Treatment with the PI3K inhibitor umbralisib was safe and effective in patients with relapsed/refractory marginal zone lymphoma, according to results of a new phase II study.
Results of this study were presented at the American Association for Cancer Research (AACR) Annual Meeting, held March 29–April 3 in Atlanta (abstract CT132).
Marginal zone lymphoma is an indolent B-cell lymphoma, and it accounts for approximately 10% of all non-Hodgkin lymphomas. In general, responses to front-line therapy are quite high. “In patients who progress after front-line therapy … there are limited treatment options,” said Nathan H. Fowler, MD, of the University of Texas MD Anderson Cancer Center in Houston. “In patients who become refractory to chemotherapy, response rates in general are low, and most remissions remain under about a year or two.”
Umbralisib is a next-generation PI3 kinase inhibitor that is selective for the delta isoform of PI3K, which Fowler said might explain the improved toxicity profile in early studies over other PI3K inhibitors.
This study is ongoing, involving multiple cohorts and malignancies. The marginal zone lymphoma cohort all received single-agent umbralisib until disease progression or unacceptable toxicity. A total of 72 patients have been enrolled; the current analysis included 69 of those patients in the safety population and 42 patients in an interim efficacy analysis. Patients had a median age of 67 years, and 55% of patients had the extranodal subtype of marginal zone lymphoma.
The median duration of exposure to the agent in the efficacy population was 10.1 months, and after a median follow-up of 12.5 months, 55% of patients continued on the study therapy. The overall response rate was 52% both by independent review and by investigator assessment. By independent review, the clinical benefit rate (responses plus stable disease) was 88%. The median time to initial response was 2.7 months, and both the median duration of response and the median progression-free survival (PFS) were not yet reached. The estimated PFS rate at 12 months was 66%.
In general the drug was well tolerated, with no reports of colitis reported. Adverse events (AEs) leading to a dose reduction occurred in 9% of the cohort, and 14% discontinued umbralisib due to an AE considered at least probably related to the treatment. Among the more common AEs were diarrhea, nausea, and fatigue; 13% of the cohort had grade 3 or 4 neutropenia.
“[Umbralisib] is highly active against marginal zone lymphoma, including multiple different subtypes,” Fowler said. “Toxicity did not appear to be worsening with prolonged exposure, and this is a bit different from what we’ve seen with other drugs in this class.” He noted that on the basis of these results the drug has been granted Breakthrough Therapy Designation by the US Food and Drug Administration, and several phase III trials are planned.
Louis M. Weiner, MD, of the Georgetown Comprehensive Cancer Center at Georgetown University, who was not involved with the study, said the results are impressive in terms of the improved response rates in what can be a difficult-to-treat malignancy. He noted that results such as these seem to be getting more commonplace across malignancies as a number of fields of cancer research continue to mature. “Only a few years ago, these [results] would have been headline news—brand-new treatments that are working so well,” he said. “We’re really in an exciting era now.”