Atlanta, GA—The investigational PI3K inhibitor umbralisib had encouraging activity as monotherapy in patients with relapsed or refractory marginal-zone lymphoma in an analysis of the phase 2 UNITY-NHL trial. Interim results were presented at the 2019 American Association for Cancer Research (AACR) meeting.
In this relapsed or refractory setting, overall response rate (ORR) with single-agent umbralisib was 52%, with good tolerability even with prolonged exposure to the drug.
“The adverse event and clinical activity data are highly encouraging at this early time point. We are excited to continue following patients for a longer time to further establish the long-term activity and side effects of umbralisib,” said lead investigator Nathan H. Fowler, MD, Department of Lymphoma/Myeloma, M.D. Anderson Cancer Center, Houston, TX.
“With the results reported so far, umbralisib has the potential to make a real difference for patients with relapsed or refractory marginal-zone lymphoma. We are planning phase 3 trials in marginal lymphoma and other indolent non-Hodgkin lymphoma subtypes,” he added.
Marginal-zone lymphoma is an indolent B-cell lymphoma that accounts for approximately 10% of non-Hodgkin lymphomas. Although responses are high with front-line CD20-directed therapy, most patients relapse and require salvage therapy, and options for these patients are limited.
Umbralisib has a novel mechanism of action; unlike the other PI3K inhibitors, it is selective for the PIK3-delta isoform and is associated with low rates of immune-related toxicity. In January 2019, umbralisib was granted breakthrough therapy status by the FDA for treatment of adults with marginal-zone lymphoma after at least 1 previous anti-CD20 treatment.
The phase 2 UNITY trial tested several cohorts of 72 patients who received treatment with umbralisib monotherapy and in combination with chemotherapy. All patients had relapsed or refractory disease after ≥1 lines of at least 1 CD20-directed therapy (monotherapy or in combination with chemotherapy) and required salvage therapy.
Safety and Efficacy
Adverse events of any grade reported in 69 of the patients were diarrhea, nausea, fatigue, elevated liver enzymes, headache, cough, and decreased appetite. Grade 3 diarrhea was reported in 7 patients. Grade 3 infections were reported in 3 patients. Grade 4 events were rare. There was no evidence of colitis.
The interim efficacy population included 42 patients who received umbralisib monotherapy 800 mg daily until disease progression. The median duration of exposure to umbralisib was 10 months. At a median follow-up of 12.5 months, 55% of patients were still receiving study treatment; 10 (24%) patients discontinued treatment because of disease progression, and 5 (12%) patients discontinued because of an umbralisib-related adverse event.
The best ORR according to an independent review and investigator assessment was 52%. Complete response rates were 19% with umbralisib monotherapy and 12% with the combination; partial response rates were 33% and 40%, respectively; and stable disease rates were 36% and 31%, respectively. The clinical benefit rate with umbralisib according to independent review was 88%.
According to an independent review, the ORRs for patients who received previous chemoimmunotherapy was 53%, and 38% in patients refractory to their last line of chemotherapy.
According to a waterfall plot, 86% of patients had some reduction in tumor burden from baseline, although not all met the criteria for partial response.
The median duration of response and median progression-free survival had not been reached at the time of data cutoff. Patients will continue to be followed for mature overall response, duration of response, and toxicity.
AACR press conference moderator Louis M. Weiner, MD, Director, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, said, “Umbralisib appears to have a better side-effect profile than first-generation PI3K inhibitors, with excellent efficacy. If further study confirms these results, umbralisib could emerge as a new treatment option for marginal-zone lymphoma and possibly other indolent lymphomas.”