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: Let's move now to the ECHELON-2 study, which is new-ish data that has affected some of how we think about treating front-line peripheral T-cell lymphoma.

Barbara, can you for the audience introduce the basic design, what the basic end points of the study were, and what we saw?

Dr Pro: As I mentioned earlier, there is a need for novel therapies in T-cell lymphoma. One of the important targets in CD30-expressing T-cell lymphoma is CD30. We now have an antibody-drug conjugate that targets CD30 and has shown, at least in the relapsed refractory setting, significant efficacy in anaplastic large-cell lymphoma that are CD30-expressing T-cell lymphomas.

Based on that, there was a phase 1 study that looked at the possibility of incorporating brentuximab vedotin over adding brentuximab vedotin to standard chemotherapy in the front-line treatment of T-cell lymphoma and showed significant results with a very high response rate in this patient population.

This supported the design of the ECHELON-2 trial, which was a large, randomized study in the front-line setting for patient with CD30-positive T-cell lymphoma. The criteria for definition of CD30-positive, per protocol, was 10 percent of positivity or higher. That, I think, should be kept in mind.

In terms of histologic subtypes, by protocol design, we included 70 percent of patients with anaplastic large-cell lymphoma. Other histologic subtypes were eligible if they had at least 10 percent of positivity of CD30.

This was a randomized study, one-to-one. The standard chemotherapy was CHOP without etoposide. We can discuss what about the addition of etoposide in a trial like this. The experimental arm was CHOP without vincristine, so CHP, and in combination with brentuximab vedotin.

The main endpoint for this study was progression-free survival as assessed by an independent review committee. The trial met the endpoint and has been presented and then published. For the first time, we are seeing an improvement not only in the progression-free survival but also in overall survival for this patient population, which I think it's very important. Even the historical data and with the standard chemotherapy.

This month at ASH, the five-year follow-up data was presented. I don't know, Steve, if you want to comment on the long-term follow-up data now in terms of both efficacy data and very importantly also in terms of the toxicity data, including their neurotoxicity.

Dr Horwitz: Sure, yeah. The long-term data confirmed the initial. The initial study was published. It was about three-year follow-up, and this was five-year follow-up, so pretty long follow-up for peripheral T-cell lymphoma. There have been some additional events in both arms, but the differences hold.

It does look like the experimental arm, BV-CHP, has better progression-free and overall survival, now, with even longer-term follow-up. We'll talk about some subtypes in a moment. It was looked at also specifically for anaplastic large-cell lymphoma, and there remains something like a plateau on those curves. It looks like a lot of those patients in remission now are probably cured.

I think you mentioned in terms of longer-term follow-up, while there is some neuropathy with both arms, including the brentuximab arm, there is some consistent improvement over time. The majority of patients have resolution of neuropathy or improvement to grade 1.

That probably is a commensurate risk of some low-grade, long-term neuropathy or not, with what looks to be a better overall survival. I think the long follow-ups are confirmatory.

Alison, as we interpret this data, maybe start off with, top-line, how are you applying this in your practice? Then maybe talk a little bit more about some of the non-ALCL subtypes in terms of what you think about that data, how you think about it, and how you incorporate it.

Dr Moskowitz: The study was planned to enroll about 75 percent of the patients to have anaplastic large-cell lymphoma. It was powered to look for a difference within the patients with anaplastic large-cell lymphomas.

Of course, there were other subtypes enrolled in the study including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified, as well as others, but those entities represented a minority within the study.

While we saw a significant improvement in progression-free survival and overall survival for the entire group, when you look at all the different sub-groups, of course, we see that difference within the anaplastic large-cell lymphoma patients since they represent the majority.

Within the smaller groups, the study was not powered to look at those groups. It's unclear for seeing as much of a benefit within those groups. To be perfectly honest, given the benefit that we saw for the larger group within the study, I do extrapolate from the data that we see from anaplastic, for the whole, entire patient population.

In my practice, I will incorporate brentuximab in the front-line setting for a patient who has CD30-positive disease, even if they don't have anaplastic large-cell lymphoma. The majority of the patients in my practice who fall into that group will have angioimmunoblastic T-cell lymphoma, of which about 30 percent or so of those patients will have CD30-positive disease.

I see brentuximab as a very active drug for patients with angioimmunoblastic T-cell lymphoma. We know that in the relapsed and refractory setting, the response rate to single-agent brentuximab in that setting was about 50 percent in earlier studies. The opportunity to potentially enhance the efficacy of CHOP for these patients is really important.

I do regularly incorporate brentuximab if the patients have CD30 positivity. The same goes for the other T-cell entities if they have CD30 positivity. This is the first randomized study that we have showing that an agent actually improved upon our standard backbone of CHOP.

Our data to support using etoposide in this setting, as Barbara mentioned, is based upon retrospective analyses of older studies. We don't have randomized data to support that. In a way, we're almost using etoposide as going on a hunch that we think it's making things better, but we didn't have clear-cut data to support that.

Now we at least have really solid data showing that brentuximab makes a difference when we add it to CHOP. When I have the ability to use it, I certainly take that opportunity.

Dr Horwitz: Are you looking at CD30 level of expression? How are you incorporating the eligibility versus what you see in practice?

Dr Moskowitz: I will not use the specific cut-off of 10 percent. If a patient has CD30 positivity noted on their pathology report, I will plan to incorporate brentuximab. I don't necessarily have a specific number that I'm using as a cut-off.

Dr Horwitz: Barbara, are you looking at that data, outside of ALCL, the same way and similar with the CD30?

Dr Pro: Yes, I have the same approach. We will see whether or not some of the new agents are going to make a huge difference in patients with angioimmunoblastic T-cell lymphoma T-follicular helper in general. We will have to see if some of these new agents, including HDAC inhibitors and hypomethylating agents, will change the landscape of treatment in those specific subtypes.

Outside of a clinical trial, I do share the same experience that Alison has. In terms of CD30 positivity, at least we know from the ALCANZA study, which was done in patients with CTCL, that the intensity and the expression of CD30 can be very valuable. That's why I also don't use a cut-off of 10 percent. I will just make sure there is some positivity. If so, I will use brentuximab probably.

Dr Horwitz: Out of curiosity, how are your pathologists reporting it? Ours tend to give a number, but maybe they'll say "5 to 10" or "less than 5." They don't always give a specific number, but they will try to report a percent positivity for us. What do you see in your reports?

Dr Pro: Same. We typically get a percentage of positivity.

Dr Horwitz: You both use this regimen a lot. Maybe, Barbara, in terms of trial data and also in your clinical practice, suggestions or tips on toxicity, side-effect management when you're treating patients with BV-CHP?

Dr Pro: It's very important to note that this regimen can be pretty myelosuppressive. We have seen that with the ECHELON-2 first analysis. All the patient type received growth factors to decrease the severity of neutropenia and the possibility of neutropenic fever. I typically do that.

Also very important to ask about neuropathy every time they come in for the next course of therapy and really pay attention to the possibility of ongoing neuropathy and then decrease the dose or even sometimes increasing interval of administration if a patient develop neuropathy.

Very important to get a very good history in patient with diabetes whether or not they have baseline neuropathy. You need to pay extra attention of dosing in those kind of situations. I think growth factor and neuropathy are the major toxicity that we need to pay attention to in patients that we decide for them.

Dr Horwitz: Thank you. Other groups that I'd be curious, maybe Alison, what you think about is, in the study, the ALK-positive ALCL, which are already more favorable, had to have two risk factors or ECOG two or greater. Are you applying that data to all patients with ALK-positive disease or selecting just for the high-risk patients? How do you incorporate that?

Dr Moskowitz: Once again, knowing that brentuximab is such an active single agent in ALK-positive anaplastic large-cell lymphoma, I am extrapolating from the study and will certainly use the opportunity to add brentuximab to CHP for those patients, as I believe it is likely benefitting them over standard CHOP.

Part of the reason why I'm comfortable -- continuing on with regard to the discussion for toxicity -- is that the Brentuximab-CHP regimen tends to be fairly well tolerated in comparison to CHOP. I think they're actually fairly similar with regard to toxicity, particularly because the vincristine was taken out of the regimen.

Certainly, neuropathy is something we have to watch. I generally do use growth factor with those regimen, but those are the same things that we're watching with someone getting standard CHOP. To me, it doesn't seem to be such a stretch to be using this regimen a little beyond, for patient populations who were not necessarily eligible for the study.

Dr Horwitz: Thank you. The other piece of data in terms of incorporating the ECHELON-2 strategy -- maybe, Barbara, I'll ask you -- is transplant. We talked about how we all have a bias towards transplant. Part of that is because we think that standard therapy doesn't cure enough people, so we're trying to intensify or consolidate to increase the cure rate.

Now, we have this regimen that has some higher CRs, higher PFS, OS. What does that do to your transplant decision? How do you think about that?

Dr Pro: Still recommending transplant. As you know, there was an analysis about patient treated on the ECHELON-2 study. As you know, this was not intended to be any type of endpoint on the ECHELON-2 study, but we do have data collected about patients who underwent stem cell transplant for consolidation and those who did not.

Again, numbers are very small, so we cannot really make many conclusion. At least, there is a trend for patients who undergo transplant to have better outcome. I'm still recommending transplant for patient with CR with the combination of BB and C.

Dr Moskowitz: I agree with that. I haven't changed my practice with regard to who I recommend a transplant to. I still would use that even if I used brentuximab-CHP as my frontline treatment.

Dr Horwitz: I feel the same way. I think the data supports that. There is still room for incremental benefit.