ASH 2017: Dr. Matthew Davids on Umbralisib (TGR-1202) for chronic lymphocytic leukemia (CLL)

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At ASH 2017, I interviewed Dr. Matthew Davids on a new PI3K∆ inhibitor, umbralisib (formerly TGR-1202) for treating CLL.

We know from our experience with the one approved PI3K∆ inhibitor, idelalisib that they are extremely effective in knocking back chronic lymphocytic leukemia.

However, side effects from idelalisib, including liver inflammation, diarrhea, colitis, pneumonitis (inflammation of the lungs) and infections have limited its utility in treating CLL.

We think that these adverse events may be immune-modulated. That may explain why idelalisib had more toxicity in the upfront setting where the immune system is less beaten up. In fact, idelalisib is not approved as a frontline therapy for CLL due to these documented increased problems.

Dr. Davids pooled data from five studies to look at the side effect profile of a new PI3K∆ inhibitor, umbralisib, to examine if the side effects were different.

Umbralisib blocks PI3K∆, but has an entirely different structure than idelalisib.

Turns out that the side effect profile is different too.

Side effects are rated grade 1-5 with 5 being death and 1 being mild. Most of us will tolerate grade 1-2 side effects.

Take Away Points

336 patients were studied from 5 different trials, some as monotherapy and some with various other drugs in combination
The most common serious side effect was neutropenia (low neutrophil count) in 17% of the patient
The most common grade 1-2 (mild to moderate) side effect was diarrhea in 44% and nausea in 39%.
Key adverse events that had been seen with idelalisib were infrequent:
- Transaminitis (liver inflammation) (9% All Grades; Grade 3/4 <3%),
- Colitis (<1.5% All Grades; Grade 3/4 <1%)
- Pneumonitis (<1.5% All Grades; Grade 3/4 <0.5%).
The overall response rate (ORR) was 85% in in relapsed/refractory CLL for single agent umbralisib. No survival data presented.

This difference in the side effects may be due to umbralisib’s effect on casein kinase-1 epsilon (CK-1ε) which may have an inhibitory effect on regulatory T-cell function, calming the immune response that might be unleashed by the PI3K∆ inhibition though this is only conjecture at this point. This is not dissimilar to some of the similar “off target” immune modulating effects of ibrutinib that may contribute to its efficacy above and beyond its ability to block BTK.

Summary:

Umbralisib appears to have a different toxicity profile than idelalisib that may make it easier to use as monotherapy or in combinations to treat chronic lymphocytic leukemia. Larger studies are ongoing to assess this.

You can view our video interview below or read the transcript here.