Dr Martin Dietrich Describes Need to Move Quickly With “Aggressive, Unpredictable” Melanoma

Martin Dietrich, MD, PhD, is a medical oncologist with Florida Cancer Specialists and Research Institute and an assistant professor of internal medicine at the University of Central Florida Cancer Center in Orlando. He spoke with The American Journal of Managed Care® (AJMC®) about risk factors in melanoma, as well as the need for genomic testing and rapid action in treatment for a cancer that can progress very quickly.

AJMC®: Could you start us off by describing the incidence and prevalence of melanoma in the United States?

Dietrich: We're seeing about 30,000 cases of melanoma a year in the United States. The majority of them are in early stages detected by dermatologists. They're surgically managed, depending on [the] level of invasion, other high-risk factors subjected to lymph node evaluation, and possible further imaging. Only a small portion of the melanomas that we're seeing are lymph node-positive or even metastatic. We have to distinguish those 2 parts; one, in the early stages carrying an excellent prognosis with surgical therapy alone. Then both local advancement, as well as metastatic manifestations are coming. Obviously, the prognosis is significantly impacted.

AJMC®: How has that incidence of melanoma changed over time? Are we seeing more cases of this, or is this a cancer that perhaps we're not seeing as many cases year-over-year as we used to?

Dietrich: Melanoma is a cancer, like all skin cancers, that actually has an increasing incidence. We're seeing a migration within the country from the Northeast and Midwest to the South and Southwest. The level of UV intensity is increasing, and this correlates with an increase in UV exposure, which is the predominant risk factor for development of melanoma. We also see that a generation that has discovered the sun and vacation travels and tropical areas [has now reached an age] where melanoma development is more prevalent. While [melanoma] can occur in any age group, including in pediatric populations, we typically see it in older patients. We are collecting that information and certainly [promoting] an increased awareness, and the importance of screening and early detection becomes more and more important.

AJMC®: You touched on one of the risk factors for developing melanoma, increased UV exposure over time. Can you go into a little more depth about other risk factors that might be involved in developing melanoma, such as genetic predispositions or phenotypic predispositions?

Dietrich: Well, melanoma is a disease that predominantly affects patients of European heritage. It has a clear correlation between skin pigmentation inversely being correlated with the risk of melanoma development. That's probably the most obvious risk factor. We're seeing that patients with green and blue eyes have higher risk of developing melanomas; both [these] factors [are] independent of skin pigmentation as well. We are seeing a hereditary predisposition with certain mutations. For example, BRCA1 is correlating with an increased risk, so we must keep this on the radar. Even though there's not a good way of preventing it, we can certainly have patients with a risk of melanoma subjected to more frequent screenings and give them the opportunity to basically include this in their surveillance care.

There are certain melanoma inhibitory factor mutations, other less common mutations that may be playing a role in screening, although we certainly have not standardized the screening recommendations, and [this] would typically be up to the discretion of the individual clinician to assess the risk factor profile. There are other clinical features, the number of nevi, the abnormal moles that are being seen. Those are all factors that are signifying a predisposition to a melanistic transformation that should be analyzed both in a preemptive as well as in a secondary prevention setting.

AJMC®: I'd like to shift gears a little bit and talk about perhaps a specific type of melanoma. Could you give us a little bit of an overview of what a BRAF mutation is and perhaps what are the implications of BRAF positivity, what that means in either melanoma or perhaps some other cancers that exhibit these mutations like non-small cell lung cancer?

Dietrich: BRAF is one of the oncogene kinases in a variety of cancers. We find them in non-small cell lung cancer, in colorectal carcinomas, in glioblastomas, but with the highest relative incidents in melanoma. Almost 50% of melanomas are positive for BRAF mutations. [We] have been seeing a number of BRAF mutations, [including] the classical, which is the BRAF-V600E followed by V600K. Then some non-canonical mutations that are happening in BRAF that are probably pathogenic, but not as important as they're not easily targetable. They carry a little bit of a different biological behavior even between V600E and V600K. We typically expect better-targeted therapy responses to V600E—maybe higher mutations and therefore a somewhat better response to immunotherapies for the B600Ks. It's very important to understand that melanoma is a genetically defined disease. We have some very common mutations, obviously, [with] BRAF being the most predominant one. It's particularly important because we see BRAF frequently in a high-risk patient population. Many times, it's younger patients that have high-risk disease that is discovered early on in life that should be considered by seeing HRAS, NRAS mutations typically in older patients, and they carry a different profile. Knowing the genotype is not only important for predictive treatment decisions, but also for prognostic implications for treatment decisions and certainly should be known at the time of diagnosis [as] part of the bigger complex to decide what therapy is appropriate for the individual patient at the right time.

AJMC®: I'd like to build off on that last part there. It sounds like BRAF is quite common. It sounds like it's associated with more advanced forms of melanoma. When should BRAF testing be considered then in a patient with melanoma?

Dietrich: Well, the general answer is as early as possible. We are running into certain issues with tissue availability. If you think about the workup of a stage 1 melanoma, it is being analyzed for depth of invasion. You're basically consuming the entire tissue prior to having molecular analysis available. Sometimes we are trying to use an epithelial removal of melanoma cells for testing, [which is] not as good and typically not done. Certainly every lymph node-positive melanoma should be tested for the disease as these are early originating mutations that should be present in every location. This is not an acquired resistance mutation that may be polyclonal. It's typically part of the first initiating events of the cancer and certainly for all metastatic melanomas. It should be part of the treatment course. Typically, we would like to see it reflexively.

As you know, melanoma is an aggressive and unpredictable cancer. I never have a patient where I would feel comfortable taking a slow route. It can be very quick, oftentimes a presentation they're already metastatic. It's probably one of the most, I want to say metastases-prone cancers—similar to small cell lung cancer—and basically constitute a medical oncology urgency at the very least. Getting this reflexively is particularly helpful. I can give you an example of a patient that I treated with a massively symptomatic lymph node burden in the axilla, and the reflex testing that we have established at our local hospital after much debate was [an] immediately available PCR test with the turnaround time of 2 days. The patient was able to start on medication within 3 days since biopsy. As you know, the BRAF dependence of melanoma is enormous. This is the defining hallmark and the propagator of cell growth and spread. The responses are virtually immediate. You can see this in clinically appreciative lesions that with the initiation of BRAF inhibition, the vasculature, the tumor content, the tumor shrinkage is virtually immediate. This is an understanding of tumor biology that can be exploited for a fast and rapid response. Oftentimes, in the heat of the moment, the patient misses the initial treatment, maybe [the patient] started on an all-comers medication like an immunotherapy and ended up on relapse. These progressions can be very aggressive and very hard to reel in, so having that information available at any step of a patient's journey is crucial in my opinion—and the earlier that is available the better. It certainly should be done in a reflexive fashion for all lymph node-positive and metastatic melanomas. I want to add that with melanoma being such a highly metastatic disease, the circulatory fraction of melanoma is actually quite interesting, and we actually have quite good successes detecting these simple point mutation alterations as we see in BRAF and melanoma on a liquid biopsy in case there's no tissue available. As you know, these turnaround times are somewhere around 5 to 7 days and really provide us all the genomic information that we need.

AJMC®: I’d like to follow up on the reflexive testing aspect you discussed. I think we're finding for some of these targeted mutation tests in a variety of cancers, access can be challenging for patients in a community oncology setting. Can you tell us a little bit more about how BRAF testing is conducted in a community setting? Is it feasible for a lot of community practices to provide the reflexive BRAF testing upfront in melanoma?

Dietrich: Most community oncology practices don't harbor their own pathology departments, so we are working with a plethora of referral systems, hospital systems. Oftentimes patients are biopsied in dermatology that are using external reference laboratories, so it's difficult to always establish a simple streamlined process for reflex testing. At Florida Cancer Specialists, we've established an in-house genomic panel that allows for both single-gene testing analysis as well as comprehensive genomic analysis, and these capabilities provide patients the full molecular understanding of disease. This is a process that is not available everywhere for patients, and certainly oftentimes [this is] not available prior to connecting with a medical oncologist, which for melanoma is really a sequential handoff. When a dermatologist or surgeon relinquishes a patient to medical oncology, this is typically at a point in time when melanoma has already reached a state of spread and concern. It's important to see where those referral sources are, where the tissue is housed and how from the tissue location molecular testing can be initiated without delays for treatment. That is a process that is very, very important. Again, for metastatic cases, I do use liquid biopsy. Sometimes the delays we are seeing with tissue testing are very challenging and 2-3 weeks can make the difference between a patient living and a patient dying.

We've had clinical trials looking at the different opportunities, and in a clinical trial setting, we're looking at a very specific subset of patients. Those are patients that are typically in good performance status and thereby almost by definition, not riddled by too much volume of tumor, too much end-organ malfunction concern. This is a different patient population; in a high-risk patient that comes [in] clinically symptomatic with brain metastases, seizures, liver metastases—which are very common in BRAF mutations—that can lead to end-organ failure. The swift responses in these high response rates seen with targeted therapy and BRAF inhibition are really a very, very powerful tool to change the course of patients' outcomes. Not every clinical trial piece of information that we are seeing with regards to targeted therapy versus immunotherapy is truly informative for the patient's clinical presentation.

AJMC®: I'd like to go back a little bit on the BRAF mutations where you started. You mentioned some of these BRAF-specific mutations V600E, V600K. Can you speak on what's the difference between these mutations and then perhaps non-V600 mutations that we see? What does it look like in terms of response to therapy and how you might choose a treatment depending on what type of mutation a patient has here?

Dietrich: In practical terms, melanoma breaks down in 2 compartments. One is BRAF mutant and in this case, I really only talk about the classical BRAF-V600E and V600K. We see very limited responses to some of the atypical BRAF mutations that certainly occur but are not responsive to any of our standard of care treatments. Those are investigated in clinical trials, but the responses there are still limited and non-BRAF mutations, where we see other drivers, HRAS, NRAS, sometimes the MEK pathways activated. There are other mutations that are defining their biology, but they're not necessarily targetable. We sometimes think of them as responsive to some of the downstream targeted therapies, but direct RAS inhibition in melanoma has not been feasible yet. We do see some mutations in c-KIT, especially in some of the uveal melanomas and some of the less frequent younger cutaneous melanomas. I do wanna say that the responses there, are also more limited, and it's not quite as clear how to use uncertainty and off-label use of the medication. Use of targeted therapy versus immunotherapy is probably one of the most controversially discussed medications.

Again, in a clinical trial setting and we've had as probably the most prominent example, the DREAMseq trial that looked at sequencing targeted therapy followed by immunotherapy versus the opposite sequence. It appeared that there was a broader benefit long-term starting patients on immunotherapy first. With that said, that is a clinical trial population that has an intrinsic selection bias for patients involved. Immunotherapy is a process that has great potential for durability but does not have typically a rapid onset response. Typically a patient doesn't have 6 to 12 weeks of life expectancy. Their chances of immunotherapy responses are significantly diminished in particular because patients that are already facing highly symptomatic disease oftentimes suffer from comorbid conditions that would affect immune function. Malnutrition is a big one. Weight loss is one. Oftentimes opportunistic infections requiring antibiotics with brain metastases, steroids, and that immunosuppressive. We are looking really at a broader population than clinical trial population can. If I have a patient that comes with clinically symptomatic brain metastasis, instead of attempting immunosuppressive steroids for management of edema plus immunotherapy, I believe is very reasonable in the first glance setting to use a BRAF inhibitor and normalize a patient's disease. We have had some attempts to combine immunotherapy plus the BRAF inhibitors in the first-line setting. The data is not quite as impressive as we would've liked it to be, but it's certainly a reasonable option for patients that have both a need for a rapid response and the intent of providing a durable response, so basically trying to capture the best of both worlds. In my clinical experience, [there is] no optimal sequence. It really has to be tailored to the individual patients. The thought of immunotherapy first really mostly applies to the clinically asymptomatic good performance status patients, which would be the clinical trial scenario where I think this is the superior approach to BRAF targeting and for higher risk of decompensation. The use of BRAF inhibitors alone or possibly in conjunction with immunotherapy.

AJMC®: Would you like to provide some closing thoughts on disease management considerations for melanoma, or even actionable mutations in melanoma that you'd like to share with your colleagues?

Dietrich: As I said, we have to understand melanoma as a very heterogeneous disease. I think we have to have considerations with regards to their molecular phenotype that should be evaluated at the very baseline. I think of melanoma for the most part as a systemic therapy that should be analyzed much in an analogy to some of the other cancers that are metastatic. Non-small cell lung cancer is probably the closest relative to melanoma clinically to have this information upfront. Starting immunotherapy for many patients is just not a good idea. When they come symptomatic and they're basically discovered through the hospital is very different when we are looking at the management of the BRAF subtype. We're seeing here usefulness very similar to immunotherapy, both in the adjuvant setting as well as in the metastatic setting. For many patients, this is very helpful. We are seeing a high degree of patients that may have been predisposed to reposition to autoimmune disease where immunotherapy may lead to an aggravation. There are certainly long-term consequences of immunotherapy that we need to discuss in a fair and balanced manner with patients. We default to immunotherapy many times because of the simplicity, but it's by no means a harmless therapy. We should have a mixed discussion about how to manage patients with locally advanced metastatic melanoma. I do want to say that there's a great deal of interest, not only about stage 3 and 4 but also about stage 2B and 2C melanomas that really carry a spread metastatic potential that is similar to stage 3A and 3B. We really have to incorporate information as early as possible. Stage 2C does deserve molecular testing. This is a piece of information that in time, the receipt can save life and preserve a patient's ability to receive treatment. As you know every delay counts. We should approach this very similarly. I think that's how the guidelines are written to really obtain all the information upfront and tailor a patient's course based on both molecular and clinical features. There's no one size fits all in any disease and certainly, no different from melanoma.