BTK inhibitor shows efficacy against B-cell malignancies with few side effects

By John Murphy, MDLinx
Published November 13, 2015

Key Takeaways

A new oral drug showed significant activity in relapsed and refractory B-cell malignancies without major drug-related toxicity, researchers reported. Patients with chronic lymphocytic leukemia had the best response, and most of them are still in the study after 3 years. The findings were published November 5, 2015 in the journal Blood.

“These patients were confronted with a cruel reality: they had failed multiple chemotherapy lines and there were no other treatment options available for them. This drug has changed their lives; from desperate and tired, they are now leading a normal and really active life,” said co-lead investigator Harriet Walter, MSc, MBChB, Clinical Research Fellow in the Department of Cancer Studies at the University of Leicester, in Leicester, UK.

The new inhibitor, ONO/GS-4059, targets Bruton’s tyrosine kinase (BTK), an enzyme that promotes survival and proliferation of tumor cells.

For this dose-response study, researchers enrolled 90 patients, from centers in the UK and in France, who had B-cell malignancies that had relapsed or were refractory to treatment. Researchers sorted the subjects into 9 dose-escalation cohorts.

Overall, patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin’s mantle cell lymphoma (MCL) responded rapidly, with elevated lymphocyte counts in the peripheral blood as well as rapid resolution of lymphadenopathy within the first few months of starting ONO/GS-4059.

About two-thirds (66%) of these patients were still on the drug at the time the researchers wrote their article. However, most patients didn’t attain complete remission due to a persistent low level of malignant cells in the blood or bone marrow.

Also, more than one-third (35%) of patients with non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL) responded, but most eventually died from progressive disease.

“A striking feature of this study,” the authors wrote, “was that ONO/GS-4059 across all disease subsets showed a low incidence of associated toxicities”—less than 30%. Of the adverse events that were reported, 75% were Grade 1 or Grade 2. Grade 3 and 4 adverse events were mainly hematological and recovered spontaneously during ongoing therapy, the authors noted.

The researchers now plan to further study this drug in combination with other targeted agents with the aim of achieving a cure.

This clinical trial was funded by ONO Pharmaceuticals.

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