Fine-Tuning the Treatment of Melanoma

Significant strides have been made in the treatment of patients with immunotherapies and targeted therapies. However, determining which therapies are best for which patients and how to treat patients who don’t respond or stop responding to these new therapies is still a challenge. For further insight on optimizing the recent treatment breakthroughs in melanoma, CURE spoke with Alan Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic.

CURE: How has the emergence of novel targeted and immunologic agents revolutionized the treatment of patients with melanoma?

Dr. Bryce: Melanoma care has been transformed in the last 5 years. This started with the approval of Yervoy (ipilimumab), which was the first immunotherapy approved for melanoma. That was followed by the approval of Zelboraf (vemurafenib), the first targeted therapy approved for melanoma. Since then we’ve had six drugs proven to benefit melanoma patients, three of them immunotherapies, three of them targeted therapies.

We really think this is just the edge of the transformation of melanoma care in the world. We really have the opportunity to get long-term outcomes in patients that we wouldn’t have otherwise prior to 2010. Before that there was a not a single drug that showed an overall survival benefit in the treatment of metastatic melanoma patients. There were hints of benefit from some very aggressive therapies, but now, in 2015, we can tell patients that we have treatments with a very high chance of giving disease control lasting at least 10 years. That is a very tremendous statement.

What options are available for patients who do not respond to immunotherapy?

The Stand Up To Cancer Trial (Personalized Medicine for Patients with BRAF Wild-Type Cancer) is looking at the value of genome sequencing for those patients with [metastatic melanoma] for which immune therapy does not work or is not an option. The advent of new tools that allow us to quickly sequence the genome of the cancer have allowed us to integrate cancers and understand them on a much deeper level than we ever have before.

In many ways, I think this is just a continuation of what we’ve always done, which is try to be more precise and understand how we define disease and how we understand how cancer forms. But the value of this in the modern era is that there are many drugs that could potentially be matched up to the information that comes out of the genome sequencing activity. That is the purpose of the Stand up To Cancer study. It really is the biggest effort to try and take the genomics of melanoma and use it to match up an individual tumor to the therapy that is right for it.

What was the significance of the Checkmate-037 trial?

In this study, we saw that patients who progressed after Yervoy had an overall response rate to next-generation immunotherapy with Opdivo (nivolumab) that was over 30 percent. This population was compared to chemotherapy, which is what we would otherwise do in this situation before the PD-1 inhibition. In the chemotherapy arm, less than 10 percent of patients had an objective response, or shrinkage of the tumor. That is an almost four-fold increase in the objective response rate.

What is very exciting about this is in those cases when the tumor shrinks, at least 80 percent still experience responses at least eight months out. That is just based on the data that have been published so far; we have earlier data that suggests that responses could be up to a year or longer.

We are talking about a population that with Yervoy the expectation was perhaps several months of life, something less than a year. Now we have a drug where we can achieve one or more year of survival. The data are still maturing, so we do not yet know how long that survival will last beyond that. We will see how long the effect lasts, but it is very exciting that we are seeing this. There is going to be a meaningful proportion of patients potentially that are going to hit that five-year mark or further.

However, there is still a group of people who don’t respond to Yervoy or Opdivo. It is a meaningful group of patients. What do we do for them? Perhaps there is a next-generation immunotherapy that is going to work there, but the alternative is to think about targeted therapy. It is never going to be one therapy that solves cancer. Cancer isn’t one disease; it is many diseases that live under the same umbrella of cancer. Melanoma is the same way. That is what genome sequencing helps us to understand. There is a group of melanoma patients that will not respond to immune approaches. So we need to find alternative treatment plans. One of those treatment plans is what we are exploring in the Stand Up To Cancer trial, which is looking at genome sequencing precisely matched to the tumor.

For a patient with metastatic melanoma, which is best in the first-line setting, a PD-1 antibody or Yervoy?

That is a very tricky question. In the first-line setting, the immunotherapy with FDA approval is Yervoy. I want to stress that this is still a very good drug. It has a 10-year disease-free survival rate of over 20 percent, which is drastically different than what we’ve seen before. When we think about the fact that less than 10 percent were alive after five years in the previous era and now we see 20 percent alive after 10 years, it is truly remarkable.

Having said that, the PD-1 inhibitors show a higher response rate and a higher percent of tumor shrinkage. That creates a great degree of interest in saying maybe we should those first. But we don’t have the 10-year data. We don’t know if the PD-1 drugs will give us the same long-term response as Yervoy. We also don’t know if we can give Yervoy after PD-1 drugs and still get that 10-year response rate.

If the goal is to get as many people as possible to live as long as possible, we still don’t know what the right strategy is. The National Comprehensive Cancer Network does give a category one recommendation to use PD-1 inhibitors in the first-line setting, but the FDA doesn’t give that approval. I think it is an entirely debatable point. It is a conversation that the clinician and the patients have to have together to weigh the pros and cons. There is not an absolute answer at this point.