The Evolving Role of Targeted Therapies in Melanoma

Hussein A. Tawbi, MD

Hussein A. Tawbi, MD

There is an ongoing discussion in the field of metastatic melanoma regarding which treatment should be used first, immunotherapy or targeted therapy, as both are approved for the frontline treatment of these patients. Clinicians currently treating this disease have a variety of treatment options to choose from when they meet with their patients, and several factors need to be considered in order to make an informed decision, explains Hussein A. Tawbi, MD.

In an interview withTargeted Oncologyduring the Chemotherapy Foundation Symposium, Tawbi, Associate Professor of Melanoma Medical Oncology, and Director of Melanoma Clinical Research at The University of Texas MD Anderson Cancer Center, discussed the considerations he makes when choosing between immunotherapy and targeted therapy and how long-term targeted therapy data can influence treatment decisions.

TARGETED ONCOLOGY:Can you share what you discussed in your talk on targeted therapies in metastatic melanoma?

Tawbi: In the last 7 years, we have been very fortunate in melanoma in that we have managed to have at least 10 or 12 new drugs approved for patients with metastatic disease. Those drugs have almost been moving in parallel, where we have a whole field of targeted therapy where the drugs are specifically targeting mutations that are driving melanoma. We also have developments that are equally exciting in immunotherapy. During the Chemotherapy Foundation Symposium, I presented the case for why targeted therapy makes sense for some patients, while my colleague, Dr Patrick Ott, gave a presentation on why immunotherapy makes sense for some patients. A clinician in this day and age faces multiple choices when they meet their patients, and they have to make an informed decision.

In the last couple of years, we have had the opportunity to look at longer-term data from the early trials of targeted therapy. We started to learn a little more about the characteristics of patients that may predict for a better response, or for a worse response. We have learned that some of the patients that do very well with targeted therapy also do very well with immunotherapy. The discussion is ongoing around which therapy you should start with, and there are multiple factors that a treating physician would need to take into account.

TARGETED ONCOLOGY:What is your current strategy for deciding if a patient should receive immunotherapy or targeted therapy?

Tawbi:That is a great question. Targeted therapy and immunotherapy are both approved in the first-line setting. Technically, all the data applies to previously untreated patients. What we look at in those patients is their mutation status, because they have to have aBRAF V600mutation to be eligible for targeted therapy, specifically with BRAF and MEK inhibitors. Then we look at the other clinical characteristics, for instance, the patient's tumor burden — do they have more than 3 sites of metastatic disease or less? We look at LDH, which in melanoma is a very important prognostic factor, and it could even be predictive of poor outcome or good outcome. We also look at the presence or absence of brain metastases. All of these factors impact our decision. Typically, if a patient has a low LDH, less than 3 sites of metastatic disease, and no brain metastases, they are set to do equally well if you give them targeted therapy or immunotherapy.

The next thing we take into account is the toxicity part of it. The emerging data on brain metastases specifically is indicating that while our initial response at this point is to think about targeted therapy for patients with brain metastases, it turns out that the responses in the brain are much shorter lived than they are outside the brain for targeted therapy, while for immunotherapy we are proving that the responses are as durable. I can tell you that 6 months ago, it used to be a toss-up and clinicians were more likely to go with targeted therapy if you have brain metastases. With the newer data, we are leaning much more toward immunotherapy.

TARGETED ONCOLOGY:What do you think we are going to see going forward in this line of research? What is the treatment paradigm going to look like in 5 or 10 years?

Tawbi: I think what we are going to be learning from this long-term data is how to best select our patients. We are going to look at these characteristics that I mentioned, and hopefully some more biomarkers, to help decide what to start with. Then the next step would be determining how to sequence therapies. If you started with a BRAF-targeted therapy, when do you switch to immunotherapy? That is a question that is being tested in clinical trials right now.

The other piece that I think is very important for all clinicians treating patients with melanoma today is stage III high-risk patients — patients that are surgically resected and stand to be cured with surgery alone. We know they have almost a 60% chance of recurrence. To date, adjuvant therapy has been almost restricted to immunotherapy, until recent data that was presented at the ESMO Congress showed that targeted therapy may be just as effective in the adjuvant setting. That throws clinicians in one more kind of dilemma, but it's good to have options, because that means more things we can do for our patients.

TARGETED ONCOLOGY:What are the side effects and toxicity profiles of these targeted therapies?

Tawbi: The current approvals are for the combination of 2 drugs together — a BRAF and a MEK inhibitor together. We know that BRAF inhibitors alone have some toxicities related to skin rashes, photosensitivity, and the development of cutaneous squamous cell carcinomas. We know that the addition of a MEK inhibitor aggregates those toxicities, so it's less toxic to the skin, and less incidence of cutaneous squamous cell carcinoma. On the other hand, because you are adding another drug, we actually do see an increase in the rate of fevers. Those are fevers that could actually be sometimes grade 3. Patients can actually get dehydrated sometimes and even land in a hospital because of them. It's very important to educate clinicians about how to manage them. Typically, it's as simple as stopping the medications for 2 to 3 days and the fever dissipates, and most of the time you can restart them at full doses.

TARGETED ONCOLOGY:What is your advice to clinicians about how to manage these adverse events?

Tawbi: Of all the toxicities that we encounter with targeted therapy, fever is the most significant. Patients should be aware that if they start developing high-grade fever, a lot of the times you might chalk it up to possibly having a viral illness or something else is going on. However, these drugs are so well known to cause fevers, the incidence is over 50%, so it's very important that they realize this and reach out to their clinicians. Hydrating themselves is extremely important. On the clinician side, learning that sometimes stopping the treatment, giving non-steroidal anti-inflammatories may be all that is needed. The next, most important step for clinicians to learn is that you can restart at the same high dose, you don't have to dose reduce those patients. Obviously, sometimes a fever recurs and becomes a bigger issue, so at some point, dose reductions may be necessary, but we generally do not dose reduce until it's a second or even third occurrence of the fever.