Advances in the Treatment of Malignant Melanoma - Episode 16

Future Treatment Landscape for Melanoma

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Jeffrey S. Weber, MD, PhD: Ryan, bring us home. Tell us about what you think are the more promising emerging approaches. We’ve heard about TILs. We’ve heard about triple therapy, BRAF-MEK, immunotherapy. What do you like?

Ryan J. Sullivan, MD: What I like and what I think is coming next are probably in line, and then there may be some of the things that I think could also be in the future. If the data with TIL therapy, for example, which in an, albeit selected population, 66 patients, they obviously had to have a tumor that could be resected. They had to be able to grow the TILs. They had to be well enough 3 or 4 weeks later to receive lymphodepleting chemotherapy and then get the TIL product and the IL-2.

The response rate in a heavily pretreated population, everybody who had PD-1 inhibition, three-quarters or more had had CTLA-4 inhibition, with a 36%, 37% response rate. It’s totally respectable. The waterfall plot definitely inflected past 50%, meaning most patients had some tumor regression.

There’s a 75- or 80-patient cohort. If there’s a similar response rate seen in that cohort, I would anticipate that that would be FDA-approved. That’s exciting. Anytime there’s a new potential drug that could be approved, it’s exciting. At centers, Jeff, you’re obviously an expert at giving TIL therapy. Most of us aren’t. Fortunately, CAR T-cell therapy has forced all of our institutions to rethink delivering cells to patients. Ten years ago, this would have been a hard thing to roll out. Now it would be a relatively easy thing to roll out. That’s one thing that came out of this. It was reinforced data that were updated from last year, but data nonetheless that are encouraging and likely speak to a near-future change in the way we manage patients in the refractory setting.

Jason J. Luke, MD, FACP: Ryan, can I make one more comment quickly?

Ryan J. Sullivan, MD: Yes.

Jason J. Luke, MD, FACP: The other data that I was impressed by in this update were that when you looked at the responding patients to lifileucel or the TIL product, they disproportionately were people who were outright refractory to PD-1. When we go back to what Adil said earlier about wringing out all the T cells, these are patients who do very poorly. The idea that they have a disproportionately more active agent for that population of patients, to me, makes this a high priority. I’m actually really excited about this because I feel like these are the patients who we have not advanced the field for. We’ve done really great for some of the patients. But for these patients, we have not made progress. Maybe this is it. We’ll have to wait and see. We still need more data.

Ryan J. Sullivan, MD: Yes. The other point that Adil made was that we need to see how durable the responses are. In fairness, the duration of response with 18 months of follow-up hadn’t been met yet. Certainly, some of these responses were very transient, and by 4 or 5 months, the response was gone, and patients had progressed and were either on to something else or unfortunately not onto something else. In the majority of patients, those responses were lasting 18 months or longer. It’s a commercial product. It’s something that we might be able to use if it gets approved, as soon as it gets approved. They are exciting data for a population of patients who don’t have a lot of exciting data.

The triple therapy, so BRAF-MEK/PD-1 or BRAF-MEK/PD-L1,, this is a decade in the making with phase 1 and phase 2 trials that many of us were part of. Then to see an idea that BRAF-targeted therapy causes changes in the tumor microenvironment, maybe adding immunotherapy would be useful. Ultimately, it seems like it might be. In the frontline setting, there seems to be an improvement in progression-free survival. There seems to be an improvement in duration of response. That’s not just in a randomized trial that we talked about before, the IMspire150 or the trilogy study, which is vemurafenib/cobimetinib lead-in for 28 days and then you add atezolizumab.

There’s also a dabrafenib/trametinib/pembrolizumab study that was randomized and showed an improvement in progression-free survival and a trend toward an improvement in overall survival in patients who received triplet therapy versus doublet BRAF-targeted therapy.

Also updated at ASCO this year was the COMBI-i study. It’s a randomized trial and that part hasn’t been updated yet. That data have not been released, and are not mature yet. The nonrandomized phase 1/2 data show a complete response rate of 44%. That’s a remarkable number. If in the randomized data you get a complete response rate in the 35% or 40% range, that’s dramatic. We anticipate that that would meet the primary end point of progression-free survival.

Ultimately, where that fits, I don’t know. That’s not comparing against PD-1 inhibitor therapy. That’s not comparing against ipilimumab or nivolumab. We’ll at least have things to argue about at our meetings for the next 5 years until somebody does that type of study. It’s still another option. There are patients who are BRAF mutated that we give BRAF-targeted therapy to because we think they’re going to die 2 weeks from now. Now we can offer those folks BRAF-targeted therapy plus a PD-1 inhibitor with some hope that they’ll do well. If we have BRAF-MEK, PD-1, and PD-L1 studies, I think that seems likely that that’s another thing that could get to the clinic. We obviously can all do it off-label. That’s something that could be approved in the next year or two as well. The more options we have, the better.

In terms of other things, I think there are first-line cancer vaccines plus PD-1 inhibitors. We’ll see where that goes.

Jeffrey S. Weber, MD, PhD: What about the thing that Jason mentioned? He talked about pembrolizumab plus a nontoxic partner. What about NKTR-214?

Jason J. Luke, MD, FACP: IL-2 is an old drug. Bempegaldesleukin is a modified version of an old drug that has a bunch of PEGylations on it, which have been shown that it seems to preferentially target the receptors on the T effector cells and the NK cells, as opposed to T regulatory cells.

The data in single agent are compelling in terms of you can see changes in tumors. It’s not so compelling in terms of single-agent efficacy. In combination with PD-1 inhibitors, it seems like there’s something there. Whether that’s so much there that you end up with a positive phase 3 trial, I don’t know, but we’ll find out, because that phase 3 trial is ongoing. It’s nivolumab plus or minus bempegaldesleukin.

There are other IL-2 analogues that are out there now too. We’ll have to see where that part of it goes. It’s a compelling concept to use IL-2 because it did set the bar for potentially curative therapy in melanoma. It just was a low bar. The question is, if you add that to PD-1, do you really raise the bar further, or are you just treating the same patients who were going to do well with PD-1 inhibitor? I guess we’ll find out. It’s exciting that these trials are out there and that they’re asking these questions, and hopefully will answer them.

Transcript Edited for Clarity