A New BTK Inhibitor for Blood Cancers?

Pirtobrutinib Shows Promise in Initial Clinical Trials

An investigational Bruton’s tyrosine kinase (BTK) inhibitor has shown promise in treating patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL), as well as other types of non-Hodgkin lymphoma (NHL), with a very low likelihood of severe side effects.

Pirtobrutinib (formerly LOXO-305) was evaluated in 323 patients with B-cell malignancies, including 170 with CLL/SLL, 61 with MCL, 26 with Waldenström macroglobulinemia (WM) and 66 with other hematologic malignancies.

In the 139 evaluable patients with CLL or SLL who were on the drug long enough to have follow-up testing, 62% responded to pirtobrutinib treatment. For those who were on the drug for 10 months or longer, that number increased to 86%. The response was 52% in MCL patients, and 68% in patients with WM. Four of eight patients with follicular lymphoma responded to the drug as well.

“This drug appears to be effective in patients who have stopped responding to all other standard treatments,” said lead study author Dr. Anthony Mato, a hematologist-oncologist at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City in an MSKCC news story. “In addition, the rate of mild or severe side effects was very low. It’s a great combination of being very active even in the sickest patients and being very well tolerated.”

The findings from the phase I/II trial were published earlier this month in the Lancet. All patients had undergone multiple previous treatments for their condition:

• 76% had taken an earlier-generation BTK inhibitor, such as ibrutinib (Imbruvica)

• 87% had received chemotherapy

• 94% had received an anti-CD20 antibody, such as rituximab (Rituxan)

• 25% had received a BCL2 inhibitor, such as venetoclax (Venclexta)

Some patients had also received PI3K inhibitors (i.e., duvelisib), lenalidomide (Revlimid) and transplant or cellular therapies.

"Across the board, no matter how you look at the patient population, even patients who had failed five prior classes of therapy, you see response rates that are quite similar," Dr. Mato told MedPage Today during an expert roundtable discussion following the 2020 American Society of Hematology, where the data was first presented.

He added: “I gave patients this drug at 25 mg who had had five prior therapies and I was seeing response, and I have worked with other agents that were similar and not had that same experience, so there was something really unique about this molecule early on.”

How is Pirtobrutinib Different from Other BTK inhibitors?

BTK inhibitors work by binding to the BTK enzyme, which is part of the B-cell antigen receptor signaling pathway. B-cell leukemias and lymphomas, such as CLL, MCL and WM, are heavily dependent on this signaling for growth and survival. By blocking this signaling, BTK inhibitors trigger the death of malignant B-cells.

Currently available BTK inhibitors — ibrutinib, acalabrutinib (Calquence) and zanubrutinib (Brukinsa) —are covalent, meaning they permanently bind to BTK. This is a problem because it puts pressure on the cancer cells to find new ways to grow, and the drug is no longer effective, the MSKCC article explained.

Patients may also discontinue treatment because of intolerance — up to 20% of patients have to stop taking them because of adverse side effects, Dr. Mato said.

Pirtobrutinib, on the other hand, is a highly selective non-covalent, reversible inhibitor. That means it is able to bind to and block the activity of BTK and then release itself. This allows the CLL and lymphoma cells that have acquired resistance to the covalent BTK inhibitors to again respond, the article explained.

In addition, pirtobrutinib is associated with fewer medical problems than earlier-generation BTK inhibitors. The most common side effects included fatigue (20%), diarrhea (17%) and bruising (13%). There were no grade 3/4 cases of atrial fibrillation (1% overall, unlike other BTK inhibitors), and only five patients stopped treatment because of side effects.

What’s Next for Pirtobrutinib?

Researchers are planning several phase III trials with a control arm, where some patients will receive pirtobrutinib while others receive another targeted drug or chemotherapy.

However, this particular phase is ongoing and still enrolling patients. Some patients are being given pirtobrutinib in combination with other leukemia and lymphoma drugs. Those patients are not included in the present study.

Dr. Mato cautioned that this is early data — it is not a randomized trial.

“It's still mostly phase I patient population,” he said at the ASH roundtable, as reported by MedPage Today. “But I think what's unique here is this is the first prospective data for a BTK inhibitor following another BTK inhibitor in the setting of progression where we see across a large patient population pretty significant activity and durable remissions.”

Interested patients can contact the Loxo Oncology at Lilly Physician and Patient BTK Clinical Trial Hotline at 1-855-LOXO-305 or email clinicaltrials@loxooncology.com.