Umbralisib Activity, Safety in Indolent Lymphomas Demonstrated in Phase 2b Trial

Data that led to the approval of umbralisib in patients with indolent non-Hodgkin lymphoma— including follicular lymphoma and marginal zone lymphoma—indicates favorable activity of the therapy versus other available PI3K inhibitors.

In the phase 2b UNITY-NHL trial (NCT02793583), monotherapy umbralisib (Ukoniq) was able to induce meaningful responses in patients with heavily pretreated marginal zone, follicular, and small lymphocytic lymphomas.

The results of this trial ultimately led to the approval of the agent earlier this year as therapy for patients with follicular lymphoma (FL) following 3 or more prior systemic therapy regimens and in those with marginal zone lymphoma (MZL) who had received at least 1 prior anti-CD20–based regimen.2

Umbralisib is a dual PI3Kδ and CK1ε inhibitor with no known relevant drug-drug interactions. It is unique from other approved PI3K inhibitors in that its high selectivity for the PI3Kδ isoform versus the γ- and other isoforms makes it less likely to induce autoimmunity and inflammation from immune suppression. Additionally, inhibition of CK1ε, which plays a role in protein translation of oncogenes, has the ability to regulate elements of the β-catenin/wingless-type MMTV integration site (WNT) signaling pathway, thereby influencing immunomodulatory effects of T cells. Taken together, the effects of dual inhibition may be responsible for the favorable safety profile of this regimen, which has demonstrated a low burden of immune-mediated adverse events (AEs).

“In UNITY-NHL, umbralisib showed meaningful clinical activity in patients with [relapsed or refractory indolent non-Hodgkin lymphoma] consistent with that demonstrated by prior inhibitors of PI3K. However, the safety profile appears improved compared with first-generation PI3K inhibitors, with manageable toxicities and a relatively low number of AE-related discontinuations,” wrote the study authors, who were led by Nathan H. Fowler, MD. “These results suggest that umbralisib has a favorable benefit-risk profile in this heavily pretreated population.”

The open-label multicohort analysis enrolled patients with relapsed or refractory disease into 5 cohorts of MZL (n = 69), FL (n = 117), small lymphocytic lymphoma (SLL; n = 22), mantle cell lymphoma, and diffuse large B-cell lymphoma. Patients with MZL were required to have at least 1 prior therapy including anti-CD20 therapy which failed to result in at least a partial response. Those with FL and SLL were required to have relapsed or refractory disease after at least 2 prior lines of systemic therapy, including an anti-CD20 monoclonal antibody and an alkylating agent.

With a median follow-up for efficacy of 27.7 months, the overall response rate (ORR) was 47.1% for the intention to treat population. By disease, independent review committee–assessed ORR was 49.3% (95% CI, 37.0%-61.6%) for MZL, 45.3% (95% CI, 36.1%-54.8%) for FL, and 50.0% (95% CI, 28.2%-71.8%) for SLL; corresponding complete response rates were 15.9%, 5.1%, and 4.5%.

The median duration of response was not reached (NR) for MZL (95% CI, 10.3-not estimable [NE]), was 11.1 months (95% CI, 8.3-15.6) for FL, and 18.3 months (95% CI, 2.4-NE) for SLL. Median progression-free survival was NR (95% CI, 12.1-NE), 10.6 months (95% CI, 7.2-13.7), and 20.9 months (95% CI, 7.4-24.1), respectively.

Follow-up for safety was 21.4 months (range, 14.6-30.8), with 207 of 208 patients reported in the study experiencing a treatment-emergent AE. The most frequent TEAEs of any grade occurring in more than 20% of patients were diarrhea (59.1%), nausea (39.4%), fatigue (30.8%), vomiting (23.6%), and cough (20.7%). Treatment with umbralisib led to treatment discontinuation in 32 patients (15.4%).

Grade 3 or greater AEs occurring in 10% of patients or more were neutropenia (11.5%) and diarrhea (10.1%). Other grade 3 or greater AEs of interest included opportunistic infections (3.4%) and rash (1.9%), elevated levels of alanine aminotransferase (6.7%) and aspartate aminotransferase (7.2%), pneumonitis (1.0%), and noninfectious colitis (0.5%).

Serious TEAEs occurred in 63 patients (30.3%), with 54 patients (26.0%) experiencing grade 3 or greater events. Serious TEAEs considered related to umbralisib were reported in 36 patients (17.3%). One patient with SLL had a fatal myocardial infarction that was considered to be unrelated to umbralisib, and there were no other grade 5 AEs.


1. FDA. FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma. FDA website. Published February 5, 2021. Accessed April 3, 2021.

2. 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. March 8, 2021. doi: 10.1200/JCO.20.03433