Managing Melanoma in the Era of Molecular Testing and Targeted Therapy: A Q&A With Ragini Kudchadkar, MD

Ragini Kudchadkar, MD

Molecular testing and novel therapies have revolutionized the management of metastatic melanoma in recent years. A review of the latest clinical developments was presented at the recent Physicians’ Education Resource meeting, Update for Clinicians on Diagnosis and Treatment of Melanoma and Other Cutaneous Malignancies. The meeting was held on September 28, 2013, at the Moffitt Cancer Center in Tampa, Florida. For insight on the evolving treatment landscape in melanoma, Oncology & Biotech News sat down with one of the expert presenters, Ragini Kudchadkar, MD, a medical oncologist in the Department of Cutaneous Oncology at Moffitt Cancer Center, and an assistant professor at the University of South Florida College of Medicine’s Department of Oncologic Sciences.

Oncology & Biotech News: What is the current approach to molecular testing in melanoma?

Dr. Ragini Kudchadkar: Outside of clinical trials, the testing that needs to be done is for patients who have a chance at targeted therapy. I think that BRAF mutational status is primarily the test that’s being done, and it’s being done primarily in stage IV disease. However, most of us believe that for a very high-risk patient with stage IIIc disease it’s reasonable to test them, as their risk of reoccurrence is very high, and in some populations almost 70% will reoccur. Many people get frustrated at the delay when it can take a week, even 2 weeks to get test results back, and when you have a metastatic patient who is sick, it’s nice to know upfront. However, I would not recommend testing patients with very early-stage disease who are likely to be cured with surgery alone.

Game Changers: Novel Agents for the Treatment of Advanced Melanoma

Agent

Trade Name

Mechanism

Approval Date

ipilimumab

Yervoy

anti-CTLA-4 antibody

March 25, 2011

vemurafenib

Zelboraf

BRAF inhibitor

August 17, 2011

dabrafenib

Tafinlar

BRAF inhibitor

May 29, 2013

trametinib

Mekinist

MEK inhibitor

May 29, 2013

dabrafenib + trametinib

Tafinlar/ Mekinist

BRAF/MEK inhibitor

January 8/9, 2014 Action Date on FDA Priority Review

Ipilimumab and vemurafenib have both been approved in the last two years. How has this changed clinical practice and treatment outcomes for patients with metastatic melanoma?

With melanoma, it’s a whole different ballgame now where people have multiple different options and you’re able to tailor the options depending on their goals of therapy, depending on quality of life, and Managing Melanoma in the Era of Molecular Testing and Targeted Therapy A Q&A With Ragini Kudchadkar, MD depending on symptomatology from their disease. It also means there are more and more patients who are long-term survivors. Melanoma used to be a universally fatal disease, and now we have more and more patients where it’s becoming a chronic disease, where they’re seeing us in follow-up but they’re living years with their disease. It has just really changed the landscape of melanoma and given patients a lot more options.

The BRAF inhibitor dabrafenib and the MEK inhibitor trametinib were approved as single agents and combination use of the drugs is being evaluated under the FDA’s priority review program. What is the therapeutic rationale for combined BRAF/MEK inhibition?

With the combination of BRAF and MEK inhibition, early data have shown that it improves outcomes over just single-agent therapy. I think it does so because the primary mechanism of resistance is that downstream in the pathway gets upregulated again. So if you block just one over time, the cancer cell figures out how to overcome that. When you combine them together, you block that mechanism of resistance, so it allows people to stay on therapy longer, and it also allows for a decrease in some of the skin toxicities that we’ve seen with single-agent use. I think that’s why it’s a priority review at the FDA, and I think that the combination will likely become the new standard of care.

Can you discuss recent developments with immunotherapy in melanoma?

Immunotherapy has really been revolutionized over the last few years, primarily via the PD-1 antibodies and the CTLA-4 antibody. I think the data on PD-1 antibodies are showing that patients are also getting rapid responses and about 30% to 40% of patients are having a response. And though the data are very early, a lot of these responses are also very durable. I think over time that these newer agents will be used more and be combined with our traditional immunotherapies— with ipilimumab—and we’ll have to monitor for the toxicity profile of that. But I think it’s going to create a group of patients that are very long-term survivors.

Research has shown that combining immunotherapeutic agents may provide an increased benefit. Is this the future of immunotherapy in melanoma?

I think combination therapy in general is probably going to be the future, and a way to get more people with long-term responses and more people with quick responses. The early data that were presented at ASCO this past year of combining ipilimumab with nivolumab, a PD-1 antibody, showed over 80% of people had tumor reduction. So, everyone is really excited about that. But I do caution—almost half the patients had to discontinue for toxicity. Although, some of those toxicities were laboratory abnormalities. We need a larger population study to really see what the toxicity profile is like because there weren’t that many melanoma patients treated. It was just over 30 patients. I think larger pools of data with a number of patients are needed, both to see if that 80% holds true and also to see if the toxicity profile is manageable.

With all of the emerging and approved agents in melanoma, what are your thoughts on the sequencing of these therapies?

For immunotherapy there are currently studies ongoing looking at sequencing CTLA-4 antibodies like ipilimumab with nivolumab or other PD-1 antibodies and looking at which comes first. It may be that the response rate is just as high when you use them in sequence rather than combining them. As far as sequencing agents in general, no one knows the answer to that. We start with one therapy over another based on symptomatology from the disease, based on patients’ age, based on BRAF mutational status of the patient, and then there has to be a personalized decision made between the physician and the patient.

Over the next 5 to 10 years, what will be emerging trends and developments in melanoma research?

We’ll continue expanding on what we already know. We’ve made leaps and bounds over the last 5 years, and we now are learning more about genomic sequencing of other mutations beyond BRAF, such as NRAS and C-KIT, as well as GNAQ in ocular melanoma. So I think over the next few years, we’ll develop better therapy targeted toward those mutations. I think that learning more about how best to combine the various melanoma drugs and how best to overcome the resistance that does develop will be part of the future, and also to find markers of who responds. We’ll learn more about that in the next 5 years so we won’t have to treat the general population of metastatic melanoma. We will be able to know beforehand who has a high probability of response.