peripheral blood samples prior to treatment and at the time of disease progression from patients with relapsed/refractory CLL who were being treated with pirtobrutinib as part of the open-label phase 1/2 BRUIN study (NCT03740529). In the phase 1 portion of the trial, pirtobrutinib was administered in a standard dose-escalation fashion in 28-day cycles. In the second phase, patients received the recommended phase 2 dose of 200 mg once a day. To be eligible for the trial, patients needed to have received 2 previous lines of treatment.

As of the data cut off, 12 patients had discontinued treatment following disease progression, 38 continued to receive treatment, and 5 discontinued for other reasons. In the population who discontinued because of progressive disease, 1 individual with primary refractory disease was excluded from the resistance analyses due to having a short treatment exposure. Additionally, 2 more patients with progressive disease who did not have specimens post treatment were excluded.

In 2 patients who experienced disease progression, investigators identified mutations in the kinase domain of BTK outside the C481 residue that were not observed prior to treatment. Aside from V416L and M437R, acquired mutations were also observed in T4741 in 2 patients and L528W in 4 patients. One patient had mutations in T474I and L528W that were identified at progression.

A total of 7 patients developed acquired non BTK C481 mutations and 2 had persistent PLCγ2 mutations that were identified prior to treatment. New C481 mutations did not arise during treatment in the population. Additionally, no other recurrent mutation or copy number alterations were identified in those who progressed.

Reference

Wang E, Mi X, Thompson MC, Montoya S, et al. Mechanisms of resistance to noncovalent Bruton’s Tyrosine kinase inhibitors. N Engl J Med. 2022;386(8):735-743. doi:10.1056/NEJMoa2114110