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Umbralisib Demonstrates Long-Term Safety and Clinical Activity in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

December 30, 2021

Patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL) have historically had poor long-term tolerance to phosphatidylinositol-3-kinase (PI3K) inhibitors. However, new study results published in the Journal of Clinical Oncology suggest treatment with the PI3K and casein kinase-1ε inhibitor umbralisib led to meaningful clinical activity and a manageable safety profile in this patient population.

Researchers led by Nathan Fowler, MD, at the University of Texas MD Anderson Cancer Center, assessed the efficacy and safety of umbralisib in 208 patients with relapsed/refractory marginal zone lymphoma (MZL), follicular lymphoma (FL), or small lymphocytic lymphoma (SLL) that was unresponsive to previous treatments. The phase IIb, open-label study included 69 patients with MZL who had received at least one prior treatment, as well as 117 patients with FL and 22 with SLL who had relapsed/refractory disease following at least two prior lines of systemic therapy.

During a 28-day screening period, patients underwent a fluorodeoxyglucose positron emission tomography with contrast-enhanced computed tomography scan of the chest, abdomen, and pelvis.

Study participants received once-daily umbralisib 800 mg, given as 200 mg tablets with food during a 28-day cycle. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal.

The median age of the overall population was 66 years (range = 29-88). More than half of patients were male (56.7%), and most patients were white (81.7%).

In total, 51.0% of patients presented to the study with stage IV disease and 28.4% were considered refractory to previous anti-CD20–based therapy. Prior to enrollment, patients had received a median of two treatments (range = 1-10).

During a median follow-up of 27.7 months in the efficacy analysis, the overall response rate (ORR) was 47.1%. By iNHL subtype, the ORRs were:

  • 49.3% for MZL
  • 45.3% for FL
  • 50.0% for SLL

In addition, 86.4% of patients experienced tumor reduction after treatment with umbralisib, including 90.6% of patients with MZL, 83.5% with FL, and 89.5% with SLL.

The median time to response was shortest in patients with SLL (2.7 months), followed by MZL (2.8 months) and FL (4.6 months).

Looking at median durations of response, patients with MZL appeared to have the longest-lasting responses (not reached), compared with 11.1 months in the FL group and 18.3 months in the SLL group.

The median progression-free survival (PFS) was 10.6 months in patients with FL and 20.9 months in patients with SLL, while the median PFS was not reached in patients with MZL. Approximately 50.5% of patients with MZL, 18.1% with FL, and 31.3% with SLL had no disease progression at two-year follow-up.

More than half of the study group (53.4%) experienced at least one grade ≥3 treatment-emergent adverse event (TEAE), and 14.9% had a TEAE that led to umbralisib discontinuation. The most frequently reported grade ≥3 TEAEs (≥10% of patients) included neutropenia (11.5%) and diarrhea (10.1%).

"[Umbralisib can serve] as a platform for the development of novel combination regimens not enabled by currently available PI3K inhibitors."

—Nathan Fowler, MD

The authors wrote that the tolerability and safety profile of umbralisib observed across iNHL subtypes was consistent with previous phase I data. Comparatively, data from previous pivotal trials of first-generation PI3K inhibitors have reported much higher rates of TEAE-related discontinuation, even in studies with shorter follow-up durations, the authors added, noting that cross-trial comparisons are limited by the variability in inclusion criteria.

Given umbralisib's long-term safety and tolerability profile in this study, the investigators concluded that the drug may offer an effective monotherapy option for relapsed/refractory iNHL and can serve "as a platform for the development of novel combination regimens not enabled by currently available PI3K inhibitors."

Study authors report relationships with TG Therapeutics, which sponsored the trial.


Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib, a dual PI3Kδ/CK1ε inhibitor in patients with relapsed or refractory indolent lymphoma [published online ahead of print, 2021 Mar 8]. J Clin Oncol. doi: 10.1200/JCO.20.03433.

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