BTK Inhibitor May Treat Drug-Resistant CLL, SLL

Bruton tyrosine kinase (BTK) inhibitors can effectively treat B-cell malignancies, but up to 40% of patients stop taking them due to drug resistance or intolerance. However, according to recently published results of a phase I/II trial, a new type of BTK inhibitor, pirtobrutinib (LOXO-305; Loxo Oncology/Lilly), yielded an overall response rate (ORR) of 62% in patients previously treated with a covalent BTK inhibitor (Lancet 2021;397:892–901).

Like the approved covalent BTK inhibitors ibrutinib (Imbruvica; Pharmacyclics/Janssen) and the second-generation agent acalabrutinib (Calquence; AstraZeneca), pirtobrutinib targets BTK to disrupt B-cell antigen receptor signaling, which malignant B cells need to survive and proliferate. Whereas covalent BTK inhibitors bind to the protein irreversibly, pirtobrutinib binds reversibly. In the trial, pirtobrutinib appeared unaffected by the most common cause of resistance to covalent BTK inhibitors: mutant BTK C481.

“The data here look very impressive,” says Carolyn Owen, MD, of Tom Baker Cancer Centre in Calgary, Canada, who was not involved in the research. “I feel really optimistic about the entry of this class of agents.”

The trial evaluated responses to pirtobrutinib at a median of 6 months in 269 patients with B-cell malignancies who had received at least two other therapies. In 139 patients with either chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), the ORR was 63%. Most patients resistant to covalent BTK inhibitors across disease types responded to pirtobrutinib, with an ORR of 67% (53/79), including 71% (17/24) of patients with the BTK C481 mutation.

“This drug seems to be active in resistant patients whether or not they have the BTK C481 mutation,” says lead author Anthony Mato, MD, of Memorial Sloan Kettering Cancer Center in New York, NY. Although researchers aren't sure why pirtobrutinib works when other BTK inhibitors have failed, Mato hypothesizes that its reversible binding mechanism could help explain its effectiveness and relatively low toxicity.

“To build a better BTK inhibitor, not only do you need it to overcome resistance, but it also has to be well tolerated,” says Mato. In the trial, only 5 patients (1%) stopped taking pirtobrutinib due to adverse events. “That's pretty impressive,” he says.

Although pirtobrutinib and ibrutinib haven't been compared head to head, pirtobrutinib's side-effect profile is encouraging, Owen says. She noted that bleeding and cardiac toxicity were uncommon in patients treated with pirtobrutinib, which is highly selective. The most common grade 3 adverse event was neutropenia, found in 10% of patients, but most adverse events were grade 1 or 2. “I think it's going to provide a lot of value for a lot of patients,” Owen says.

If pirtobrutinib is approved, it would be a good option for patients with CLL whose disease has worsened on other treatments or who cannot tolerate other BTK inhibitors or the BCL2 inhibitor venetoclax (Venclexta; AbbVie/Genentech). In addition, longer-term data on the duration of response to pirtobrutinib would help clarify whether clinicians should use the drug earlier in treatment, Owen says.

A recently announced phase III trial will compare pirtobrutinib with approved BTK inhibitors in patients with mantle cell lymphoma who have not received a BTK inhibitor, measuring responses for up to 2 years. Another phase III trial will compare pirtobrutinib with idelalisib plus rituximab or bendamustine plus rituximab in patients with CLL or SLL previously treated with a BTK inhibitor, measuring responses for up to 4 years. –Conor Gearin