Alan Byrce, MD
Immunotherapies and targeted therapies have led to significant strides in the treatment of patients with melanoma. 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, OncLive
spoke with Alan Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic.OncLive: 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 ipilimumab, which was the first immunotherapy approved for melanoma. That was followed by the approval of 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 ipilimumab had an overall response rate to next-generation immunotherapy with nivolumab that was over 30%. 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% 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% still experience responses at least 8 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 ipilimumab 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 5-year mark or further.
However, there is still a group of people who don’t respond to ipilimumab or nivolumab. 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 ipilimumab?