Weber Explores Advances in Metastatic Melanoma

Jeffrey S. Weber, MD, PhD

Metastatic Melanoma

In an interview with OncLive, Jeffrey S. Weber, MD, PhD, from the Moffitt Cancer Center, University of South Florida, Tampa, explored the utilization of molecular and immune-targeted therapies as treatments for patients with advanced melanoma. Weber has focused his research on translational clinical trials including development of novel trials in melanoma, including the monitoring and characterization of T-cell responses to vaccination in cancer patients and the establishment of in-vitro models to facilitate an understanding of how immune modulating antibodies amplify T-cell responses in patients. He is interested in the mechanisms by which achieving autoimmunity induces regression of cancer.OncLive: What are some of the important advances in terms of targeted therapies for metastatic melanoma that we have seen in recent years?

Dr. Weber: There’s no question that there have been huge numbers of advances made in the field over the last 5 years or so. All of this began a little more than 10 years ago. In 2002, an article in Nature demonstrated that BRAF mutations were commonly present in cancers and that they could be drivers of tumor cell growth, proliferation, and oncogenesis. If you overcame them, eliminated them, or blocked the influence of the mutated BRAF, you would reverse or transform cell behavior in the test tube.

The race began to come up with BRAF inhibitors, and sorafenib was one of the first. However, sorafenib turned out not to be a very good BRAF inhibitor, as it didn’t really have much activity in melanoma. It was a bit of a disappointment, but meanwhile, a number of companies were pursuing more selective BRAF inhibitors that had higher potency. It turned out that sorafenib wasn’t very potent, and that, in terms of inhibition of BRAF, it wasn’t very selective.

A small company was synthesizing a variety of compounds to inhibit BRAF at the time. This company came up with a drug around 7 years ago that looked promising in early testing: They could see some evidence of tumor regression, but when they looked at the pharmacokinetics, the drug formulation wasn’t very bioavailable. The blood levels went up a little bit after a dose, but then they sank down quickly, and the drug just wasn’t doing the job. However, it did have some promise, as there was some evidence of tumor regression early on. They stopped the trial, and at this point the company was bought out by Roche.

The chemists at Roche made a bioavailable formulation of the drug. When they evaluated pharmacokinetics, modest oral doses of the drug, given twice a day produced very high levels in the bloodstream. They started increasing the dose and did another phase I study, and very early on they were seeing some very large responses. So they were off and running with PLX4032, otherwise known as vemurafenib (Zelboraf). Between the BRAF discovery in 2002 and the approval of Zelboraf, it was 9 years, which is very impressive. This drug has a solid 50%-plus objective response rate and 80% rate of stability or regression. However, it had about a 6-month progression-free survival. Patients were having fantastic responses, but eventually almost everyone was relapsing, which was a little bit depressing.

Nonetheless, there were other targeted drugs that seemed to have activity in BRAF-mutated melanoma, such as MEK inhibitors. There is the MAP kinase pathway that signaled and was overly active in melanoma, either through mutation or through other alterations. It is a cascade—Ras-Raf-MEK-ERK. Therefore, if you could block it at any step of the way, theoretically you could shut down melanoma growth, proliferation, and invasion. It turns out that BRAF inhibition worked the best, but MEK inhibition, which is downstream, also worked.

Then it turned out that if you added the MEK drug to the BRAF drug, you could block at two places in the cascade, and it worked extremely well; in fact, in the test tube, it worked synergistically so that both added together were better than either one alone. It also reduced some of the skin side effects that were beginning to be seen with the BRAF inhibitors. At this time, the BRAF inhibitors vemurafenib and dabrafenib were developed, as well as a very good MEK inhibitor called trametinib. A trial was done with around 400 patients for these combination agents, which was eventually a multiple phase I trial with extension cohorts, and later a fairly large phase II trial was done. They found fantastic results, with around a 75% response rate with longer progression-free survival. The survival data are about to come out, but will almost surely look very impressive. That led to a couple of registration trials that are completed, and the results of these studies will be out soon.

So, we started with the BRAF drugs, then we had BRAF plus MEK, and now we are working on all kinds of other drugs to overcome resistance to the BRAF drugs. All of these combinations of oral drugs are being tested, which is great for patients. Many patients are in clinical trials for 2 years or even 4 years out, so this is looking very promising. I think we are really helping patients in these trials.

These agents are ideally used initially in combination rather than sequentially, then?

If you use these agents sequentially, it isn’t as good as using them in combination. The way to deal with metastatic melanoma is to hit it hard upfront rather than treat them, wait for resistance, then try to overcome resistance. So the best way to approach treatment is to hit them hard, hit them quick, and hit them often. Melanoma is a difficult disease, and backing off is a sure-fire way to not benefit the patient.

Meanwhile, we have all these fantastic targeted therapies that are very impressive, and there is going to be great progress made in that field because eventually we will figure out how to overcome resistance. I think we will be able to cure some patients with these drugs. Right now, most of the patients will eventually relapse, but progress is being made.

You mentioned several clinical trials. Are there any other clinical trials that you think community oncologists would be interested in or should be aware of?

I think that they should be aware of the use of adoptive cell therapy, which is a new treatment that is complex and toxic and is done at MD Anderson at the NIH, where you can take patients who have

failed every other therapy for melanoma, and you can put them into complete remission in a modest proportion of cases, and probably cure some patients as well. I think community oncologists should also consider patients for combination BRAF inhibitor trials—not just treat them on vemurafenib, but consider them for a trial of combination therapy. The combination therapies are all investigational, of course. You can always treat someone with vemurafenib, but they are almost always going to progress. So why not try to do something where they may not progress? And I would send patients for combination ipilimumab/PD-1 trials, because it turns out that the combination, despite a fair amount of toxicity, has a very impressive response rate. Many patients become complete responders, which is very encouraging. I think there are many good combination therapy trials under way, as well as trials with adoptive cell therapy, that look very promising to me.

Immunotherapy

Lastly, I think every patient with metastatic melanoma should be considered upfront for a clinical trial. In other words, in the community setting there should be a reason not to enter them in a trial, as opposed to needing a reason to think about a trial.Can you comment on the current status of immunotherapy for metastatic melanoma?

Immunotherapies go back to the 1990s, as this is an older concept. [Researchers were] developing the concept that there are checkpoint proteins that inhibit T-cell responses. We knew a lot of activating molecules, but didn’t understand the so-called “brakes” on the immune system as well. [Researchers] came up with a molecule that they isolated and cloned—CTLA-4, or cytoxic T-lymphocyte antigen 4, which essentially became known as a brake on the immune system. It competed with other molecules on antigen-presenting cells, and when it was overexpressed it would block the ability of the immune T cell to bind to the antigen-presenting cell and get activated. So when CTLA-4 was upregulated, it basically killed T-cell activation and function. So, if you could block CTLA-4, you would cut the break, which might be useful in cancer.

Experiments in mice suggested that this was very promising. If you combine blocking of CTLA-4 in the mouse with some sort of vaccine strategy, tumors could be cured. In fact this was seen in some tumors that otherwise were very difficult to treat in the mouse model. This was studied around 2001, and initial studies were at the National Institutes of Health and in Los Angeles, where I was at the time.

The drug [ipilimumab] turned out to have evidence of activity in melanoma, but also unusual side effects. Ipilimumab is a human monoclonal antibody that blocks CTLA-4. I was in on the early studies of this. We found that a modest proportion of patients (about 15%) would have significant responses that were slow to develop but lasted a long time, and some of these patients were probably cured, because years later they were still in either partial or complete remission without the need for further treatment, and were feeling well. It was a 10-year developmental pathway to reach two registration phase III trials showing that the drug in second- or first-line melanoma could prolong survival. It was approved by the FDA in 2011. It has unusual immunologic side effects, but it definitely has activity in melanoma and definitely prolongs survival compared with chemotherapy or compared with no treatment. That being said, it is also a modestly toxic drug that has a modest level of activity—we aren’t seeing 50% response rates.

This set the paradigm for the development of other checkpoint protein inhibitors. [Several companies] began to develop inhibitors of yet another brake on the immune system, PD-1, or programmed death-1. In human cells, very dramatic effects in blocking PD-1 were seen in the test tube. This same phenomenon wasn’t seen in human cells in the test tube with blocking of CTLA-4 antibody. When nivolumab got into phase I early studies—low doses and dose escalation—dramatic responses occurred earlier than with ipilimumab. [Nivolumab] looked very promising and has gone on through extensive phase I testing. I was involved in the earlier studies, which are about to be published.† When used with vaccines, it has the best-looking activity as an adjuvant treatment for stage 4 melanoma that I have ever seen.

Nivolumab is now in registration trials. Some trials are almost done, and some are in the middle, but this drug or one of the others in this class is almost sure to be approved within the next couple of years. So this represents a whole new class of checkpoint protein inhibitors. You can block either PD-1 or its ligand, PD-L1. So now we have at least six or seven other checkpoint protein inhibitors against which antibodies have been made, and things are looking positive.

How do you think management of adverse events for these agents will differ, in terms of their effect on clinical practice?

There is a learning curve to managing adverse events for immunologic agents. But in my opinion, it is no different than adverse events of complex chemotherapy regimens that community oncologists currently manage all the time. It is just a matter of education, experience, and getting through the learning curve. So to me, there is really nothing unusual about it.

What do you see as the role of chemotherapy in the near future, given the availability of these new agents?

There are two issues. First, I almost never use chemotherapy anymore because patients do so well on these other treatments. And by the time they fail all these other treatments, they are not going to be in any shape to get chemotherapy. Many patients don’t even need this consideration, because they stay on these newer therapies for years and there is no need to go to chemotherapy.

That being said, there are some interesting data that were developed as part of our SPORE [Specialized Programs Of Research Excellence] grant showing that chemotherapy can actually promote immunity, not suppress it. So chemotherapy may make a comeback as an adjunct to some of these immunotherapies. But right now, I would say that chemotherapy is probably way in the background.

*For survival data on nivolumab, go to http://news.bms.com/press-release/rd-news/additional-survival-data-nivolumab-investigational-pd-1-immune-checkpoint-inhi Accessed December 11, 2013.