Metastatic Melanoma: The New Millennium - Episode 1
Keith Flaherty, MD: Hello and thank you for joining this OncLive TV Peer Exchange, “Metastatic Melanoma: The New Millennium.” I’m Dr. Keith Flaherty, and I’m director of the Termeer Center for Targeted Therapy at Massachusetts General Hospital in Boston.
Joining me today are Dr. Rene Gonzalez, a professor of medicine and director of the University of Colorado Melanoma Research Clinic; Dr. Jason Luke, an assistant professor of medicine at The University of Chicago; and Dr. Jeffrey Weber, a medical oncologist, deputy director of the Perlmutter Cancer Center at NYU Langone Medical Center in New York City.
The tools we have available for treating patients with advanced melanoma continue to expand, as do the data to help us use these novel therapies in more effective ways than ever before. Today, we will talk about the most recent advances in melanoma research and will provide perspective on how you can apply the newest data to individualize treatment strategies for your own patients. Thank you to each of your joining us today. Let’s get started.
Dr. Luke, I was hoping to start off on the topic of local therapies for advanced melanoma. This is not a concept that really ever gelled in clinical practice as having a lot of impact, certainly not for systemic management of disease—as palliation at best, but not really as a disease-modifying strategy. But it seems like we’re on the dawn of something more meaningful than that, and with the recent approval of T-VEC, I thought that might be the place to start in terms of really trying to understand what that agent has to offer and then also maybe trying to project where might it fit in in the years to come. But, for this audience, it might be useful just to start off with what is T-VEC, what’s its mechanism of action.
Jason Luke, MD, FACP: Absolutely. T-VEC is an interesting novel approach in the treatment of cancer. T-VEC is a modified oncolytic herpes virus in which the replication machinery of the virus has been changed such that the virus only replicates in the tumor. And the idea is that upon infection of the cancer cells, the virus will grow and cause lysis of the cancer cells.
As another modification of the virus, part of what has been changed was the inclusion of some immune genes, notably GMCSF, and what that does is when the cells lyse, it then recruits in other immune cells which hopefully can amplify a larger immune response. And so to date, T-VEC, as a drug, is administered as an injection into individual tumors on the skin or maybe in the lymph nodes and really works in that local fashion.
The question becomes on a larger scale then, is there more to it than that, and I think we’ll have some discussion about that here moving forward. But on the FDA label as it currently stands, the drug is injected into lesions that are on the skin or in the lymph nodes. And the data suggest that as compared with injection of GMCSF alone, there is a durable response rate of 16% relative to 2% for that injection, meaning that you can get local control of tumors on the skin or in lymph node basins.
The larger data regarding survival is a little bit less clear and likely stratifies by AJCC stage, and I don’t think we fully understand that yet. But if we stay within the context of the FDA label, certainly this is a treatment that’s highly efficacious for management of local melanoma.
Keith Flaherty, MD: For listeners to this discussion, I’ll bet this is really new territory. And immune checkpoint antibodies, of course, had been now standard treatment with ipilimumab dating back to 2011. Rene, in your experience and investigation, and just considering the data in aggregate, how would you summarize the safety/tolerability profile of T-VEC?
Rene Gonzalez, MD: It’s an extremely easy drug to use. We were involved in the early studies, and it’s an easy intralesional injection. The toxicity is fairly minor—local injection—type reactions, such as fever and chills. But I can’t recall a patient that we actually had to stop the drug because of toxicity. The response in the injected lesion is certainly higher. The concern is what happens really with the distant disease: does it have a distant effect? It seems like it does, but it’s less than the local injection.
Keith Flaherty, MD: It’s interesting in the FDA approval. The language of the package insert, FDA label, almost cautions against physicians trusting that they’re going to get a result. But what’s your sense in looking at the data? If you have a patient who’s got predominantly locally regionally advanced disease, but some visceral metastatic disease, do you consider this to be potentially a systemic therapy for that patient or are you really just initiating local control measures and anticipating moving to a more systemic therapy soon after?
Rene Gonzalez, MD: Potentially, it wouldn’t be my first choice as a systemic therapy. At the time this began to develop, it was quite a while ago, and we have now drugs that are highly effective and it wouldn’t be my first choice for systemic effect. Even if the patient only has an injection lesion, or two or three, I still probably wouldn’t start with this drug because I would be more worried about the systemic disease. But I think there’s possibly a role for it, especially in combination with some of the newer agents, to achieve local control.
Keith Flaherty, MD: What’s your take on the kinetics of response? I mean, sort of the time course from beginning of injection in the trials, they were generally repeated but didn’t always have to be repeated in the same lesions. New lesions could be injected or one could rotate around. So, what was your sense of kind of how long it would take a lesion to show signs of response?
Rene Gonzalez, MD: Usually multiple injections, but I’ve seen some disappear after just one injection, and you can move on to the next one or if something new appears, just go ahead and inject it there. You can inject into the lymph nodes, into the subcutaneous tissue. Occasionally, it’s useful to have something like ultrasound guidance to guide the injection. The dose is split up. I think it’s up to four lesions at a time or 4 mL, so up to 1 mL per lesion.
Keith Flaherty, MD: So, Jeff, if you were to think about the armamentarium we have now, some of which we’re going to talk about later in the discussion, how would you see this agent fitting in? As it stands now as a single agent, could you imagine sort of a sequence, trying to leverage its mechanism or do you await combination data before you think that you really have a role for it?
Jeffrey Weber, MD, PhD: I could look at it in two ways. I see this as a niche drug in the same way that we look at isolated limb perfusion as a niche in melanoma. Because, as you all know, melanoma is an unusual tumor in that there are many patients who have local regionally confined disease, almost unlike any of the other of the common malignancies, where you’ll have someone relapse and relapse and relapse only in the left lower extremity below the groin, and this could go on for years.
You could also have people with subcutaneous local regional disease in the trunk and it could go on for years and years, literally on one side of the body. I almost cannot imagine the biology of that scenario, but, nonetheless, it opens up possibilities for local regional therapy. I would say this again is a niche.
Only a relatively modest number of patients in this country and in the EU, for example, would have a need for a local regional therapy only. I think the data clearly show that when T-VEC is used alone as a direct injectable into tumors that are subcutaneous and nodal, the likelihood of visceral metastatic benefit is very low. If you look at the data from the original trial that led to its approval—the randomized trial versus GMCSF alone—when you look at the outcome for visceral metastatic disease, there is no real difference in survival. So, certainly, I would not use this as a standalone agent in someone with visceral disease. I would rank it with an isolated limb perfusion, not by response rate because it’s probably not as good as an ILP. But it is so nontoxic, as Rene pointed out, so well tolerated, I would see it in the patient who might otherwise get an ILP as a perfectly reasonable possibility.
Now, you were alluding to the fact that it would appear to be the perfect immune primer. In animal models, if you have local destruction of tumor from whatever maneuver, you could use BCG injections as we used to do with these tumors in the old days—interferon, IL-2—and then you add a systemic immunotherapy. Sometimes you can see a priming effect, which will amplify the effect of the systemic immunotherapy, and that’s been tested in clinical trials. I think it is worth waiting for those data, which we will have, I hope, quite soon.
So, I wouldn’t willy-nilly go give someone T-VEC and then after eight weeks stop and put them on pembrolizumab. I think that’s an expensive approach to local regional disease. If, on the other hand, the current trials of T-VEC plus pembrolizumab—whose initial toxicity data that were presented by Georgina at ESMO show that you have an impressive response rate beyond what you would see with pembrolizumab alone—I think that a lot of docs would take patients with local regional disease, inject the T-VEC, and then stop at a certain period of time and then give them pembrolizumab or some other immunotherapy off protocol.
Transcript Edited for Clarity