Treatment Update: Advanced Skin Cancer

At the time of diagnosis, most cases of basal cell skin cancer (BCC) and squamous cell skin cancer (SCC) have not spread from their original locations and are managed with local treatments, including the use of topical medications (applied directly to the skin) such as fluorouracil (Efudex) or surgical removal of the tumor.

Imiquimod cream can be applied to the biopsy site of certain BCCs to treat any cancer cells that remain. This treatment is typically given 5 days a week for 6 weeks. The most common side effect is irritation at the site of application.

There are certain superficial types of BCC and SCC that can be treated by performing small in-office procedures, including electrodessication and curettage (sometimes called “scrape and burn”) for BCC and two cycles of cryotherapy (freezing) for SCC.

Mohs micrographic surgery, a precise surgical technique, is often used to treat BCC and SCC that appears on the head and neck. This is a skin-sparing technique, in which pieces of skin are progressively removed at the site of the tumor and examined under a microscope until only cancer-free tissue remains.

If surgery is not an option, radiation may be considered. Radiation may also be used after surgery if there is concern about the risk of the skin cancer recurring (coming back).

Even though these types of skin cancers are very common, relatively few evolve into cases that require more intensive treatment. In advanced cases of BCC and SCC, surgery or radiation may not be an option. In these situations, the use of oral (by mouth) or intravenous (through a vein) drugs is often considered.

Advanced Basal Cell Skin Cancer

More than 90 percent of BCCs have certain gene mutations (changes) in what is called the Hedgehog pathway. These changes activate the growth of cancer cells and allow for their survival. Drugs have been designed to target mutations in the Hedgehog pathway. The Hedgehog inhibitors approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced BCC are vismodegib (Erivedge) and sonidegib (Odomzo). Taken orally, these drugs are used in cases where the BCC has spread to other parts of the body, has recurred after surgery or cannot be treated with surgery or radiation. Hedgehog inhibitors are sometimes used before surgery to shrink the size of a tumor, making surgery an easier process and increasing its chance of success.

In February 2021, the FDA approved cemiplimab-rwlc (Libtayo) for the treatment of locally advanced or metastatic BCC that was previously treated with a Hedgehog inhibitor or for which a Hedgehog inhibitor is not appropriate.

Advanced Squamous Cell Skin Cancer

There are two immunotherapies used in the treatment of advanced SCC, both of which are given via intravenous infusion:

• In 2018, the FDA approved the immunotherapy cemiplimab-rwlc (Libtayo) for the treatment of people with metastatic or locally advanced SCC who are not candidates for surgery or radiation.

• In June 2020, the FDA approved the immunotherapy pembrolizumab (Keytruda) for the treatment of recurrent or metastatic SCC that is not curable by surgery or radiation. In July 2021, the approval was expanded to include treatment of locally advanced SCC that is not curable by surgery or radiation.

The targeted therapy cetuximab (Erbitux) is sometimes prescribed to treat people whose SCC tumors cannot be surgically removed or treated with radiation. By attaching to a structure on the cell called the epidermal growth factor receptor (EGFR), cetuximab can block one of the signals that tells a tumor to grow.

Melanoma is the most serious type of skin cancer. It develops in the cells that produce melanin, the pigment that gives color to skin, hair and eyes. Most cases of melanoma are diagnosed at an early stage, after a tumor appears on the skin. In the majority of people, the melanoma is effectively treated by the surgical removal of the tumor.

If surgery does not remove all of the melanoma, imiquimod cream may be used to destroy the remaining cancer cells. It can also be used to treat patients for whom surgery is not an option. Advanced (metastatic) melanoma has spread from where it originated to another part of the body, including lymph nodes or other organs. Deciding what treatment option is best is based on factors unique to the individual, including their health history, energy level, where the cancer appeared initially and where it appears currently.

Factors specific to the melanoma itself, such as whether the tumor has a mutation in the BRAF gene, also influence treatment options.

As there are a number of options for treating advanced melanoma, it’s important for people to consult with their doctor to understand what treatment may be most effective for them.

Immunotherapy in the Treatment of Advanced Melanoma

Our immune system is constantly working to keep us healthy. It recognizes and fights against danger, such as infections, viruses and growing cancer cells. In general terms, immunotherapy uses our own immune system as a treatment against cancer. There are a number of immunotherapies approved to treat advanced melanoma:

• Interferon (Intron A, Sylatron). In 1995, the FDA approved interferon as an adjuvant (post-surgery) therapy for people whose advanced melanoma tumors were surgically removed. The use of interferon in these circumstances may stop the growth and spread of any remaining melanoma cells. Interferon is rarely used today, because newer and more effective treatments are now available.

• Aldesleukin (interleukin-2, Proleukin). Since the late 1990s, aldesleukin has been used as a treatment for advanced melanoma. Given intravenously, aldesleukin helps the body’s immune system shrink and destroy tumors more effectively. As is the case with interferon, aldesleukin is not used as frequently today as a standalone treatment as it was in the past.

• Ipilimumab (Yervoy). Ipilimumab was approved by the FDA in 2011 for the treatment of advanced melanoma. Ipilimumab binds onto CTLA-4, a protein that inhibits immune system cells (called T cells). By blocking the action of CTLA-4, ipilimumab is thought to help the immune system destroy melanoma cells. Ipilimumab is given intravenously.

• Pembrolizumab (Keytruda). Given intravenously, pembrolizumab blocks the PD-1 cellular pathway (a pathway that inhibits the body’s immune system from working properly). Pembrolizumab is approved for the treatment of melanoma that is advanced or unresectable (unable to be removed) and for post-surgery treatment of melanoma with or without lymph node involvement.

• Nivolumab (Opdivo). Nivolumab was approved for the treatment of advanced melanoma in 2014. In 2017, the approval was extended for the post-surgery treatment of melanoma that has lymph node involvement. Like pembrolizumab, nivolumab works by blocking the PD-1 pathway and is given intravenously.

• Talimogene laherparepvec (Imlygic). This drug, often referred to as TVEC, was approved by the FDA in 2015 for the treatment of advanced stage melanoma. TVEC is injected directly into the melanoma lesions, where it can cause the destruction of cancer cells. As TVEC may also improve the immune system’s response to cancer, melanoma lesions that were not injected with the drug may also shrink or disappear.

There are also two combination immunotherapies approved for the treatment of advanced melanoma:

• Ipilimumab plus nivolumab (Yervoy plus Opdivo). Approved by the FDA in October 2020, this combination is designed to block the actions of both the CTLA-4 and PD-1 pathways.

• Nivolumab plus relatlimab (Opdualag). Approved in March 2022, this treatment combines a PD-1 inhibitor with a novel (new) therapy that blocks the LAG-3 pathway.

Targeted Therapy in the Treatment of Advanced Melanoma

Targeted therapies are designed to inhibit specific cell mechanisms important for the growth and survival of tumor cells. People who may benefit from targeted therapies have tumors possessing specific DNA changes (mutations) that allow cancers to develop and grow.

Up to 50 percent of melanomas have a mutation called BRAF. A number of targeted therapies have been approved by the FDA for the treatment of melanoma with a BRAF mutation:

• Vemurafenib (Zelboraf). In 2011, the FDA approved vemurafenib, a drug that inhibits the “signal transduction” pathway in people with a BRAF gene mutation.

• Dabrafenib (Tafinlar). In 2013, the FDA approved dabrafenib, which targets the BRAF gene mutation in the same way as vemurafenib.

• Trametinib (Mekinist). Trametinib was approved by the FDA in 2013 to treat people with advanced melanoma that cannot be removed by surgery. In 2014, the approval was extended to include use in combination with dabrafenib. Trametinib blocks a protein called MEK, which is “switched on” by the BRAF gene mutation. In 2018, the combination of dabrafenib and trametinib was granted approval by the FDA for the treatment of melanoma that has spread to the lymph nodes and which has a BRAF mutation.

• Cobimetinib (Cotellic). In 2015, the FDA approved cobimetinib for the treatment of people with inoperable or advanced melanoma that has a BRAF mutation, for use in combination with vemurafenib.

• Encorafenib (Braftovi) and binimetinib (Mektovi). In 2018, the FDA approved the combination treatment of encorafenib (a BRAF inhibitor) and binimetinib (a MEK inhibitor) for the treatment of people with unresectable or advanced melanoma with a BRAF V600E or V600K mutation.

• Atezolizumab (Tecentriq) plus cobimetinib (Cotellic) and vemurafenib (Zelboraf). In July 2020, the FDA approved atezolizumab (an immunotherapy) in combination with the targeted therapies cobimetinib and vemurafenib for the treatment of BRAF V600-positive advanced melanoma.

As you manage your cancer, it’s important to remember that you are a consumer of health care. The best way to make decisions about health care is to educate yourself about your diagnosis and get to know the members of your health care team, including doctors, nurses, nurse practitioners, physician assistants, dietitians, social workers and patient navigators.

Here are some tips for improving communication with your health care team:

Start a health care journal. Having a health care journal or notebook will allow you to keep all of your health information in one place. You may want to write down the names and contact information of the members of your health care team, as well as any questions for your doctor.

Prepare a list of questions. Before your next medical appointment, write down your questions and concerns. Because your doctor may have limited time, ask your most important questions first and be as specific as possible.

Bring someone with you to your appointments. Even if you have a journal and a prepared list of questions or concerns, it’s always helpful to have support when you go to your appointments. The person you bring may also think of questions to ask your doctor or remember details about your symptoms or treatment that you may have forgotten.

Write down your doctor’s answers. Taking notes will help you remember your doctor’s responses, advice and instructions. You can also ask the person who accompanies you to take notes for you, either in your journal or on a tablet or smartphone.

Record your visit if your doctor allows it. Recording the conversation with your doctor gives you a chance to hear specific information again or share it with family members or friends.

Incorporate other health care professionals into your team. Your medical oncologist is an essential member of your health care team, but there are other health care professionals who can help you manage your diagnosis and treatment:

• Your primary care physician should be kept updated about your cancer treatment and any test results.
• Your local pharmacist is a great source of knowledge about the medications you are taking. Have all of your prescriptions filled at the same pharmacy to avoid the possibility of harmful drug interactions.
• Make sure your oncologist knows of any other medical conditions you have or any pain you are experiencing so that they can consult with your primary care physician or specialist as needed.

Remember, there is no such thing as over-communication.

**Q: Can you explain the “ABCDEs” of melanoma and why they are important?

A: A change in the appearance of a mole, described in words beginning with A, B, C, D and E, may be the first sign of melanoma. Consult with your doctor if you have any moles with the following features. There is a high likelihood of a successful outcome if the melanoma is recognized and treated at an early stage.

• Asymmetrical: One side of the mole looks different from the other
• Border: Irregular or vaguely defined borders
• Color: Uneven coloring or multiple colors
• Diameter: Larger than a pencil eraser or growing in size
• Evolution: Growing or changing in any way

Q. What is Gorlin syndrome?

A: Gorlin syndrome, also called basal cell nevus syndrome or nevoid basal cell carcinoma syndrome, is a rare inherited condition. People with Gorlin syndrome develop many basal cell carcinomas (BCC) over their lifetime, often starting in childhood or in their teen years. Unprotected exposure to ultraviolet (UV) radiation from the sun or indoor tanning can increase the incidence of these tumors. Sometimes people with Gorlin syndrome are put on Hedgehog inhibitor therapy to try to control the development or progression of BCC.

Q: Are melanomas genetic (inherited)?

A: Most melanomas occur in people where no family or genetic link can be found. However, there may be rare cases, not related to sun exposure, that have a genetic predisposition. For melanomas related to sun exposure, having a close relative with melanoma is a risk factor, but it’s not clear if the link is genetic or behavioral. Annual skin screenings for melanoma are recommended if you have a close relative with melanoma.

Q: I was treated with immunotherapy for my melanoma, and it has now recurred. Can I be treated with another immunotherapy?

A: More than likely, yes. Different types of immunotherapy work in different ways. It may even be that in some cases the immunotherapy you were treated with initially may be effective in treating the recurrence of the melanoma. This area is the subject of ongoing research.