Transcript:Michael A. Postow, MD: Immune therapy is a very important treatment option for patients with advanced melanoma. Because despite our best efforts and the fact that chemotherapy can help some people with melanoma, traditionally it hasn’t been as effective as we would like it to be. And therefore, for many, many decades, people have been trying to study different ways that the immune system could be manipulated to take care of patients with advanced melanoma. And remarkably among many different cancers that can respond very well to immune therapy approaches, melanoma is the one tumor type that has been very responsive to immune therapy approaches, and it’s really amazing how, in some patients, we can have these really impressive responses to immune therapies in advanced melanoma. There are many theories as to why melanoma may be the most responsive or one of the most responsive diseases to immune therapy. I don’t think we’ve completely hashed that out just quite yet, but it is a cancer type that really can benefit from immune therapy. In many, many contexts, immune therapy is far greater, more effective than chemotherapy.

When I talk to my patients about immunotherapy, I think the most important issue to describe to them is it’s entirely different than what they may think about for traditional cancer therapy. And when many patients are thinking about what type of treatment they’re going to receive for their cancer, they’re thinking about chemotherapy, radiation treatment, or other kinds of standard treatment approaches, which include targeted therapy — pills that go in and specifically target particular mutations within the cancer.

When I have a patient that I’m talking to about immune therapy, I think the first thing that’s important to them is what is done to enhance the normal body’s immune system. So, we all have an immune system, and I think of the immune system as an army within our own bodies that is important for attacking and protecting the body against foreign invaders like bacterial infections, viral infections. But, this army is actually also important against protecting against cancer. And so, in patients that develop cancer, for whatever reason, that army of defenders that we all have in our body called the “immune system” is just too weak. We need immune therapy when patients have these types of cancers to boost that army’s ability to defend the body against cancer. In many cases, that can even result in the tumor shrinking — sometimes, in rare cases, going away completely — and in some cases, just controlling the cancer so that the patients can live long, productive lives despite having cancer, and it’s cancer that we can see on a CAT scan. So, it’s really a strategy of improving the body’s normal, natural defenses against the cancer that’s within the patients’ bodies, and there are a number of different strategies that are being done to try to boost the body in that type of a way.

Michael B. Atkins, MD: How do I explain to patients about targeted therapy and what it is? Well, typically, I tell patients that about half of melanomas have mutations in a gene called BRAF, which tends to act as a dominant driver mutation driving the tumor and controlling its biology. And we can test for that by just taking a piece of tumor tissue that has often already been collected and having it analyzed to detect that BRAF mutation. Targeted therapy consists of pills that have been developed to actually block the function of that mutation. Those pills are BRAF inhibitors, such as dabrafenib and vemurafenib, that are very effective at shutting down and inhibiting tumor growth in tumors that have that BRAF mutation. Because any time you’re just blocking one point in a pathway driving a tumor, the tumors are very good at getting around it eventually. So, what we found in clinical trials, if we add a second drug called the MEK protein that blocks another step further down in that pathway, we can make the BRAF inhibitors work better and delay resistance to that therapy.

How do we use BRAF mutation testing in our clinical decision making? We can when patients are diagnosed with advanced melanoma and we want to get a quick test to see whether or not there’s a BRAF mutation because it could influence some of our treatment options. If patients have a BRAF mutation in their tumor, it opens up another set of treatment options, including the BRAF and MEK inhibitors, which are also very effective options. We want to know whether that option is available, even if we’re going to give immune therapy, because it serves as a safety net when we’re giving immune therapy. In addition, we’re starting to try some protocols that help determine whether patients should start with BRAF inhibitor therapy or immune therapy when they’re first diagnosed, and knowing whether a patient has a BRAF mutation or not could help us consider patients for those very important protocols. In patients who are BRAF wild-type, we tend to give them immune therapy as their first treatment option. But, if they don’t respond to immune therapy — particularly if their disease is progressing — we may, at that point, do more sophisticated tumor typing using next-generation sequencing to see whether there’s an NRAS mutation, some variant mutation in BRAF, or potentially another targetable mutation in their tumor that might influence the way we treat those patients after immune therapy.

Transcript Edited for Clarity