The Biology of Advanced Melanoma

Transcript:Keith T. Flaherty, MD: Hello, and thank you for joining us today for this OncLive Peer Exchange Panel Discussion on the Treatment of Advanced Melanoma and Basal Cell Carcinoma. In the last 5 years, there have been FDA approvals for 12 new agents and combination therapies for patients with advanced melanoma. This is only the tip of the iceberg, with extensive research still ongoing in the field. With this explosive progress, there is a lot to learn about optimal use of newly developed agents and emerging agents. This OncLive Peer Exchange will focus on personalized approaches to treatment as well as looking at schedules, dosing, and sequencing of novel agents.

I’m Dr. Keith Flaherty. I’m the director of the Termeer Center for Targeted Therapy at the Massachusetts General Hospital in Boston, Massachusetts, and professor of medicine at Harvard Medical School. Joining me today are Dr. Georgina Long, professor of melanoma medical oncology and translational research at the Melanoma Institute of Australia, the University of Sydney; Dr. Jason Luke, assistant professor of medicine and in the Melanoma and Developmental Therapeutics Clinics at the University of Chicago; Dr. Jeff Weber, the deputy director of the Laura and Isaac Perlmutter Cancer Center and professor of medicine at NYU Langone Medical Center in New York; and Dr. Jonathan Zager, a professor of surgery and the director of regional therapies at Moffitt Cancer Center in Tampa, Florida. Thank you all for joining us. Let’s begin.

So, to the distinguished panel today, I thought it would be useful before diving into the therapies to take a little bit of a look at the biology of melanoma and how that sets us up for thinking about the application of targeted therapy, immune therapy, the same. Again, saving the therapies for a moment, maybe Georgina, just give the audience a little bit of a sense of how it is that we think about the important genetic subgroups or subpopulations within melanoma.

Georgina Long, BSc, MBBS: Sure. What we really know and understand very well are these driver mutations which we see commonly in melanoma. And that would be mutated BRAF, particularly V600, NRAS mutations, and in alterations in NF1. However, having said that, we know from the extensive research and the recent data from the TCGA (The Cancer Genome Atlas) that there are many mutations and aberrations in melanoma, particularly cutaneous melanoma, which is the most common of the melanoma subtypes. And how this relates to what’s happening with genes being expressed, the immune system, and the microenvironment, it’s still something we’re working out. But in terms of how we approach it therapeutically, we think in terms of that big group of BRAF, NRAS, NF1, and then CK, of course, but there are many aberrations. And we know that cutaneous melanoma is highly, highly mutated and has a strong UVC (ultraviolet C) signature in general. The proportions are important as well. About 40% have a BRAF mutation in cutaneous melanoma.

Keith T. Flaherty, MD: And in your practice, how would you quote this? The NRAS mutant population for which new therapies may be emerging, how many patients, what percentage?

Georgina Long, BSc, MBBS: In Australia it’s around 20% to 25%. We know NRAS is associated with some chronic sun damage and highly mutated state. So, in Australia it’s around 25%. But if we looked across the world, it’s probably around the 20% mark.

Keith T. Flaherty, MD: Yes. Jeff, melanoma has long been favored by the tumor immunology field as a tumor type in which to investigate therapies. Now, of course, it’s the first home of many of the recently developed therapies. What is it about the biology of melanoma, the immunobiology of melanoma, that sets it apart from other cancers?

Jeffrey S. Weber, MD: Well, I think there are two things, Keith. One is that it is a tumor of transformed melanocytes. And melanocytes, as part of their physiologic processes, tend to export things to the surface. They express antigens or molecules at the surface that potentially could be recognized by the immune system. Perhaps more importantly, it appears almost amazingly that the mutational load in a tumor determines whether or not new epitopes, new molecules that could be recognized by the immune system, could arise. So, as Georgina was saying, if you look at the average mutational load, melanoma is the number one of all tumors that’s a median of about 600 or 700 individual nonsynonymous mutations—meaning a mutation present in the DNA of the tumor that’s not present in the DNA of the normal cell, and it’s not a so-called SNP, a single nucleotype variant. They would have the potential to then encode a peptide, a fragment of a protein that could be recognized by the immune system. Because of all those mutations—even though I guess that’s bad news for the transformed state of the cell—a lot of mutations mean the cells grow out of control and make cancers. It contains within it the potential seed of its own destruction so that it could be recognized by the immune system.

Keith T. Flaherty, MD: So, Jason, the past few years there’s been this theme developing a deep look at tumor cells and their genetic makeup, and then over here the constituents of the tumor microenvironment—immune cells in the environment. But there’s more and more insights, including from your group, that suggest there’s actually an interplay. Like the tumor cell actually essentially interacts with the microenvironment, probably in its development most importantly. Maybe a couple thoughts about merging evidence along those lines about what it is about tumor cells and target pathways that otherwise relate to this immunobiology.

Jason J. Luke, MD: Absolutely. What we’ve been finding is that there appear to be, actually, tumor-intrinsic mechanisms of immune exclusion. Meaning molecular signaling pathways that are perhaps not recurrently mutated in a way that we have thought of, like BRAF and NRAS, but may influence whether or not an immune infiltrate can enter the tumor. And we’ve been finding, particularly around beta-catenin, signaling was the first of these, but now P10 has been identified. Some other molecular signaling pathways that people have heard of that perhaps weren’t considered quite so important may be part of our future consideration when developing combination immunotherapy approaches. So, we’re going to get into it, and BRAF inhibitor is very effective, immunotherapy very effective, and there’s going to be an intersection. But perhaps there’s going to be a role for targeted therapy drug development to enhance immunotherapy beyond just going after those driver mutations in the future.

Transcript Edited for Clarity