Pirtobrutinib Inhibits BTK C481 Clones in Patients With CLL

Patients with chronic lymphocytic leukemia (CLL) who progressed after treatment with the noncovalent Bruton tyrosine kinase inhibitor (BTKi) pirtobrutinib (Jaypirca) showed clearance of BTK C481 clones and the development of non-C481 clones, specifically the gatekeeper T474 and kinase-impaired L528W mutations, and other less common mutations. Investigators reported an objective response rate (ORR) of 80% (95% CI, 65.7%-89.8%) in a poster presented during the 2023 International Workshop on Chronic Lymphocytic Leukemia.¹

“Many patients discontinue covalent BTK inhibitors for either progression or intolerance,” investigators wrote. “BTK C481 substitution is known to contribute to covalent BTKi acquired resistance for patients treated with ibrutinib [Imbruvica], acalabrutinib [Calquence], and zanubrutinib [Brukinsa]. Pirtobrutinib uses a different BTK binding mechanism that may benefit this covalent BTKi–resistant population. Acquired mutations have been identified in a limited number of patients treated with pirtobrutinib.”

Findings from the phase 1/2 BRUIN trial (NCT03740529)2 show a distinct genetic evolution in patients with B-cell malignancies. However, the baseline BTK mutations did not impede the effectiveness of pirtobrutinib. These observations highlight the resistance mechanisms allowing for alternative potential treatment paths, tailored CLL therapies, or earlier use of pirtobrutinib in treatment protocols.

Out of 279 patients, 49 patients had a prior covalent BTK inhibitor (cBTKi) and then switched to pirtobrutinib. This was determined through next- generation sequencing at baseline and disease progression. The median age was 69 years (range, 36-86), and the median number of prior lines was 4 (range, 1-10). Due to disease progression, 41 of the 49 patients (84%) had discontinued a prior cBKTi: 1 or more of ibrutinib (n = 44, 90%), acalabrutinib (n = 10, 20%), or zanubrutinib (n = 1, 2%).

At the onset, the most common genetic changes found were in BTK (51%), TP53 (49%), ATM (27%), NOTCH1 (20%), SF3B1 (18%), and PLCG2 (10%). Out of 49 patients, 35 patients (71%) had developed at least 1 BTK mutation at the onset: C481S (n = 23), C481R (n = 4), C481Y (n = 2), C481F (n = 1), and T474I (n = 1). In the 35 patients, a total of 82 newly acquired mutations were found.

At time of disease progression, 92% of the BTK C481 clones decreased or were eradicated, 35 of 49 patients (71%) developed new genetic mutations, and 27 of 49 patients (55%) developed a BTK mutation. Among the 27 patients, investigators identifi ed 36 newly acquired BTK mutations.

The most common were gatekeeper mutations T474I/F/L/Y (35%), then kinase-impaired mutations L528W (18%), and other unknown variants near the ATP-binding pocket of the BTK protein. Regardless of acquired BTK mutation, the ORR across these groups was similar. AII showed 31 of 36 mutations with an ORR of 86%, BTK C481 was 23 of 25 with an ORR of 92%, BTK T474 was 16 of 18 with an ORR of 89%, BTK L528 was 8 of 9 with an ORR of 89%, and BTK other was 5 of 6 with an ORR of 83%.

Patients who had acquired BTK non-C481 clones at disease progression responded similarly to pirtobrutinib, with 6 of 8 having an ORR of 75% (95% CI, 35%-97%) at a median 11.2 months (range, 3.9-14.5).

These patients were among those who received ibrutinib (n = 4), acalabrutinib (n = 3), and ibrutinib plus acalabrutinib (n = 1) prior to pirtobrutinib. Unlike cBTKi treatments that form lasting bonds with their target, pirtobrutinib stabilizes and encloses BTK, forming it into an inactive conformation that does not allow for cellular process and prevents upstream kinases and phosphorylation of Y551.

The process acts like a disruptor to the scaffolding interactions that support kinase-independent BTK.

Investigators observed that various BTK non-C481 clones were already present in small quantities before the start of the study. This signifies that they emerged during previous treatments with cBTKi.

Neither the baseline nor the acquired mutations in the kinase domain of BTK hindered the effectiveness of pirtobrutinib, highlighting the potential of pirtobrutinib as a second treatment option even for patients with existing BTK mutations.

“Approximately half of patients did not acquire BTK mutations, and 29% did not acquire any mutations in this targeted panel, suggesting alternate resistance mechanisms. Several non-C481 BTK mutations were shown to be preexisting at baseline at low variant allele frequency, suggesting emergence on prior cBTKi. Importantly, these baseline and acquired kinase domain BTK mutations did not preclude pirtobrutinib efficacy,” investigators wrote in the poster.

REFERENCES

1. Brown JR, Desikan SP, Nguyen B, et al. Genomic evolution and resistance to pirtobrutinib in covalent BTK-Inhibitor pre-treated chronic lymphocytic leukemia patients: results from the phase I/II BRUIN study. Presented at: 2023 International Workshop on Chronic Lymphocytic Leukemia; October 6-9, 2023; Virtual and Boston, Massachuse s. Abstract 1548587.

2. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/ S0140-6736(21)00224-5