A Phase 2 Study Investigating Umbralisib Monotherapy in Patients with Relapsed/Refractory MZL

Although rituximab given as monotherapy, or in combination with chemotherapy, has substantially improved outcomes for patients with marginal zone lymphoma (MZL), relapse is common, and not all patients respond to current salvage therapies.1 Umbralisib is a novel next-generation phosphoinositide 3-kinase (PI3K)δ inhibitor with a unique mechanism of action and a differentiated tolerability profile compared with earlier PI3Kδ inhibitors. This study evaluates the efficacy and safety of umbralisib in patients with relapsed or refractory MZL.

To be included in the study, patients had histologically confirmed MZL, an Eastern Cooperative Oncology Group performance status 0 to 2, and ≥1 prior therapies, including ≥1 anti-CD20 monoclonal antibody (mAb)-containing regimens. Patients received an 800-mg dose of umbralisib orally once daily until progressive disease or unacceptable toxicity. The primary end point was overall response rate (ORR), as assessed by independent review, per 2007 International Working Group criteria.  Secondary end points included duration of response, progression-free survival (PFS), and safety.

A total of 69 patients were enrolled in the study; this analysis reports on the initial 42 patients who were eligible to be followed for 9+ cycles as of the data cutoff. Of the 42 patients, 23 had extranodal disease, 12 had nodal disease, and 7 had splenic involvement. The median age was 67 years, and the median number of prior systemic therapies was 2, with a range of 1 to 6. Seven (17%) patients had rituximab monotherapy only, and 32 (76%) had ≥1 anti-CD20 mAb-containing chemoimmunotherapies.

At median follow-up of 12.5 months, ORR was 52%. Of the patients, 19% achieved complete response and 33% achieved partial response. A total of 36% of patients had stable disease. The median time to initial response was 2.7 months; neither median duration of response nor median PFS was reached as of the data cutoff. The estimated 12-month PFS rate was 66%.

Overall, umbralisib was well tolerated; however, adverse events leading to dose discontinuation occurred in 6 patients. Grade 3 infections, including bronchitis, pneumonia, and influenza (1 each) occurred in 3 patients.

As of the data cutoff date, 55% of patients continued treatment. Researchers concluded that umbralisib given as monotherapy is active and well-tolerated in patients with relapsed or refractory MZL, and responses appear to be durable thus far. Further studies are expected to determine whether umbralisib can help to address the unmet therapeutic need that exists in this patient population.

Abstract 7506; Fowler NH, et al.


  1. Burris HA 3rd, Flinn IW, Patel MR, et al. Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018;19:486-496.

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