Transcript

Dr Horwitz: I'd like to welcome everyone to an Oncology Learning Network program discussing the impact of the ECHELON-2 trial in T-cell lymphoma.

My name is Steven Horwitz. I'm a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. It's my distinct pleasure to be joined today by Dr Barbara Pro, medical oncologist with an expertise in T-cell lymphoma from Northwestern University, and my colleague, Dr Alison Moskowitz, a medical oncologist, also with an expertise in T-cell lymphoma, from Memorial Sloan Kettering. Welcome, both.

Dr Pro: Thank you for the opportunity.

Dr Horwitz: I think the ECHELON-2, in my mind and I think yours too, has been the biggest advance we've had lately in how we standardly treat patients. That being said, there's a number of new strategies and treatments being looked at in this field.

Alison, you want to talk about some of the things that you think are interesting or some of the things in development as we look forward in T-cell lymphoma?

Dr Moskowitz: Our hope is that we're going to start to individualize patients with T-cell lymphoma a little better. Brentuximab is an example of where we're starting to do that for the CD30-positive disease. Of course, there's many non-CD30 positive diseases where we need better approaches and more individualized approaches.

That comes to potentially targeted therapies that specifically target particular subtypes of peripheral T-cell lymphoma or specific histologies such as angioimmunoblastic T-cell lymphoma.

Some of the targeted therapies that are looking promising in the T-cell lymphomas include duvelisib, which is a PI-3 kinase inhibitor, which has been shown to have a response rate of about 50-percent in the T-cell lymphomas. It's currently being evaluated in a registration study to clarify the efficacy and potentially lead to approval.

In my own experience, this has been quite an effective drug, where I've seen very nice responses, nice durable responses. Based upon this data, there's hope to look at this drug potentially in combination with CHOP-based therapy in the frontline setting.

Another class of drugs are HDAC inhibitors, which seem to preferentially be active in diseases associated with T-follicular helper phenotype, such as angioimmunoblastic T-cell lymphoma and in the subtype of peripheral T-cell lymphomas.

Romidepsin actually was a little disappointing. It was looked at in the frontline setting in combination with CHOP. This was a randomized study comparing romidepsin plus CHOP versus CHOP, and it actually did not show a benefit in outcomes, but this was looking at an overall population of patients with T-cell lymphoma.

When you look specifically at the patients with angioimmunoblastic T-cell lymphoma, there's the sense that maybe that group might have benefited a little bit more, but it wasn't statistically significant and the study wasn't designed to really look specifically at that group.

Moving forward, as far as looking at epigenetic modifiers in this particular subgroup, hypomethylating agents, such as azacitidine look promising in angioimmunoblastic T-cell lymphoma, as well as the other T-follicular helper diseases, as a single agent.

Recently, in a small study, which was led out of Cornell University and we had the opportunity to participate in, azacitidine was looked at in combination with CHOP potentially to help sensitize the patients to CHOP, but also, particularly, build upon this single agent activity that is seen in the T-follicular helper phenotypes.

Combining azacitidine with CHOP, the complete response rate and durability of responses, at least in this small study, looked very promising, a bit higher than what we would have expected with CHOP alone in this disease. This is, again, a combination that's going to be looked at further in a study in the future.

We're starting to look specifically at all of the individual subtypes of the T-cell lymphomas to try to identify which ones may benefit from epigenetic modifiers or rituximab, or potentially, a PI3 kinase inhibitor. We will eventually get to the point where we have various frontline therapies for the T-cell lymphomas rather than just one or two.

Dr Pro: Alison, you also have experience with JAK2 inhibitors and the combination of JAK2 with other agents, right?

Dr Moskowitz: Yeah. We also are running a Phase II study of ruxolitinib in the T-cell lymphomas. This study was specifically aimed to look at patients with T-cell lymphoma that potentially have upregulation of the JAK/STAT pathway, either through mutations or overexpression of FOS plus STAT3.

There is certainly a suggestion amongst these patients that those who have upregulation of the JAK/STAT pathway are probably more likely to respond to ruxolitinib.

There's also some entities that seem to benefit from ruxolitinib, regardless of our ability to find upregulation of JAK/STAT. Particularly, we've observed that in LGL, for example, where it often is associated with a STAT3 mutation, but even patients without that mutation seem to have some benefit from the treatment.

That's some exciting data that we plan to build upon, looking further into LGL, for example, in some of these other subtypes, and also, looking at combinations based upon inhibition of the JAK/STAT pathway.

Dr Horwitz: Barbara, anything to add to that? Any comments on immunotherapy? T-cell lymphoma's been kind of late in that, where we're seeing that used routinely in other areas of oncology and hematology. Any quick thoughts on that?

Dr Pro: Yeah. The use of checkpoint inhibitors in T-cell lymphomas, as you well know, has been a little bit disappointing in terms of efficacy data.

Right now, with the exception of an isotype, NKT-cell lymphoma, maybe because it's BTS-associated, there is definitely very significant efficacy data, at least in the relapsed and refractory setting.

I know there are many ongoing trials that are actually looking at the possibility of moving checkpoint inhibitors a little bit earlier in the therapy of this disease.

I think we'd be shocked to know that we don't really have strong data. The other factor is that cutaneous T-cell lymphoma, where there is definitely efficacy of checkpoint inhibitors. In other disease subtypes, unfortunately, the results were pretty disappointing.

Dr Horwitz: Thank you, that was great. I really thank you both for joining this roundtable. It was a great discussion of T-cell lymphoma overall and a nice highlighting of ECHELON-2, where we have an upfront treatment that, at least compared to CHOP, has shown benefit in progression-free and overall survival. For us, and for our patients, that's a really huge advance.

The other thing it does is it sets up this paradigm that we're all working on, which is moving away from a one-size-fits-all approach, where we treat everybody with intensive combination chemotherapy.

We're seeing in ECHELON-2, maybe in follicular helper T-cell lymphomas that there are subtypes we can build upon by adding treatments onto chemotherapy backbones.

There's probably going to be other disease entities where we really need a totally new paradigm or approach just because chemotherapy is relatively ineffective.

You can see the path moving in that direction where understanding a better individual approach is for either diseases or other tissue vulnerabilities. Maybe it's FOS/STAT3 or mutations in the JAK/STAT pathway. Maybe it's mutations in the epigenetic modifiers, but starting some of that understanding.

I thank you for joining us. That was great.

Dr Moskowitz: Thank you so much.