Melanoma: From Impossible to Treat to Poster Child for Targeted Therapies
Published Online: October 23, 2013
Produced by Nicole Beagin
In September, Mark Fendrick, MD, co-editor-in-chief of The American Journal of Managed Care, led a discussion of experts about advances in the treatment of metastatic melanoma, which examined both the promise offered by new therapies and the issues surrounding cost, payment, and delivery. The text of their discussion has been edited for clarity, style, and length. To hear the full discussion, please visit http://www.ajmc.com/ajmc-tv/panel-discussion. Joining Dr Fendrick were:
• Jeffrey Weber, MD, PhD, senior member of the H. Lee Moffitt Cancer Center and director, Donald A. Adam Comprehensive Melanoma Research Center, Tampa, Florida.
• Antoni Ribas, MD, PhD, of the Johnson Comprehensive Cancer Center, University of California, Los Angeles.
• Jennifer Malin, MD, PhD, manager and medical director of Oncology, Well-Point.
Frederick: To start, I’m going to call on you, Dr Weber. Why don’t we start with a therapeutic overview and perhaps a broader discussion of the unmet needs in our current therapeutic armamentarium?
Weber: There has been a tremendous amount of progress in cancer therapeutics in the melanoma field in the last 5 years. Melanoma has gone from being regarded by many oncologists as an impossible to treat and hopeless malignancy to a disease that one would argue is the poster child for new targeted and immunologic therapies, so we’ve come a huge distance in the last 5 years, and it has been very gratifying. That being said, there are major unmet needs in our field because while we are achieving good response rates with targeted therapy, prolonging survival with immunologic therapies, we still have a pretty narrow repertoire of drugs to use and they still have pretty serious toxicities, and we are a long way from curing a significant proportion of our patients. So, to me, the biggest unmet need is understanding essentially how to cure patients, and I use the word “cure” in the sense of having someone adoptive cell therapy, an area that both Dr Ribas and I are interested in, trying to figure out how to bring that into the mainstream is very difficult, and how to overcome resistance to the targeted drugs, because a lot of patients get great response with these targeted personalized drugs that impact on the signaling pathways for melanoma growth and proliferation, but almost all of them will eventually progress. We are trying to figure out how to overcome the resistance.
Ribas: I fully agree with everything you said because having seen this remarkable change in a short period of time with agents that have come from understanding biology, the melanoma biology or the immune biology of melanoma, and leading to rational drug development and to this remarkable benefit to patients, it has been something that has invigorated all of us, but we are still faced when we go to the clinic with many patients who are either not responding, responding for a short time and progressing, or having side effects. But, the process has gone so rapidly and based on things that we can rationalize and understand, that your point of saying we are shooting for a home run, we are trying to get durable responses in the majority of patients, I don’t think it is an unrealistic goal anymore in melanoma, when it was a completely unrealistic goal 5 years ago. Having said that, I would move on to the next point of the agenda, which would be these recent successes, and, what do they mean? Dr Weber has already pointed to the general theme of targeted therapies giving an initial response rate that tends to not be durable, and the appropriate immunotherapies interleukin-2, aldesleukin, or ipilimumab that are good for blocking antibodies, giving a much lower frequency of responses, but clinically very significant for the patients who respond because they can go on to have years of response and probably be cured.
Patients who were treated 2 to 5 years ago, some of them by Dr Weber, continue to respond and patients with T24 blocking antibodies, the longest one is now going for 12 years, a patient in my clinic continues to respond and we just see each other once a year. So the goal is there, but we need to make it more efficient for everyone. The particular agents that we will discuss and try to understand the cost-benefit ratio would be the B-RAF inhibitors, vemurafenib being the first one, and then the B-RAF that is called dabrafenib, which is a very recent approval. These are agents that when we select patients with the B-RAF mutation, which is around 50% of melanomas, we are close to guaranteed to have some kind of patient benefit.
Over 80% of the patients have some shrinkage of disease at some point over time, and that is shown in impressive particle plots with these agents, but the majority— not all of them, but the majority—will progress within a matter of months usually, and the median duration of response is around 6 to 7 months, although there are some patients from the Phase I trial of vemurafenib who are now going beyond 4 years and are continuing to respond, but that is the minority.
The benefit to patients is very rapid. These are targeted therapies that block the driver oncogene, which leads to cell cycle arrest and responses in the majority of patients, but then the majority of patients will progress. Around two-thirds of the progression mechanisms go through reactivation of the same pathway and a signal through an immediate downstream, a factor which is called MEK, which is a kinase under BRAF and them we have the MEK inhibitor trametinib that has been approved to use a single agent in B-RAF mutant melanoma. But that is not where we are going to be using it because by itself, trametinib is less effective in mutant melanoma and more toxic, so it is probably one of the only approvals by the FDA that we know from the start that we are not going to be using it the way the current label is written. You can use it in combination with the B-RAF inhibitor and you can use it in patients who progress on the B-RAF inhibitor because there is actually no activity there. But there is a lot of activity when you put it together, and that is something that Dr Weber has reported on, where it is one of the first examples that I would know in medicine where you have 2 effective drugs, that you put them together and they are not only more effective but they are less toxic when you keep them together, which should impact on the cost-benefit ratio because even though obviously 2 drugs are more expensive than 1, the side effects decrease and the benefits of the drugs is markedly improved and randomized trials are still ongoing, and that is why it is not in the label. It would suggest to me that in the near future I think most of us will agree that this will be a drug that is cost-effective.
PDF is available on the last page.