Advances in the Management and Treatment of Metastatic Melanoma

Jeffrey Sosman, MD

In this podcast we discuss recent advances in the management and treatment of metastatic melanoma with Jeffrey Sosman, MD, medical oncologist and director of the Melanoma and Tumor Immunotherapy Program at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

In the last 2 years, there have been significant advances for treatment of this aggressive tumor type with the approval of two very different types of therapies in 2011. These agents are the first in over a decade to demonstrate an overall survival benefit in patients with advanced melanoma. The first is ipilimumab (Yervoy), an immunotherapy antibody that boosts the patient’s own immune system to fight the cancer. The second, vemurafenib (Zelboraf), is a targeted therapy, an oral inhibitor of BRAF for the approximately 40% of patients whose tumors harbor the V600E BRAF mutation. Since then, two other targeted agents have shown substantial efficacy-dabrafenib, also an oral BRAF inhibitor, and trametinib, an oral MEK inhibitor. Both have been recently filed with the US Food and Drug Administration (FDA) for approval as monotherapies for metastatic melanoma.

-Interviewed by Anna Azvolinsky, PhD

Cancer Network: Let’s talk about the progress of immunotherapy for treating metastatic melanoma. Besides the approval for ipilimumab more than a year ago, the immunotherapy antibody, anti-PD1, has shown high activity for metastatic melanoma. There are also several vaccines and combination immunotherapies also in development. Do we understand why melanoma appears to be particularly amenable to the immunotherapy approach?

Dr. Sosman: I think it's been for a long time we've noted that melanoma has been associated with immune phenomenon. When I say that, we've seen patients with spontaneous remissions, without really any obvious therapy. We have seen patients who have had infections, and in association with infections their tumors can regress and more recently, we now know that there is a whole set of tumor antigens that are associated with melanoma. Most of them are lineage, in other words, they are associated with the skin, and the pigmented cells, the melanocytes. But we have known for a while that that association makes melanoma, possibly, somewhat more immunogenic.

However, the real breakthrough in the last few years has come from sort of the other side of the formula. That is that the ipilimumab that you mentioned, the anti-CTLA-4 or anti-PD1 actually are drugs that break tolerance. And I think we have known that there is a lot of immune activity centered around melanoma, but we have never been able to take really good advantage of it. It probably has to do more with the inability of the immune system to break tolerance to the cancer. And once we have figured out what kind of markers, checkpoints, there were that induced this tolerance, these recent antibodies, the ipilimumab and anti-PD1, appear to be approaches that will break that tolerance and allow the host antitumor effects to take center stage and actually attack the tumor itself.

Cancer Network: The MAGE-A3, which is a vaccine, and ipilimumab are two therapies currently in development for adjuvant melanoma, among others. What is your perspective on when immunotherapies should be given to melanoma patients? Should we be developing these immunotherapies for earlier stage, nonbulky-disease patients to prevent progression and recurrence?

Dr. Sosman: I think that MAGE-A3, ipilimumab and, probably in the future, even anti-PD1, will be brought into the earlier stage of disease where there is no gross disease. That has always been the paradigm that we have developed immune therapy by. The problem is that paradigm, up until this point, has not been very effective. Probably because we have not had any really effective drugs, vaccines, or antibodies that are able to work when we see more advanced disease. Now that we have those drugs, such as the ones you mentioned, I am much more hopeful that we can use them in earlier stage disease. But until we demonstrate this, until we have done clinical trials, phase III clinical trials that show that there is some advantage (survival advantage or progression-free survival advantage to patients receiving these drugs), then we still have not completely closed the loop, and we are still left in the situation where we need to prove it. It is a really nice theory, it has been a really sound theory and certainly takes place in animal systems, but I think we need to show it in humans to really make it convincing. You know, we have had a long history of negative adjuvant vaccine trials, and you can always find reasons why they have been negative: the vaccine wasn’t good enough, the setting wasn’t a good setting to use it in, all of those certainly may be true, but we really need to find and develop the evidence that it can work in that setting.

Cancer Network: Are there any specific immunotherapy agents in development, including some of the ones we have already mentioned, or specific trials that you are particularly excited about?

Dr. Sosman: In terms of immune therapy, right now there have been several trials that have involved ipilimumab. A trial that is closed to accrual, that was run out of the [European Organisation for Research and Treatment of Cancer]. That trial, which involved sites in the United States completed accrual about a year or 15 months ago (maybe a little bit longer), and so we are waiting for that trial. That was a randomized trial comparing ipilimumab to placebo in patients that are high-risk for recurrence. They were all stage III patients and they tended to be stage III with slightly higher risk factors. We also have a trial that is ongoing right now that is looking at the ipilimumab (Yervoy), and it is in even higher risk patients-stage IIIB patients who have had either large lymph nodes or had ulcerated primary [tumors] with small lymph nodes or stage IV disease. And these patients are randomized between interferon and ipilimumab. So that is a slightly different design and that trial is ongoing and I think about 600 patients have been accrued and probably has another year or two to complete accrual, but is actually accruing well which is important for a national study done in the United States. Those are good numbers.

The other areas I said have not moved forward yet, but I think everyone is anticipating the anti-PD1 antibody being exciting and certainly potentially effective in the adjuvant setting. But those studies as far as I can see are not very well developed, and we are still looking at stage IV disease heavily. And then you mentioned the MAGE-A3 vaccine and those studies have also been completed as far as accrual. There was a phase III study that completed about a year or a year and a half ago that accrued patients with very high-risk disease and those patients were randomized to either placebo or the MAGE-A3, and so we are really anticipated that study. So if any of these studies show positive results, it would change the landscape of melanoma therapy drastically.

Cancer Network: Switching now to targeted therapies, as I mentioned, vemurafenib has been approved, and dabrafenib and trametinib phase III trials were published this summer. Would you talk about the differences between these agents and how they will ultimately be used?

Dr. Sosman: Vemurafenib and the dabrafenib are both BRAF inhibitors. Vemurafenib is a Roche/Genentech product and dabrafenib a GlaxoSmithKline product. They have very, very similar antitumor effects. They both work between 50% to 60% of patients have objective response. Most patients have tumor shrinkage, probably over 85% of patients get actual shrinkage and the median duration of shrinkage or the median duration of progression-free survival that we see is somewhere in the neighborhood of 6 to 7 months. I think that you could overlap those two curves. The side effects are different. The vemurafenib causes significant photosensitivity and sunburn, and so you really need to be careful and put on a lot of sunscreen and stay out of intense sunlight. This can be an issue. The dabrafenib probably has more fevers and chills, very much less sunburn, in fact very little if anything. And then there are skin cancers, squamous cell skin cancers. While initially the feeling was that patients receiving dabrafenib may have had a lower incidence of squamous cell cancer of the skin, I don’t believe that is really very hard data. I think they are similar. What gets a little more complicated is when you combine the dabrafenib with the trametinib, which is the MEK inhibitor. That is data that we have. It is a phase II study, but it is a randomized phase II study and in that study we saw two things. First, we saw higher response rate, instead of 50% to 60%, we saw more like 75% of patients getting an objective response. We also saw an increased progression-free survival. So instead of the 6 to 7 months I told you about, it is more like 9 to 10 months. Finally, when you combine the two, you see much less squamous cell cancer, which is probably quite important. There is one negative aspect of the combination. And that is fevers and chills. As I told you, the dabrafenib has fevers and chills associated with it, but when you add the trametinib it is much worse. So, in all cases, you are dealing with some trade-offs. But I think most people right now feel that over the next few years, it is very likely that the combination of a BRAF inhibitor with a MEK inhibitor will become a standard of therapy.

Cancer Network: There is also a trial combining the two approved agents, vemurafenib with ipilimumab, so an immunotherapy/targeted therapy combination. Is there a scientific rationale for this specific combinations or the immunotherapy/targeted therapy approach in general?

Dr. Sosman: I think there is both a strong scientific rationale, and the latter, what you just said, that it is just putting two very different approaches together. I think the view is that targeted therapy has a very pronounced upfront effect. You get a lot of tumor dying, you get patients who are alive who would die quickly from their disease without this drug. And so, the immediate effect and the effect on the overall survival curve is very different. On the other hand, with immune therapy, the effect you get is rather unimpressive initially. It is not that you see 80% of patients with tumor regression. You probably see more like 15% or 10%. But when you continue to follow these patients, you realize that there are a number of patients who are alive and doing well who are out 2 years and 3 years and even more, up to 5 years. They are doing quite well, they are still alive and the survival rate is almost, probably double the survival rate of the control arm at 3 years. So if you look at those two curves and you combine them, you would think that you could really increase initial outcome and then give this long tail in which you see the whole curve rise up. Now, there is a scientific rationale to this to. That is the tumor itself, when it is exposed to the BRAF inhibitor, it dies quickly, so there is a release of antigen. That is very quick and very potent and so you are sort of getting your own vaccine, endogenously, by killing all of those tumor cells, and the hope is that you could do that and follow that with this ipilimumab or even anti-PD1, and you could maximize that immune effect. So I think there is a lot of good rationale. The trials of ipilimumab and vemurafenib have been slow at coming-I have to be honest, I have been closely involved with them-and I am not quite sure why, because it has been a real priority for a couple of years.

Cancer Network: Thank you so much for joining us today, Dr. Sosman.

Dr. Sosman: OK, I hope that was helpful.

Cancer Network: Thank you!