Dual PI3Kδ/CK1ε Inhibitor Umbralisib in Relapsed or Refractory Indolent Non-Hodgkin Lymphoma

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As reported in the Journal of Clinical Oncology by Nathan H. Fowler, MD, of The University of Texas MD Anderson Cancer Center, and colleagues, a phase IIb trial (UNITY-NHL) has shown that the dual PI3Kδ/casein kinase (CK)1ε inhibitor umbralisib produced durable responses in patients with relapsed or refractory indolent non-Hodgkin lymphoma.1

The study supported the February 2021 accelerated approval for treatment of adults with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20–based regimen and adults with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.

Nathan H. Fowler, MD

Nathan H. Fowler, MD

As related by the investigators, umbralisib is highly selective for the PI3Kδ isoform, which may reduce the frequency of immune-mediated adverse events believed to be associated with inhibition of other isoforms by other PI3K inhibitors (eg, immune-mediated hyperglycemia associated with α isoform inhibition). The agent also inhibits CK1ε, an enzyme that plays a crucial role in translation of oncogenes (eg, MYC, BCL2, and CCND1) and regulates elements of the β-catenin/WNT signaling pathway, potentially influencing T-cell immunomodulatory effects.

Study Details

In the multicohort trial, 208 patients with relapsed or refractory MZL (n = 69), FL (n = 117), or small lymphocytic lymphoma (SLL, n = 22) unresponsive to prior treatments (≥ 1 for MZL, ≥ 2 for FL and SLL), including ≥ 1 anti-CD20–based therapy, were enrolled from sites in nine countries between May 2017 and September 2018. Patients with MZL had to have had at least one prior line of therapy, including at least one CD20-directed regimen, with failure to achieve at least a partial response or with progressive disease after the most recent systemic regimen. Patients with FL or SLL were required to have relapsed or refractory disease after at least two prior lines of systemic therapy, including an anti-CD20 monoclonal antibody and an alkylating agent. 

Patients received oral umbralisib at 800 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was overall response rate on independent review committee assessment.

For the entire population, median patient age was 66 years (range = 29–88 years), 57% were male, and 82% were White. Eastern Cooperative Oncology Group performance status was 0 (56%) or 1 in 97% and 2 in 3%. Disease stage was I in 9%, II in 12%, III in 26%, and IV in 51% (unknown in 2%); 64% had relapsed on and 28% were refractory to prior anti-CD20 treatment. 

The median number of prior systemic therapies was two (range = 1–10), including one in 26%, two in 28%, three in 19%, and more than three in 27%. All patients had received prior rituximab, with anti-CD20–based chemoimmunotherapy having been received by 75.4%, 100%, and 90.9% of patients; 2.9%, 8.5%, and 22.7% had received a prior Bruton’s tyrosine kinase inhibitor. Autologous stem cell transplantation had been performed in 12 patients with FL more than 6 months before study entry.


Median follow-up was 27.7 months for efficacy and 21.4 months for safety. An objective response was observed in 47.1% of patients overall, and tumor reduction occurred in 86.4% of patients. An objective response was observed in 34 patients (49.3%) with MZL (complete response in 11, 15.9%), 53 patients (45.3%) with FL (complete response in 6, 5.1%), and 11 patients (50.0%) with SLL (complete response in 1, 4.5%). An additional 33.3%, 34.2%, and 36.4% of patients had stable disease. 

Disease control rates were 82.6%, 79.5%, and 86.4%. Among 198 patients with at least one postbaseline radiographic assessment, reduction in tumor volume was observed in 58 of 64 patients (90.6%) with MZL, 96 of 115 patients (83.5%) with FL, and 17 of patients (89.5%) with SLL.

The median time to response was 2.8 months, 4.6 months, and 2.7 months among MZL, FL, and SLL responders. Median durations of response were not reached (95% confidence interval [CI] = 10.3 months to not estimable) for responders with MZL, 11.1 months (95% CI = 8.3–15.6 months) for responders with FL, and 18.3 months (95% CI = 2.4 months to not estimable) for responders with SLL.

Median progression-free survival was not reached (95% CI = 12.1 months to not estimable) for patients with MZL, 10.6 months (95% CI = 7.2–13.7 months) for patients with FL, and 20.9 months (95% CI = 7.4–24.1 months) for patients with SLL. At 2 years, 50.5%, 18.1%, and 31.3% of patients remained progression-free.

Adverse Events

The most common adverse events of any grade were diarrhea (59.1%), nausea (39.4%), fatigue (30.8%), vomiting (23.6%), and cough (20.7%). Grade ≥ 3 adverse events occurred in 53.4% of patients, the most common being neutropenia (11.5%) and diarrhea (10.1%).

Elevated alanine aminotransferase and aspartate aminotransferase levels occurred in 20.2% and 18.8% of patients and were of grade ≥ 3 in 6.7% and 7.2%. Among other adverse events of interest, pneumonitis occurred in 1.4% of patients (grade ≥ 3 in 1.0%) and noninfectious colitis occurred in 1.9% (grade ≥ 3 in 0.5%). Grade 3 or 4 opportunistic infections occurred in 3.4%, and grade 3 or 4 rash occurred in 1.9% (any grade in < 10%).

Serious adverse events considered related to treatment were observed in 17.3% of patients, the most common being diarrhea (3.4%), acute kidney injury (1.4%), anemia (1.4%), dehydration (1.4%), febrile neutropenia (1.4%), pneumonia (1.4%), sepsis (1.4%), and urinary tract infection (1.4%). Adverse events led to discontinuation of treatment in 15.4% of patients. An adverse event led to death in one patient in the SLL group (myocardial infarction considered unrelated to treatment).

The investigators concluded: “Umbralisib achieved meaningful clinical activity in heavily pretreated patients with [indolent non-Hodgkin lymphoma]. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event–related discontinuations.” 

DISCLOSURE: The study was supported by TG Therapeutics. Dr. Fowler has served as a consultant or advisor to Bayer, Celgene, Novartis, Roche/Genentech, TG Therapeutics, and Verastem; and has received research funding from AbbVie, BeiGene, Celgene, Gilead Sciences, Novartis, Roche, and TG Therapeutics.


1. Fowler NH, Samaniego F, Jurczak W, et al: Umbralisib, a dual PI3Kδ/CK1ε inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol 39:1609-1618, 2021.


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