New Targets to Improve Patient Outcomes in MZL and FL - Episode 7

The UNITY-NHL Trial of Umbralisib in MZL and FL


Key opinion leaders in hematology-oncology discuss the recent UNITY-NHL trial and the FDA’s accelerated approval of umbralisib in relapsed/refractory marginal zone lymphoma and follicular lymphoma.

Anthony Mato, MD, MSCE: Let’s delve into the fourth agent approved in this space, umbralisib, which was approved based on the UNITY-NHL trial. This one is also unique in that it’s a PI3K-delta specific and a CK1 [casein kinase 1] epsilon inhibitor. I’m embarrassed to say that I don’t remember all of the biology associated with casein kinase 1 epsilon. Do you have anything to add about that unique target, or should we move on to the clinical data?

Lori A. Leslie, MD: It may be mitigating some of those immune-mediated toxicities by affecting T regulatory cells, but outside of that, I leave it to our basic science friends.

Anthony Mato, MD, MSCE: I agree with you completely. Maybe it dampens the T-cell response a bit. I’m not sure. On a day-to-day basis in the clinic, it’s probably a less relevant topic. How is it administered? Is the dose of umbralisib 800 mg?

Lori A. Leslie, MD: Yes, it’s 800 mg and taken once daily. The other oral medications are twice daily. This is the first once-daily dose. It has a similar toxicity profile. On comparison there’s maybe a little less prominent grade 3 or higher colitis and pneumonitis. It is the first approved PI3K inhibitor in marginal zone lymphoma [MZL].

What caught my eye in the UNITY-NHL study is that patients with marginal zone lymphoma had 2 prior lines of therapy. The responses rate was 43%. About 15% had a complete remission [CR]. Another one-third or so had stable disease. Out of the patients who had CR, there were no progressions at the time of presentation of the data. That is encouraging for patients with marginal zone lymphoma. Other PI3K inhibitors have been listed in the NCCN [National Comprehensive Cancer Network] guidelines, but this is the first approval for patients with 1 or more prior lines. The other interesting thing to me was that in follicular lymphoma [FL], it’s approved for patients in the fourth-line setting vs the other PI3Ks are approved for the third line. I wasn’t sure why that was, other than to say it wasn’t as big an area of unmet need. That could be why it was approved later on. What are your thoughts about the differences in those labels for FL and MZL?

Anthony Mato, MD, MSCE: I was going to ask you the same question. I am wondering if in your practice you would plan to wait until the fourth line, or if this is basically another agent that you think of as being appropriate in the third-line space. That’s what I think: third line and beyond. It’s hard to imagine another line of therapy that I would place in front of it in sequencing outside a clinical study.

Lori A. Leslie, MD: I agree. I put it in the same place where I put other PI3-kinase inhibitors. Tazemetostat, the EZH2 inhibitor that was approved in follicular lymphoma in June of 2020, is one other agent I might sequence differently, depending on EZH2-mutated or wild-type cohorts, which in the study were different baseline characteristics, and FL included high-grade 3b and transformed. It’s a little hard to compare across, but overall, in the mutated population response rates were around 70%, and in the wild-type group, about 30%. It has a really favorable toxicity profile, very low rates of grade 3 or higher adverse events [AE]. That’s another potential agent we would sequence with PI3Ks, maybe depending on the patient’s biology, if they have follicular lymphoma. With marginal zone lymphoma, that wouldn’t play a role.

Anthony Mato, MD, MSCE: One other thing I wanted to bring up related to this agent was something you touched on. There may be subtle differences in terms of the AE profile, quantitatively or qualitatively, as well. It’s important for both of us to emphasize that the same PI3K inhibitor-specific toxicities are still potentially reportable with this agent. The expertise that you would need to give idelalisib is still the same expertise that you need to keep in mind when you’re giving this drug. Are there any head-to-head comparisons of PI3K inhibitors that you can cite? I can’t think of any in this phase.

Lori A. Leslie, MD: I’m not aware of any, either. I completely agree. I know you have a lot experience with PI3K in general. How do you prep your patient? How does your team help you with the education to try to get the patients through the AEs and help them stay on therapy?

Anthony Mato, MD, MSCE: Just like your practice, we’re multidisciplinary. There are physicians, nurses, nurse practitioners, and pharmacists. Everybody plays a role in educating about the adverse event profile. We’re pretty old fashioned. We see patients a lot and ask a lot of questions to make sure we are picking up on subtle things before they become a big issue. We also make sure that the team is educated enough about the adverse events that subtle things like a cough or loose stool are picked up upon, taken seriously, and patients are brought into the office for evaluation. It is as important for the physicians as it is for the rest of the team to be educated. You know as well as I do that we probably hear about 10% of the calls at the end of the day. For 90%, the nurses are triaging them and helping to make those important decisions. While this agent is very well tolerated and has a favorable AE profile, it’s a mistake to say that those adverse events are not possible, so we take them seriously regardless of which agent and class we are using.

Lori A. Leslie, MD: I agree. The other thing is that these don’t overcome resistance, to our knowledge. I was hoping that wouldn’t get confused with the different approvals. If someone progresses on idelalisib, you shouldn’t switch them to umbralisib. Certainly, you could consider switching if you felt they were having benefit but might have a different toxicity profile. Similar to what you often do in CLL [chronic lymphocytic leukemia] with BTK inhibitors, more options are better so you can individualize the toxicity profile to whichever patient you’re thinking of starting on the drug.

Anthony Mato, MD, MSCE: That’s a great insight and very important to point that out.

Transcript Edited for Clarity