Umbralisib, an inhibitor of the PI3K delta protein, has a better long-term safety profile than equivalent treatments for advanced leukemia and lymphoma patients, those whose cancer failed to respond to multiple therapy regimens, a pooled analysis of data from five clinical trials shows.
TG Therapeutics — the investigative therapy’s developer — presented these findings at the 2018 Congress of the European Hematology Association (EHA) in Stockholm. The poster was titled “Long Term Integrated Safety Analysis of Umbralisib (TGR-1202), a PI3K-delta/CK1-epsilon Inhibitor With a Differentiated Safety Profile, In Patients With Relapsed/Refractory Lymphoid Malignancies.”
Umbralisib (TGR-1202) is a next-generation, once-daily, oral PI3K delta (δ) inhibitor, meaning it blocks a type of protein active in patients with lymphoid malignancies — like leukemia and lymphoma — that either return after prior therapies (relapse) or are resistant to treatment (refractory).
Other PI3Kδ inhibitors — such as the approved Zydelig (idelalisib) and the investigational duvelisib — are often associated with significant side events, including elevated liver enzymes, diarrhea/colitis, and pneumonitis.
These side effects can be severe and lead to treatment termination or withdrawal. They can also arise long after patients have started these treatments.
Although previous data suggested that umbralisib has a better safety profile, long-term follow-up was not available to judge its rate of late-onset adverse events.
To address its long-term safety, researchers analyzed data from patients given umbralisib for several months at least — a median of 6.5 months, with the longest use in a patient on daily umbralisib for more than four years.
Safety data was pooled from 347 patients enrolled in five completed or ongoing Phase 1 or 2 trials. These evaluated umbralisib alone or in combination with other agents — ublituximab, Imbruvica (ibrutinib), ublituximab plus Imbruvica, or ublituximab plus bendamustine — in patients with relapsed or refractory lymphoid cancers.
Among the group, 34% had chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), 33% had diffuse large B-cell lymphoma (DLBCL), 21% indolent non-Hodgkin lymphoma (NHL), and 12% other lymphomas.
Umbralisib was given daily until disease progression or toxicity, while dosing of combination agents varied depending on the agent.
The most common side effects were diarrhea (44%), nausea (39%), and fatigue (35%), low neutrophil counts (22%), anemia (20%), and low platelet counts (18%).
Importantly, adverse events that were frequent in other PI3Kδ therapies were seen to be uncommon in patients treated with umbralisib, including high levels of liver enzymes (8.6%), colitis (1.4%), and pneumonitis (1.4%).
Likewise, patient withdrawals due to therapy-related adverse events were rare, below 10% in all five trials.
“In this integrated analysis with long term follow-up, once-daily umbralisib exhibited a differentiated safety profile compared to prior generation PI3Kδ inhibitors. In particular, late onset diarrhea or colitis commonly associated with first-generation PI3Kδ inhibitors was infrequent,” the researchers concluded.
The study also showed that umbralisib can be safely combined with multiple agents to treat lymphoid malignancies.
The therapy has shown promise in terms of safety and efficacy results in chronic lymphocytic leukemia and lymphoma patients enrolled in a Phase 1 clinical trial (NCT01767766).
Umbralisib is also being evaluated in the UNITY-CLL Phase 3 trial (NCT02612311) and UNITY-NHL Phase 2b randomized trial (NCT02793583) as a potential treatment for patients with these conditions.
