Immunotherapy in Melanoma

Jeffrey A. Sosman, MD

Jeffrey A. Sosman, MD, is professor of Medicine and director, Melanoma and Tumor Immunotherapy Program at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. At the 11th International Congress on Targeted Therapies in Cancer, held August 16-17, 2013 in Washington, DC,The International Journal of Targeted Therapies in Cancerspoke with Dr. Sosman about his conference presentation on advances in immunotherapy in melanoma.

IJTT: In your presentation, you mentioned that in clinical trials involving immunotherapies, you would see relatively few responses, but the responses that you did see when the patients received these treatments were durable, and that appears to be the case for all immunotherapies currently being studied. Can you explain this phenomenon and what research has been done to determine what is happening in these instances?

The patient is a 53 year old woman with metastatic melanoma to multiple subcutaneous sites and retroperitoneum.Source: Dr. Steven Rosenberg, the Web site of the National Cancer Institute (http://www.cancer.gov).

Dr. Sosman:There is no question that when we used drugs like interferon and interleukin 2 in the past we saw relatively few responses. However, among patients who responded, some responded for long periods of time. I think what’s believed to happen is that memory forms in their immune response against their cancers. In fact, I have never seen a renal cancer patient who has relapsed after three or four years free of disease following interleukin-2. Now there are few of these post-IL-2 long-term responders, but it seems as if they have less chance of relapsing than someone who has been free of disease after nephrectomy. So there is some critical immunologic change. I think that the best example is the vitiligo seen in patients with melanoma who receive effective therapy. When we see responses, we frequently see some parallel destruction of their melanocytes, and this can even surround the melanoma. The immune response persists and even gets more consistent and more diffuse with time, as a sign of the memory that treatment has induced.

What is the mechanism of action of ipilimumab? What has allowed it to be proven to be efficacious for patients with metastatic melanoma?

Dr. Sosman:There is an easy answer to that and then a little more complex answer. The simpler way of thinking is that the brakes on the car are bound by ipilimumab releasing the car (an immune cell, a T cell), and by binding the brakes it prevents the immune cell from braking normally, thereby basically running away without the ability to turn off its motor or its immune response. That’s the simpler way of thinking about the drug action. There are some recent data that suggest that ipilimumab might also play a role in eliminating one of the subsets of cells that I spoke about that are immunosuppressive, the so-called “regulatory T cells.” They express CTLA4 on their surface, and Alan Korman has recently shown that these regulatory T cells are eliminated as part of the treatment in animal models. But most of us think of this loss of brakes as unregulated activation of the T cells, which leads to both the response and some of the toxicity as well.

In your talk you mentioned that using singleagent small-molecule inhibitors is not really an option once a patient’s disease progresses. Can you tell us a little bit more about what you mean by that, and how immunotherapies fit into this discussion?

Dr. Sosman:I think small-molecule inhibitors clearly are not going to be very effective for longterm, durable responses. In general, as a single agent, whether it is vemurafenib in melanoma or erlotinib or crizotinib in subsets of non-small cell lung cancer, despite the fact that they are all very good agents that can improve survival, 100% of the patients receiving these agents will ultimately relapse. So there are two strategies addressing that. The first strategy is to add more inhibitors, and the second is to add a different modality, and most of us—at least those of us working with melanoma and probably those working with lung cancer as well— are thinking about adding the immune treatment. Now, whether the immune treatments directed at CTLA4 and PD-1 can be used in combination really will be the key. There is a big trial to look at that, and we will see if it really is better. But when you start talking about combining all of these, you do have some cost issues.

As someone who specializes in melanoma, it must be interesting that so many new agents have recently been approved for the treatment of this disease. What do we know about sequencing these various therapies at this point in time?

Dr. Sosman:Right now in the practical sense, that’s a really important question, and hopefully there will be a trial in the cooperative groups that looks at that. One of the problems with developing such a trial has been deciding what agents will make up the sequence. That’s been changing. Initially, it was ipilimumab or vemurafenib, but now it is anti- PD-1/PD-L1 and maybe ipilimumab versus a MEK inhibitor, trametinib with dabrafenib. I think most of us right now believe that some patients will probably have a better chance and a long-term durable response if they receive immune therapy first. Now even with that said, it is not so easy that we can predict speed of disease progression. I think we make a judgment when we see the patient. If they have indolent disease, we might have more time, and we might be able to treat them later with a targeted agent. However, that’s not always the case, and frankly, some of those patients I think are harmed by doing that, but we make a guess to the best of our ability. I think we need a trial--some of the patients who get targeted therapy, specifically small molecules initially and then, when they relapse, some of them relapse with fairly aggressive disease, and at that point it can be very difficult to give immunotherapy. So there is a belief and many anecdotes that in certain groups of patients, it would be better to give immune therapy first. That’s not a patient who has rapidly growing disease or high LDH or poor performance status who needs response. That is instead the patient who has a performance status of 0 and feels great and has small-volume disease.

What should community oncologists know about the adverse events associated with these newer therapies, and are there any other challenges?

Dr. Sosman:I think one thing I have to really applaud is something that the pharmaceutical industry is trying to do. It is trying to really regiment the approach to toxicity, and they have refined the algorithms over and over, and I think they are getting to a point where as long as there is good communication between the patient and the physician’s office, these patients can probably be managed very effectively. Now, if you don’t have that communication or if you don’t have an effective algorithm that really needs to be done, you can get into big trouble. I think especially with ipilimumab where we have seen that toxicity, there are now really nice diagrams and approaches that have been very clearly outlined, and I think that’s a real advantage. I tend to probably err on the overly aggressive side in terms of reacting to side effects. I think with PD-1 and similar molecules, I am actually a little concerned that sometimes we’re overreacting to cough or to a little shortness of breath. We are still trying to refine the approach to anti-PD-1 pneumonitis.

So it is really still a learning curve for the therapy?

Dr. Sosman:I think there is still some, but little by little, the pharmaceutical industry, and obviously with input from physicians in making those decisions, I think we have done a good job, and it is their role to really get that out into the community and make doctors comfortable. Community oncologists have not been overly comfortable with ipilimumab.

In your presentation, you mentioned a study presented at this year’s ASCO meeting that looked at the combination of ipilimumab with GM-CSF. Could you give us your thoughts on the toxicity profile seen in that combination and what it really means for patients? You noted that there was a survival benefit but not a progression-free survival (PFS) benefit.

Dr. Sosman:First, I don’t know for any certainty why there was a survival benefit. It is feasible that it was just enhancing the immune response. The PFS being similar doesn’t really bother me very much because we have seen that in immunotherapy- based trials. What makes me suspicious that it is more a toxicity issue is that those overall survival curves separate fast if you look, and it is not like vemurafenib versus DTIC. In that trial you are saving very sick patients who are still alive as opposed to being dead from their disease. I think if you look overall at that study—and I am not sure that this is a concern—it may not be so clear what GM-CSF is doing in that case. Now, if it is enhancing survival, truthfully who cares? The question is, it may enhance survival of a regimen that we may never use. That’s why the 3-mg dosage versus 10-mg dosage study which has been completed, is really important to see what those results are.

Many clinical trials require patients to have a performance status of ECOG 0 or 1, yet many times, patients in the community might be presenting with ECOG 3 or 4. What should community oncologists do in those cases?

Dr. Sosman:I think those are difficult patients, and I think the point [an audience member at the conference] made about treating them with these investigative drugs is totally valid. I think the immune- targeted drugs in those really sick patients, at least from what I have seen so far, are really unlikely to turn patients around if that performance status is due to the tumor. On the other hand, I do believe that the targeted small molecules that you will hear about can really have an impact on those patients rapidly and really have this so-called “Lazarus effect.” Now, the problem is that it is all too short, but it does provide some really quality time. On the other hand, Paul Chapman has tried to do a ECOG 2 and 3 study with vemurafenib, and it was very difficult to try to find patients who were poor performance status for a trial, yet not so poor that it is just totally unreasonable. I think we would like to do those studies because those are kind of real-world important studies, but they are not easy to do. So we will see if they can be done.

You have investigated the use of imatinib in melanoma for patients with KIT mutations. Could you tell us a little about how this wellestablished targeted therapy might be used in melanoma? How common are KIT mutations in patients with melanoma?

Dr. Sosman:I think the latter question is really important, and I think that from our data and other people’s data, the frequency of KIT mutations is quite low. It is really in the neighborhood of 1% to 3% of the whole population. It also appears that almost all of them come from three locations or three general body areas. One is the mucosal membranes, second is the hands and feet, the acral areas, and third to a much lesser degree is the head and neck area where there is chronic sun exposure. In some areas where primary melanomas come from the torso or extremities, you almost never see it. So it is a long, hard journey finding those patients. Also, some of those mutations are not responsive to KIT inhibitors, and we know that from imatinib, in GIST tumors or in other situations. But if you have one of a few mutations at a few codons, the studies now— Stephen Hodi just published the study and Richard Carvajal had a previous study—if you look at that small group of patients, it looks like it is in the neighborhood of 50% and some are durable. Obviously they are all going to relapse with resistant disease, but I think if someone presents to me and has a KIT mutation, which we screen for, and it is one of those mutations, I certainly would consider using something, whether it is imatinib or a study looking at another KIT inhibitor.

Overall, where do we stand in terms of the use of immunotherapy in cancer? What is its future? Do you feel that it is firmly here to stay in cancer treatment? What are the most promising next areas of exploration?

Dr. Sosman:I think I have become a believer again, for certainly the checkpoint inhibitors have had a huge impact. And I think they will get approved and probably in all three diseases, melanoma, renal cancer, and non-small cell lung cancer. I don’t know if the 30% or 40% response rate will hold up, but I have confidence that the response rate will not be as low as 5% or 10%, and responses will be durable. So I think immune therapy agents are clearly here. How do we best utilize them? In the future, I think we will have to see. We certainly want to bring them to an earlier point, certainly from metastatic disease, and use them earlier upfront. Obviously the question is, can we use it in high-risk patients and prevent relapse? That’s a really important question. I think the options now are going to be combining those two, and there is certainly a rationale to do so with ipilimumab and nivolumab. I think the other area that’s of greatest interest is the combination of small molecules with these drugs, with immune therapy, because we know that a really high percentage of patients have tumor regression with targeted therapy. If we could somehow have the durability of the immune response to that, we can make a huge impact.

Could you talk about the trial comparing the 3-mg and 10-mg dosages of ipilimumab and the importance of doing that trial? What is it going to mean going forward with the use of ipilimumab?

Dr. Sosman: