Having Skin Cancer on Maui or in Hawaii: Melanoma and Other Skin Cancers treatment & Research
Much progress has been made in treating people with melanoma that has spread in their bodies (metastatic melanoma). Yet many people still don't benefit from the newest drugs, and others may relapse after initially successful treatment.
Melanoma Treatment
Surgery remains the standard treatment for early-stage melanoma and may also be used as part of therapy for more advanced disease. However, researchers are now focusing on developing treatments that directly target specific mutations in melanoma cells or that harness the body’s immune system to attack melanoma.
Both of these approaches—targeted therapies and immunotherapies—have led to dramatic improvements in survival for patients with advanced melanoma over the last decade. Researchers are continuing to explore ways to make these treatments more effective for more patients.
Targeted Therapies
Targeted therapies use drugs or other substances to attack specific types of cancer cells with less harm to normal cells. About half of people with melanoma that has metastasized or can’t be removed with surgery (unresectable melanoma) have mutations in the BRAF gene. These mutations result in abnormal B-Raf proteins that can cause uncontrolled growth of melanoma cells.
Drugs have been developed that block the effects of these altered B-Raf proteins. Other new drugs block proteins that work together with altered B-Raf proteins to promote cancer cell growth. These include proteins produced by the MEK genes. The combination of blocking both B-Raf and MEK has been found to be particularly successful in treating melanoma that has a mutation in the BRAF gene. Three such combinations are approved for people with metastatic or unresectable melanoma that has mutations in the BRAF gene:
dabrafenib (Tafinlar) and trametinib (Mekinist)
encorafenib (Braftovi) and binimetinib (Mektovi)
vemurafenib (Zelboraf) and cobimetinib (Cotellic)
However, although these drug combinations may be effective initially, most people develop resistance to them within a year. Researchers are studying how melanoma cells manage to grow in the presence of these targeted therapies, with the goal of finding ways to overcome resistance. Ideas being tested include new drug combinations and drugs that target the B-Raf pathway in different ways than existing drugs.
Immune Checkpoint Inhibitors
Immunotherapies are treatments that help the body’s immune system fight cancer more effectively. Melanoma tends to have a relatively high number of genetic mutations that can be recognized by the immune system compared with other cancer types. This makes it more likely that melanoma will respond to immunotherapy.
One type of immunotherapy, called immune checkpoint inhibition, has shown impressive results in some people with advanced melanoma. Four immune checkpoint inhibitors are now approved for the treatment of melanoma that can’t be removed with surgery or that has metastasized:
ipilimumab (Yervoy)
pembrolizumab (Keytruda)
nivolumab (Opdivo)
atezolizumab (Tecentriq), when used in combination with two targeted drugs
The combination of ipilimumab and nivolumab is also approved for some patients with metastatic or unresectable melanoma. In the study that led to its approval, more than half of the people who received the combination were alive 5 years after treatment. Another clinical trial showed that this combination can also shrink melanoma that has spread to the brain in some patients.
The combination of nivolumab with a new type of immune checkpoint inhibitor called relatlimab also improved the amount of time people with advanced melanoma lived without their cancer getting worse. This combination received FDA approval in 2022, under the name Opdualag, for people aged 12 or older with untreated melanoma that can't be removed surgically or has spread within the body.
Scientists are looking for ways for more people to have success with these drugs. Unfortunately, even when used in combination, immune checkpoint inhibitors don't work for all patients with metastatic or unresectable melanoma. However, patients whose tumors do shrink or disappear often have responses that last for years. Researchers are now testing ways to increase the number of people with melanoma who benefit from this type of treatment, such as these below.
Combining immune checkpoint inhibitors with immunostimulants. Immunostimulants produce a type of chemical alarm in the body that tells the immune system that a threat exists. In a small clinical trial that combined pembrolizumab with an immunostimulant, tumors shrank in almost 80% of people who received the two treatments together. Larger trials of this and other combinations of immunotherapy drugs are underway.
Testing new and existing immune checkpoint inhibitors in combination with targeted therapies and other types of drugs.
Changing people’s gut microbes before treatment with an immune checkpoint inhibitor. For example, a study found that changing some people’s gut microbes could make their melanoma more likely to shrink during treatment with an immune checkpoint inhibitor.
What treatments to give first?
Melanoma researchers are also looking to understand how best to use existing therapies. One pressing question had been whether it is better for people who have advanced melanoma with mutations in the BRAF gene to receive targeted drugs or immune checkpoint inhibitors first.
A new clinical trial, DREAMseq, has helped answer this question. Patients with advanced melanoma were randomly assigned to receive either a combination of targeted drugs or a combination of immune checkpoint inhibitors. When their cancer recurred, they received the other combination. The study found that more people who received the immune checkpoint inhibitor combination first were still alive 2 years later than people who received the combination of the targeted drugs first.
Researchers are also searching for biomarkers in melanoma that can predict which tumors might respond to other immunotherapies or drug combinations.
Immunotherapy Post-surgery For Treating Advanced Melanoma
Adjuvant therapy is additional cancer treatment given after primary surgical treatment. Nivolumab, ipilimumab, and pembrolizumab have all been approved as adjuvant therapies for melanoma that has spread to nearby lymph nodes but can be removed with surgery. In clinical trials, all three immune checkpoint inhibitors reduced the risk of recurrence for some patients when given after surgery, although many patients experienced serious side effects.
Another study tested pembrolizumab in patients with early-stage melanoma that has not spread to the lymph nodes but had a high risk of doing so. It found that giving pembrolizumab after surgery reduced the chance of the cancer coming back or spreading elsewhere in the body. However, the treatment can cause significant side effects. More studies are needed to understand how to identify the people with this type of high-risk, early-stage melanoma who would benefit the most from such treatment.
Researchers are also exploring whether immune checkpoint inhibitors might be more effective if given before surgery. One clinical trial compared the outcomes of patients with melanoma at high risk of recurring who receive pembrolizumab both before and after surgery with those in patients who receive the drug only after surgery. That trial found that people who received the drug both before and after surgery had a substantially lower risk of their cancer coming back than those who only received adjuvant treatment.
Rare Melanoma Types
Some rare types of melanoma have lagged behind melanoma of the skin in terms of advances in treatment. These include intraocular (uveal) melanoma, which starts in the eye; desmoplastic melanoma, a rare form of melanoma of the skin; and mucosal melanoma, which begins in the mucosal membranes, such as the linings of the nose and mouth.
However, recent small clinical trials suggest that these types of melanoma may also respond to immunotherapies. One clinical trial tested pembrolizumab in people with desmoplastic melanoma. Initial results from this trial showed that the drug shrinks both tumors that can be removed surgically and those that cannot. The trial participants are still being tracked to see if pembrolizumab improves how long they live overall.
Immune checkpoint inhibitors have been less effective in intraocular melanoma than in other types of melanoma. However, a different type of immunotherapy called a bispecific fusion protein has shown promise for treating this rare cancer. These drugs bind to melanoma cells and the body’s own immune cells at the same time, to bring them together. This allows the immune cells to kill the melanoma cells. In a clinical trial, one such drug, called tebentafusp, became the first drug to show an improvement in overall survival for patients with metastatic intraocular melanoma.
Another rare type of skin cancer, called Merkel cell carcinoma (MCC), has been shown to be the most sensitive of any tumor type to treatment with a single immune checkpoint inhibitor. In 2017, an immunotherapy called avelumab (Bavencio) received the first-ever FDA approval for a drug to treat MCC. In addition, more than half of patients with MCC in a small clinical trial had their tumors shrink or disappear during treatment with pembrolizumab, which received FDA approval for the treatment of MCC in 2018.
In 2023, a third immunotherapy drug called retifanlimab (Zynyz) received FDA approval for the treatment of MCC that has recurred or spread elsewhere in the body. Other immunotherapy drugs are currently being tested in this rare cancer type.
Treatment for Advanced Basal Cell Carcinoma and Squamous Cell Carcinoma
Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin are the most common cancers in the United States. They rarely spread to other organs and are seldom fatal. However, every year many people are diagnosed with advanced BCC or SCC.
Recent breakthroughs in targeted therapies and immunotherapies have changed the way people with advanced BCC and SCC are treated. Ongoing research seeks to build on these breakthroughs such as:
The targeted drugs sonidegib (Odomzo) and vismodegib (Erivedge) which can control tumors for a long time in some people with BCC. However, resistance often develops. In addition, side effects can cause some patients who need to take the drugs for a long time to stop taking them. Researchers are now looking for ways to change when and how much of these drugs are given, both to delay the development of resistance and to make them easier to tolerate.
FDA-approved immune checkpoint inhibitors for some people with advanced or metastatic BCC and SCC:
cemiplimab (Libtayo) for some people with metastatic or locally advanced SCC that can't be removed with surgery. Cemiplimab is also being tested as a treatment given before surgery for some people whose cancer can be removed.
pembrolizumab for some people with recurrent or metastatic SCC
cemiplimab for some people with advanced BCC whose tumors have become resistant to targeted therapy
New clinical trials are now testing other immunotherapy drugs and combinations in SCC and BCC.
For people whose BCC or SCC has not spread, surgery remains the mainstay of treatment. But less-intensive versions of radiation therapy have been developed for people who can’t tolerate surgery for larger tumors, such as the frail elderly.