Improved Public Awareness and Immunotherapy Drive Down Melanoma Mortality Amid Rising Incidences

Vincent Ma, MD

Although the incidence of melanoma has increased significantly over the past several decades, melanoma-related mortality rates have declined—an encouraging trend that reflects both improved public awareness and the impact of modern immunotherapy regimens, according to Vincent Ma, MD.

“[Immunotherapy] is an ever-evolving field,” Ma said in an interview with OncLive®. “As we consider more combination therapies to reduce recurrence, particularly with individualized neoadjuvant strategies, it will be exciting to see how these approaches fit into the broader neoadjuvant treatment landscape.”

During the interview, Ma outlined factors contributing to the rising incidence of melanoma diagnoses, including cumulative ultraviolet (UV) damage, an aging population, and increased screening and diagnostic sensitivity; the impact of immune checkpoint inhibitors, dual checkpoint regimens, and individualized treatment decisions on the management of advanced melanoma; and the growing role of adjuvant and neoadjuvant immunotherapy in resectable stage II and III melanoma.

Ma is an assistant professor in the Division of Hematology, Medical Oncology, and Palliative Care within the Department of Medicine and a faculty affiliate of the Department of Dermatology at the University of Wisconsin Carbone Cancer Center in Madison.

OncLive: What factors could be contributing to the rising incidence of melanoma in recent years?

Ma: A few years ago, there was a recent publication in The New England Journal of Medicine that actually mentioned a pretty alarming statistic: it found that the melanoma incidence has significantly increased over the last several years. In fact, in terms of the numbers, the incidence has increased by 6 times over the past 40 years, and this is actually despite the number of non-cutaneous melanoma cases otherwise [remaining] relatively stable.

What’s interesting is that, ironically, even over the past decade or so, we’re still seeing a decrease in mortality and death rate from melanoma. Of course, much of that is due to the availability of modern therapies that have improved the survival of advanced-stage melanoma, but that doesn’t fully account for why we’re seeing a higher incidence of melanoma over the last several years.

There’s a lot of speculation as to why we’re seeing this, despite our better understanding over the years of how UV damage contributes to the development of melanoma. One of the things we think about is the aging population in the United States. We know that melanoma tends to be associated with older age, and what we know is that for a lot of folks in the older generation—back in the day—people promoted and used a lot of tanning oils, for example, and were frequently exposed to a lot of sun. What we know is that the consequences of all that cumulative UV damage have subsequently led to the development of things like melanoma and skin cancer. The cumulative effects of UV damage over time have led to what we’re seeing in these statistics of increased incidence over the last several years.

With the heightened awareness of how UV damage contributes to melanoma, I think the population now better understands how important it is to screen for melanoma. One reason we might be seeing a higher incidence is that we’re doing more frequent screening. There might be a lower threshold for patients to come into the clinic when they identify an abnormal mole or lesion, and there’s a lower threshold to biopsy those lesions. We’re also speculating that there might be a lower pathological threshold to label morphologic changes in these biopsies as melanoma.

Despite us seeing more melanomas over the last several years in this country, the good thing is that it may be due to increased awareness of the disease. It is reassuring, as a melanoma medical oncologist, that we’re not seeing an increase in death rates associated with the disease.

How has the standard of care for advanced melanoma evolved over the past decade, and what are the key considerations in selecting first-line treatment today?

The management of advanced-stage melanoma has dramatically improved over the last decade. Coming from the University of Wisconsin, where we actually have a lot of farmers who develop skin cancer, I see a large proportion of patients in my practice with advanced-stage disease. When I meet with them for an initial consultation, it’s not uncommon for me to give a brief history lesson. I’ll say, “If you were to see me with advanced-stage melanoma back in the early 2000s, at that time we had very limited treatment options.” We would use something like chemotherapy, and the survival outcomes were around 6 months or so.

Nowadays, there was a recent publication showing 10-year follow-up [data from] patients who were treated with combination ipilimumab [Yervoy] and nivolumab [Opdivo] that showed the median melanoma-specific survival was greater than 10 years. We’re just at an unprecedented time now, where our current therapies for advanced-stage melanoma are so much better than what we were dealing with back in the early 2000s.

Regarding the current standard of care, we now consider using immune checkpoint inhibitors, particularly in the first-line setting for advanced-stage melanoma. There was a recent publication from the [phase 3] DREAMseq study [NCT02224781], which demonstrated the overall benefit of starting with dual checkpoint therapy rather than BRAF/MEK-targeted therapy among patients with a BRAF V600 mutation. That finding has persuaded a lot of medical oncologists, including myself, to favor immune checkpoint inhibitors in the first-line setting.

Dual checkpoint therapies, including ipilimumab and nivolumab, and more recently, nivolumab and relatlimab-rmbw [Opdualag], are major therapies we often consider in the first line. But we also have to take into account several factors, because not every patient can tolerate dual checkpoint therapy. We know that dual checkpoint therapy is associated with higher toxicities, so when deciding on the most optimal therapy for a patient, I usually consider, for example, performance status, medical comorbidities, and the sites of disease. Whether or not there is the presence of brain metastases may also influence the decision. I may also take into account the pace of the disease. For patients who need rapid tumor reduction, we might consider using BRAF/MEK-targeted therapy.

What role do neoadjuvant and adjuvant immunotherapy strategies currently play in the management of resectable stage II and III melanoma, and how might ongoing trials shift practice in the near future?

As of right now, for patients who have resected stage IIB, IIC, and III melanoma, we have FDA approval for [several] immune checkpoint inhibitors. We have anti–PD-1 agents, including pembrolizumab [Keytruda] and nivolumab. For patients who have a BRAF V600 mutation, we can also use adjuvant dabrafenib [Tafinlar] and trametinib [Mekinist], which is specifically approved for resected stage III disease. For high-risk stage IIB and IIC disease, we can use adjuvant anti–PD-1 monotherapy, such as pembrolizumab or nivolumab.

There are a lot of scientists currently investigating novel approaches to improve recurrence-free survival. We know that a good proportion of patients, despite receiving adjuvant therapy, can still develop recurrence, relapse, or metastatic progression. One ongoing study is looking at the role of combining individualized neoantigen therapy—an mRNA-based vaccine—with adjuvant anti–PD-1 therapy. A recent phase 2b study, KEYNOTE-942 [NCT03897881], evaluated a randomized comparison of adjuvant pembrolizumab alone versus pembrolizumab in combination with the individualized neoantigen therapy. The results were promising and showed an improvement in recurrence-free survival in the combination arm. A phase 3 study evaluating this approach has recently completed accrual, and we are anticipating a potential readout within the next year or two to determine whether there is a clinical benefit to using individualized neoantigen therapy to reduce the risk of melanoma recurrence following resection.

In the neoadjuvant space, this is also a growing and exciting field. The [phase 3] NADINA trial [NCT04949113] and the [phase 2] SWOG S1801 study [NCT03698019] have significantly shifted our understanding of how best to manage patients with clinically detectable disease. These studies focused on patients with clinically detectable lymph nodes—meaning bulky disease that can be seen, biopsied, and confirmed. They found that introducing immunotherapy in the neoadjuvant setting, followed by resection, led to improved event-free survival compared with the traditional approach of surgery followed by adjuvant treatment.

This neoadjuvant approach makes a lot of sense because while the tumor is still intact, immune checkpoint inhibitors can be introduced to allow for greater T-cell diversity. The presence of more neoantigens promotes a broader T-cell response, which can lead to more effective immune surveillance once the tumor is removed. In contrast, with an adjuvant approach, once the tumor is resected, there are fewer neoantigens available, which may limit T-cell diversity and subsequent immune surveillance.

The neoadjuvant approach has been a game changer in melanoma management. In the future, we may begin to consider bringing the neoadjuvant strategy into earlier-stage melanoma, not just in high-risk or bulky stage III cases. For example, it may be relevant for high-risk stage II or stage III patients who may have occult lymph node involvement. This is an ever-evolving field. As we consider more combination therapies to reduce recurrence, particularly with individualized neoadjuvant strategies, it will be exciting to see how these approaches fit into the broader neoadjuvant treatment landscape.

Overall, what is the importance of Skin Cancer Awareness Month?

We've improved mortality associated with advanced-stage melanoma over the years, but toxicity remains a concern associated with these therapies. The best way to prevent the need for systemic treatment is primary prevention. We know that the biggest risk factor for melanoma is UV damage. In terms of statistics, 5 sunburns or 1 blistering sunburn during the adolescent years doubles the risk of developing melanoma. It's important for us to campaign and educate our patients about the importance of protecting their skin, not only at a young age but even into adulthood, as well.

Skin cancer is like the straw that broke the camel's back. You never know if that last sun exposure is really what's going to tip your skin into turning into skin cancer. A tan is temporary, but the skin never forgets, so primary prevention is important.