who discontinued prior Bruton’s tyrosine kinase (BTK)–inhibitor treatment due to resistance or intolerance, according to the results of the , a phase 1/2 study.
Pirtobrutinib (formerly known as LOXO-305) is an oral-dose, highly selective, reversible BTK inhibitor, which might address a growing, unmet need for alternative therapies in BTK-inhibitor treatment failure patients, according to, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. Their was published in The Lancet.
The study included 109 women (34%) and 214 men (66%), with a median age of 68 years, who were treated with pirtobrutinib. Of these, 203 patients were assigned to pirtobrutinib (25-300 mg once per day) in the phase 1 portion of the study, and 120 patients were assigned to pirtobrutinib (200 mg once per day) in phase 2.
Pirtobrutinib, showed promising efficacy and tolerable safety in patients with CLL or small lymphocytic lymphoma, mantle cell lymphoma, and Waldenström macroglobulinemia who were previously treated with a BTK inhibitor. In 121 efficacy-evaluable patients with CLL or SLL treated with a previous covalent BTK inhibitor, the overall response rate with pirtobrutinib was 62% (95% confidence interval, 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (67%), covalent BTK inhibitor intolerance (52%), BTK C481-mutant (71%), and BTK wild-type (66%) disease.
In 52 efficacy-evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI, 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but 8 remain progression free to date, the authors stated.
In 19 efficacy-evaluable patients with Waldenström macroglobulinemia, the ORR was 68%. Among eight patients with follicular lymphoma who were efficacy evaluable, responses were observed in four (50%) patients, and six (75%) of eight efficacy evaluable patients with Richter’s transformation identified before enrollment responded to treatment, the authors stated.
No dose-limiting toxicities were observed and the maximum tolerated dose was not reached, according to the researchers. The recommended phase 2 dose was 200 mg daily. The adverse events, which occurred in at least 10% of 323 patients, were fatigue (20%), diarrhea (17%), and contusion (13%). The most common grade 3 or higher adverse event was neutropenia (10%). Five patients (1%) discontinued treatment because of a treatment-related adverse event.
In this “first-in-human trial of pirtobrutinib, we showed promising efficacy and safety in patients with B-cell malignancies, including CLL or SLL, MCL, Waldenström macroglobulinemia, and follicular lymphoma. Activity was observed in heavily pretreated patients, including patients with resistance and intolerance to previous covalent BTK inhibitor treatment. Global randomized phase 3 studies in CLL or SLL, and MCL are planned,” the researchers concluded.
Birth of a third generation?
“The pirtobrutinib study, by opening the way for a third generation of BTK inhibitors, could improve such a personalized molecular approach in the treatment of B-cell malignancies,” according to accompanying editorial comment by, and , both of the Institut de Cancérologie Gustave Roussy, Villejuif, France.
They discussed how BTK inhibitors have been a considerable therapeutic advance in the treatment of NHL-B and CLL and how the three currently approved BTK inhibitors, namely ibrutinib, acalabrutinib, and zanubrutinib, are all covalent and irreversible inhibitors at the protein – the C481 binding site. “Ibrutinib was the first approved drug. The second-generation inhibitors, acalabrutinib and zanubrutinib, were designed to be more BTK selective,” they added. However, the covalency and irreversibility of the drugs, considered therapeutic strengths, have resulted in induced resistance mutations occurring at the covalent binding, rendering the drugs inactive. “Two advantages of this new drug class are highlighted. First, the selectivity of the drug on BTK appears to be increased,” they wrote. “Second, this class does not bind BTK to the C481 residue, and the efficacy of the drug is therefore not affected by mutations in the BTK binding site.”
Several of the study authors reported receiving grants and personal fees from Loxo Oncology (a wholly owned subsidiary of Eli Lilly), which sponsored the study, as well as financial relationships with other pharmaceutical and biotechnology companies.
Dr. Michot and Dr. Ribrag reported that they had no disclosures relevant to the discussion.