How Advances in Therapy Are Changing Skin Cancer Care

Dr. Jesse Miller Lewin sat down with CURE to discuss how recent advances in systemic and local therapies are reshaping the treatment landscape for skin cancer. During the conversation, he explained how immunotherapy and targeted treatments are being used across melanoma, squamous cell carcinoma, and basal cell carcinoma, as well as how surgical approaches such as Mohs micrographic surgery remain central to care.

He also shared insight into how tumor biology, genetic testing, and patient goals guide individualized treatment decisions, emphasizing the importance of balancing cure rates with quality of life.

Lewin is an associate professor at the Icahn School of Medicine at Mount Sinai and serves as director of The Kimberly and Eric J. Waldman Melanoma and Skin Cancer Center. He is also vice chair of surgical operations, system chief of the Division of Dermatologic and Cosmetic Surgery, and program director for the Micrographic Surgery and Dermatologic Oncology Fellowship within The Kimberly and Eric J. Waldman Department of Dermatology. In addition, he is a spokesperson for The Skin Cancer Foundation.

CURE: How have recent advances in systemic and local therapies changed the treatment landscape for skin cancer? What should patients understand about how these options are selected?

Lewin: Depending on what type of skin cancer you are talking about, there have actually been some fairly major advances in systemic therapy. In particular, regarding melanoma, the checkpoint inhibitor drugs, such as Keytruda (pembrolizumab) and Opdivo (nivolumab), are anti-PD-1 targeted immunotherapy agents. What is exciting about them is that they do not have the systemic toxicity of standard, traditional cytotoxic chemotherapy, and so they are much better tolerated for patients than previous chemotherapy agents. Those older agents essentially had a wider field of side effects because they targeted many cells, not just cancer cells; for example, they would target cells in the GI tract, causing vomiting, or hair cells, causing hair loss.

Essentially, these targeted immunotherapy checkpoint inhibitors are able to treat either early but aggressive melanoma or later-stage melanoma in a much more targeted fashion. Those drugs are used either adjuvantly, meaning after surgery, or neoadjuvantly, before surgery, for higher-risk melanomas, and they produce long, durable remissions for patients. That is an exciting development on the forefront of melanoma treatment.

For patients who may be hearing terms like “adjuvant” and “neoadjuvant” for the first time, how do you explain these approaches and their potential benefits in melanoma care?

In terms of other melanoma treatments, the BRAF inhibitors are a little bit older than immunotherapy but still fairly novel. This set of drugs targets specific mutations that might be expressed by a particular patient’s melanoma. If you have a BRAF mutation, you can be treated with a drug like Tafinlar (dabrafenib) or Mekinist (trametinib); these are targeted small-molecule drugs that treat melanomas with those particular mutations.

Regarding advanced basal cell carcinoma, I should also mention that PD-1 drugs like Keytruda are particularly helpful not just for melanoma, but also for cutaneous squamous cell carcinoma. This has been used mostly in the adjuvant setting, after surgery for high-risk squamous cell carcinoma, or for locally advanced, recurrent, or metastatic squamous cell carcinoma. These drugs have been a game-changer for advanced squamous cell carcinoma.

Squamous cell carcinoma is often viewed as less dangerous by the public. Why is it important for patients to take this diagnosis seriously?

Cutaneous squamous cell carcinoma does not always get the respect it deserves; probably more people die of cutaneous squamous cell carcinoma than melanoma, but melanoma seems to garner the most fear and respect among the public because it is seen as so deadly. When you look at the numbers, there are far more squamous cell carcinomas than there are melanomas. While only a small subset of squamous cell carcinomas leads to death, those numbers likely equal or exceed melanoma deaths every year in the United States, so it is very important to keep that on everyone’s radar.

Returning to targeted treatments, we also have another class of drugs called hedgehog inhibitors, such as Erivedge (vismodegib) and Odomzo (sonidegib), which are good options for locally advanced basal cell carcinoma. These are used for basal cell carcinomas that are considered inoperable, or in the neoadjuvant setting to shrink very large tumors. For instance, if there is a basal cell carcinoma in the medial canthus region near the eye, a functionally important area, where surgery would result in a significant functional issue, some providers treat those tumors with systemic hedgehog inhibitors to shrink them prior to Mohs surgery.

How do you determine when systemic therapy should be used to shrink a tumor before surgery rather than proceeding directly to an operation?

Finally, in terms of cancer vaccines, these are not yet ready for prime time. Trials are being conducted in melanoma looking at vaccines plus certain checkpoint inhibitors versus vaccines alone, but they are currently in clinical trial phases and not yet widely used for treatment.

How do you approach treatment selection for different skin cancers, and how do tumor characteristics and patient preferences factor into those decisions?

As a Mohs surgeon, I spend basically all of my time performing Mohs micrographic surgery for non-melanoma and melanoma skin cancer. There are certain indications for Mohs surgery; for instance, if a patient has a basal cell or squamous cell carcinoma on a cosmetically or functionally important area, such as the face, we often choose Mohs surgery because it is the gold standard of surgical treatments. It offers the highest cure rate while preserving as much healthy tissue as possible. These procedures are very safe, performed in the office under local anesthesia using lidocaine. By and large, Mohs surgery is the go-to treatment for most patients with non-melanoma skin cancer on the head and neck.

There is a small set of patients who are either surgery-averse or are not candidates for surgery. However, because local anesthesia is so well-tolerated, I have patients as old as 100 undergo Mohs surgery. It is often preferable to radiation, which can require treatments four or five days a week for a month. For low-risk non-melanoma skin cancers in low-risk areas, such as the trunk or extremities, tumors can often be destroyed through electrodesiccation and curettage (ED&C). If the cancer involves both layers of the skin, a standard excision may be used, removing the cancer with a five-millimeter margin and stitching the area. This differs from Mohs surgery, where we use narrower margins and examine slides under a microscope while the patient waits to confirm the margins are clear before completing the repair.

Melanoma on the trunk and extremities is also treated with standard excision, with the amount of tissue removed depending on the stage. Stage zero melanoma (in situ) requires a five-millimeter margin. Thin melanomas, such as stage 1a or 1b, are excised with a one-centimeter margin. For deeper melanomas, patients may undergo a wide local excision plus a sentinel lymph node biopsy. Performed in an operating room by a surgical oncologist, this involves injecting a tracer to see where the area drains and testing the lymph node for tumor cells. If melanoma is found, those lymph nodes are removed.

At Mount Sinai, we perform Mohs surgery for thin and in situ melanomas on the head and neck to preserve normal tissue. In these cases, we use an immunohistochemical stain called MART-1, which highlights the cells under the microscope and allows us to define the borders better. Unlike standard excision, where results take several days, Mohs surgery provides confirmation in several hours.

We also use genetic testing to inform treatment. Beyond checking for BRAF mutations, molecular tests from companies like Castle Biosciences allow us to profile a patient's individual cancer. This risk stratification helps us decide whether to be more aggressive, such as performing a sentinel lymph node biopsy for a borderline melanoma or ordering a CAT scan and considering adjuvant radiation for a high-risk squamous cell carcinoma.

Ultimately, treatment selection depends on both the tumor and the patient. While we prioritize the highest cure rates for tumors with metastatic potential, like melanoma and squamous cell carcinoma, we also consider the individual's quality of life and life expectancy. For an elderly patient with a slow-growing basal cell carcinoma, we discuss whether the tumor will impact their mortality or become a functional issue. Even if a patient has a limited life expectancy, excision may be reasonable if a tumor is bleeding or causing pain. We tailor the treatment by balancing the tumor's histology and location with the patient’s values and physical status.

Transcript has been edited for clarity and conciseness.

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