Umbralisib: Treatment for a Rare Lymphoma?

Umbralisib (TGR-1202; TG Therapeutics) may be a promising therapy for patients with relapsed/refractory marginal zone lymphoma (MZL): In a phase IIb trial, patients had high 1-year progression-free survival (PFS) and response rates and manageable side effects. Results were presented at the American Association for Cancer Research Annual Meeting 2019 in Atlanta, GA, on April 1.

MZL is a rare, slow-growing non-Hodgkin lymphoma often treated first with the anti-CD20 therapy rituximab (Rituxan; Genentech), either alone or with chemotherapy. However, most patients relapse or develop resistance. At that point, treatment options are limited to more rituximab, chemotherapy, or the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica; Janssen), said Nathan Fowler, MD, of The University of Texas MD Anderson Cancer Center in Houston, who presented the study's findings.

Preclinical studies have suggested that the PI3Kδ inhibitor umbralisib acts against MZL by interrupting the PI3K pathway—a key pathway for B-cell receptor signaling in the disease. Fowler and his team are now testing umbralisib in the phase IIb UNITY-NHL trial as a second-line option for relapsed/refractory MZL. In an interim analysis of 38 patients with at least 6 months of follow-up, umbralisib elicited an overall response rate of 55%, including four complete and 17 partial responses; 11 other patients had stable disease. The 1-year PFS rate was 71%, and the median duration of response was not reached. The most common side effect was diarrhea, occurring in 45% of patients; the most common grade 3 to 4 adverse events were neutropenia and febrile neutropenia, which affected 8% and 5% of patients, respectively.

“The tolerability of the drug looks really good and the efficacy looks promising,” said Matthew Davids, MD, MMSc, of Dana-Farber Cancer Institute in Boston, MA, who was not involved in the trial but has previously studied the drug.

The results, Davids said, could be strong enough to merit FDA approval, but clinicians are likely to stick with ibrutinib as a second-line therapy because they are more familiar with it, opting for umbralisib once ibrutinib stops working. However, umbralisib may be a better second-line option for patients with cardiovascular concerns or those taking anticoagulants who can't tolerate ibrutinib due to the risk of heart problems and bleeding. In Davids's experience, umbralisib also has a more favorable toxicity profile than the PI3Kδ inhibitor idelalisib (Zydelig; Gilead) and the PI3Kδ and γ inhibitor duvelisib (Copiktra; Verastem), which are approved for other B-cell malignancies.

The results now need to be confirmed in a larger, randomized trial that compares umbralisib to other drugs, Fowler said, noting that a phase III trial is being planned. Phase III trials in other B-cell malignancies, including follicular lymphoma and chronic lymphocytic leukemia, are ongoing.

Fowler sees umbralisib as part of a broader trend: “It's exciting to see the newer, targeted, nonchemotherapy options have activity in rare subtypes of lymphoma such as marginal zone lymphoma. Patients who traditionally have had to rely on standard chemotherapy in the relapsed/refractory setting may have better options in the future.” –Catherine Caruso