Umbralisib Expands the Treatment Landscape for Non-Hodgkin Lymphomas

OncologyLive, Vol. 22/No. 08, Volume 22, Issue 08

A favorable risk profile and clinically meaningful response rates have made umbralisib a new therapeutic option for patients with heavily pretreated indolent non-Hodgkin lymphomas.

A favorable risk profile and clinically meaningful response rates have made umbralisib a new therapeutic option for patients with heavily pretreated indolent non-Hodgkin lymphomas. The agent’s enhanced selectivity for the PI3Kδ isoform as well as inhibition of CK1ε resulted in improved overall response rates (ORR) for patients with relapsed or refractory marginal zone lymphoma (MZL) and refractory follicular lymphoma (FL).1

On February 5, 2021, the FDA granted accelerated approval to umbralisib for the treatment of adult patients with relapsed or refractory MZL who have received at least 1 prior anti-CD20–based regimen and adults with relapsed or refractory FL who have received at least 3 prior lines of systemic therapy. The approval was based on findings from 2 single-arm cohorts of the phase 2 UNITY-NHL trial (NCT02793583).2

Results of the trial showed that umbralisib therapy resulted in an ORR of 49% (95% CI, 37.0%-61.6%) in patients with MZL (n = 69) with16% of patients achievinng a complete response (CR) and 33% had a partial response (PR). With a median follow-up of 20.3 months, the median duration of response for patients with MZL was not reached (95% CI, 9.3-not estimable).

Patients with FL (n = 117) had similar outcomes, with 50 patients experiencing a CR or PR for a reported ORR of 43% (95% CI, 33.6%-52.2%). Specifically, 3% had a CR and 39% had a PR.3 At a median follow-up of 20.1 months, the duration of response was 11.1 months (95% CI, 8.3-16.4).

In an interview with OncologyLive®, Nathan H. Fowler, MD, a lymphoma specialist in the Department of Lymphoma-Myeloma at The University of Texas MD Anderson Cancer Center in Houston, and lead author of the UNITY-NHL trial, discussed how umbralisib could potentially shift the treatment paradigm for patients with MZL and FL.

What was noteworthy about the efficacy data that led to the approval?

The primary objective of the study was to look at the ORR of this single agent in these relapsed, low-grade lymphomas. With a median of 28 months’ follow-up, the ORR was 49%, and that’s pretty good for a patient population on their second, third, or fourth line of treatment. Almost all patients had reductions in their tumor volume; in fact, 86% of patients had shrinkage of their tumor. The median duration of response has not been reached for [patients with] MZL; it was approximately 1 year 11 months, for [patients with] FL and 18 months [for patients with] SLL [small lymphocytic lymphoma].

Please describe the mechanism of action of umbralisib.

Umbralisib is a selective PI3 kinase inhibitor. It hits the δ isoform, as well as a couple other isoforms but it’s highly selective for the δ isoform of PI3 kinase. It also hits CK1ε, which is a protein that is involved in translation of multiple oncogenes, such as MYC and BCL2.

Regarding safety, what do we know about umbralisib’s tolerability, and what adverse events are important to keep in mind when prescribing it?

[Umbralisib] as a single agent was very well tolerated. Very few patients had to discontinue the drug; only 14% of patients had to stop therapy because of an adverse event. We saw grade 3 events, which are serious events, in not many patients; [we saw] neutropenia [in] approximately 11%, grade 3 diarrhea in 10%, and occasionally we saw elevation of liver function tests in approximately 7% of patients.

For patients who are given the agent, I think it’s important to monitor [for] drop in blood counts along with GI [gastrointestinal] adverse effects. But I think the study showed that if you manage the drug [dosage] and interrupt dosing when patients develop an event, very few patients actually have to stop the drug due to toxicity.

How does this approval advance the MZL and FL treatment paradigm?

Patients who have FL [with multiple relapses] unfortunately tend to have worse outcomes with each subsequent line of treatment. We know that patients, when they get to their second, third, fourth line of therapy, often can have short remission rates. We need new drugs in that category—patients with multiple relapses. Many of the drugs that are currently available for patients in this setting are either associated with significant toxicity or low efficacy.

Umbralisib represents another drug in a unique class that is relatively tolerable and has tumor activity in the vast majority of patients [in which] it’s used. I believe this option will be utilized by clinicians for patients with third- or fourth-line follicular lymphoma. For patients with FL who experience multiple relapses, we need more treatments. This treatment is very active, and it’s associated with a very limited toxicity profile. Plus, it’s oral, so it’s easy to give, the toxicity is not too high, and it appears very active in patients after multiple other lines of therapy.

What are the next steps for umbralisib in lymphoma and possibly beyond?

The promising activity profile [and] toxicity rate suggest this drug could be an agent that would work well in combination, both in the relapse setting and potentially earlier lines of treatment. I hope that we will begin to see combination studies involving umbralisib across many different cancers, including low-grade lymphomas.

Interestingly, a portion of patients achieved complete remissions with durable, long remission rates. I think that we need more research into potential biomarkers of response for these patients so we can identify patients who are most likely to derive really deep and long remissions with targeted therapy.


  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. Published online March 8, 2021. doi:10.1200/ JCO.20.03433
  2. FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma. FDA. Updated February 5, 2021. Accessed March 24, 2021.
  3. Ukoniq. Prescribing information. TG Therapeutics Inc; 2021. Accessed March 24, 2021. https://