Treatment Glossary

To repair superficial skin damage, the physician applies trichloroacetic acid and/or similar chemicals to the face, causing the top skin layers to slough off. New skin generally regrows within a few weeks. This method may require local anesthesia. It can cause temporary irritation and discoloration.

A chemical peel can be used to remove superficial facial actinic keratoses (precancerous skin lesions), especially when previous treatments have not succeeded. It is also used as a cosmetic skin rejuvenation technique.

In cryosurgery (“cryo” means cold), most commonly used to treat actinic keratoses (precancerous skin lesions), the dermatologist applies liquid nitrogen to the growth with a spray device or cotton-tipped applicator. This freezes the tissue without requiring any cutting. It may cause a mild stinging sensation, but usually local anesthesia isn’t needed. Later, the lesion and surrounding frozen skin may blister or become crusted and fall off. Temporary redness and swelling can occur. Cryosurgery may cause a loss of pigment in the area treated.

Cryosurgery is especially useful when a limited number of precancers are present. It is also used for superficial basal cell carcinomas and, more rarely, for superficial squamous cell carcinomas.

This technique can be used for both actinic keratoses (skin precancers) and certain skin cancers. Using local anesthesia, the physician scrapes off part or all of the lesion with a curette, an instrument with a sharp ring-shaped tip. Then the doctor uses electrodesiccation, which cauterizes the area with heat or a chemical agent to stop the bleeding and destroy any residual abnormal cells that the curette did not remove. When treating a skin cancer, the doctor may repeat the entire procedure twice at the same session.

While curettage and electrodesiccation can be used to remove actinic keratoses as well as some superficial basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), it is usually not recommended for larger, aggressive or invasive BCCs or SCCs or for lesions on the face. The treated area may not regain its pigment.

Using a scalpel, the physician removes, or excises, the entire cancerous tumor along with a surrounding border of presumably normal skin as a safety margin, then sends the tissue specimen to a lab to make sure the margins are free of cancer. Depending on its size and location, the wound may be left open to heal or the doctor may close it with stitches. If the lab finds evidence of skin cancer beyond the safety margin, the patient may need to return for another surgery.

Excisional surgery can be used for basal cell carcinomas and squamous cell carcinomas as well as melanomas. For tumors discovered at an early stage that have not spread beyond the tumor margin, excisional surgery is frequently the only treatment required.

The dermatologist uses a beam of light of a specific wavelength to destroy skin precancers as well as certain superficial skin cancers. Some lasers vaporize (ablate) the skin cancer, while others (nonablative lasers) convert the beam of light to heat, which destroys the tumor. Ablative lasers (such as CO2 lasers) give the physician good control over the depth of tissue removed, without causing bleeding. The doctor may remove the skin’s outer layer and/or variable amounts of deeper skin, so local anesthesia may be needed. The risks of scarring and pigment loss are slightly greater than with other techniques.

Laser surgery is effective for removing precancerous actinic keratoses from the face and scalp, and precancerous actinic cheilitis from the lips. It can also be used to treat superficial basal cell carcinomas and, in rarer instances, superficial squamous cell carcinomas. In addition, it can serve as a secondary therapy when topical medications or other techniques are unsuccessful.

Mohs surgery has long been the gold standard for treating many basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). It is especially beneficial in areas of the face where preserving normal tissue is essential for function and appearance. It is also used for BCCs and SCCs that have recurred following standard treatment. Mohs surgery can pinpoint and remove microscopic extensions, or “roots,” of the cancer, and because SCCs have a higher risk of spreading (metastasizing) than BCCs, complete microscopic removal is extremely important.

The Mohs procedure is done in stages, with each removed layer of tissue examined under a microscope in an on-site lab at the time of surgery, while the patient waits. This is different from standard excision, in which the physician closes the wound after removing the tumor, allows the patient to go home and sends the excised tissue to a lab for a pathologist to review.

After injecting a local anesthetic, the Mohs surgeon first removes the visible cancerous tumor and a very small margin of presumably healthy tissue.  After the wound is bandaged, the patient waits.

The surgeon color-codes the excised tissue and draws a map that correlates the tissue with the surgical site on the face or body of the patient. Next, a technician processes the tissue in an on-site laboratory by freezing the tissue, slicing it horizontally and placing the slices on slides. These “sections,” encompassing the margins of the tissue, are stained with special chemicals that help identify cancerous tissue. The Mohs surgeon then examines these sections under a microscope. If the doctor finds any remaining cancer cells, he or she pinpoints the areas on the map, and calls the patient back into the operating room. The Mohs surgeon then removes more tissue exactly where cancer cells remain.

The team repeats this process until the surgical site contains no microscopic evidence of cancer. If more than one or two rounds are needed, the entire process can take up to several hours. Depending on its size and location, the wound may be left open to heal or the surgeon may close it with stitches. In some cases, a wound may need reconstruction using neighboring tissue or a skin graft. In some cases, a plastic surgeon may perform the reconstruction.

This precise technique has the highest cure rate and lowest recurrence rate of any skin cancer treatment, while preserving the maximum amount of normal tissue and allowing the smallest scar possible.

Long considered the single most effective technique for removing BCCs and SCCs, Mohs surgery had not been widely used for melanomas until recently, as this type of cancer was hard to distinguish on frozen sections. But advances in the field are changing that, and a growing body of evidence suggests that the Mohs procedure is safe and effective for both in situ and invasive melanoma. The use of Mohs surgery for any type of skin cancer requires special training.

Photodynamic therapy (PDT) is a noninvasive, FDA-approved treatment for precancerous lesions called actinic keratoses (AKs). It is especially useful for widespread AKs on the face and scalp and can be used to treat a large area. It is sometimes used for superficial basal cell carcinomas or squamous cell carcinomas.

PDT is a two-part process. A dermatologist applies a topical medication called aminolevulinic acid (ALA) to lesions and some of the surrounding skin. This medication is left to incubate on the treatment area for one to several hours and is converted into a light-sensitive agent when it penetrates the skin. Second, the dermatologist uses a special red or blue light or pulsed-dye laser to activate the light-sensitive agent and destroy the lesions, while causing minimal damage to surrounding healthy tissue. (Sometimes controlled natural sunlight may be used to activate the ALA.)

Some redness, peeling, flaking and swelling may result. The treatment makes your skin more sensitive to light, so it’s important to apply sunscreen and avoid sun exposure on the treated areas for at least 48 hours following treatment. Exposure to ultraviolet (UV) light from the sun or from tanning beds after treatment can increase activation of the medication and may cause severe sunburns.

Radiation, directing low-energy X-ray beams to destroy the tumor, is sometimes used to treat basal cell or squamous cell carcinomas that are hard to manage surgically and for elderly patients or others in poor health. It may require several treatments over a few weeks or daily treatment for a month. Cure rates are around 90 percent. Although radiation limits damage to adjacent tissue, it can involve long-term cosmetic problems and radiation risks.

Physicians may combine radiation with other treatments for advanced squamous cell carcinoma. Radiation is also being tested in combination with certain treatments for advanced melanoma.

5-fluorouracil (5-FU) cream or solution, a topical chemotherapy, is one of the most commonly used treatments for actinic keratoses, the most common skin precancers. It is especially effective for “field therapy,” treating areas of skin with multiple lesions. Efudex® cream is also FDA-approved to treat superficial basal cell carcinoma, with cure rates between 80 and 90 percent, and is sometimes used for superficial squamous cell carcinoma.

You rub this medicine gently onto and around the lesion once or twice daily for two to four weeks. Side effects include redness, swelling and crusting, but for many people, the therapeutic benefits outweigh any temporary discomfort. 5-FU can treat both visible and invisible lesions with a minimal risk of scarring. It is available in concentrations ranging from 0.5 to 5.0 percent.

This combination of three drugs taken by mouth, atezolizumab (Tecentriq®), cobimetinib (Cotellic®) and vemurafenib (Zelboraf®), combines immunotherapy and targeted therapies, both of which have been making great strides in the treatment of advanced melanoma.

Using synthetic versions of natural immune system chemicals, or by inhibiting proteins that suppress immune functions, immunotherapies boost the immune system’s ability to fight disease. These drugs block certain molecules that inhibit or “check” T-cell production to prevent excessive and potentially dangerous inflammatory and autoimmune reactions under normal circumstances. Cancer cells can keep these checkpoints active, preventing the release of T cells that would combat the cancer, but checkpoint blockade therapies can inhibit them and release the T cells.

Atezolizumab blocks a checkpoint called programmed death-ligand 1 (PD-L1), a molecule that binds to another molecule called PD-1 (programmed death-1) on tumor cells. Together these two molecules form a complex that inhibits T-cell activation. By blocking PD-L1, atezolizumab prevents it from binding with PD-1, thereby restoring T-cell activation and anti-tumor activity.

Atezolizumab was the first anti-PD-L1 drug approved by the FDA. It was approved in May 2016 for advanced urothelial cancer and since then has been approved for use as a monotherapy or in combination with other therapies for other cancers.

In patients with stage IV melanoma, targeted therapies are for those who have a cancer-producing version of the BRAF gene. About half of all melanoma patients have this defective gene. Normally, BRAF controls skin cell growth, but the defective version essentially becomes stuck in the “on” position, leading to out-of-control growth of cancer cells. Though vemurafenib (a BRAF inhibitor) may be prescribed alone, cobimetinib, which blocks a protein called MEK, is only used in combination with vemurafenib, not as an individual therapy.

Cobimetinib plus vemurafenib was approved by the FDA as a targeted treatment in patients with stage IV inoperable or metastatic melanoma in 2015.

The FDA approved the combination of atezolizumab plus cobimetinib and vemurafenib as treatment for patients with BRAF V600 mutation-positive melanoma in July 2020. Atezolizumab is not approved as a monotherapy for melanoma. In the IMspire150 clinical trial, patients given atezolizumab plus cobimetinib and vemurafenib saw median progression-free survival of 15.1 months while median progression-free survival for the combination therapy of cobimetinib plus vemurafenib was 10.6 months.

Using synthetic versions of natural immune system chemicals, or by inhibiting proteins that suppress immune functions, immunotherapies boost the immune system’s ability to fight disease. Approved by the FDA in 2017 as a treatment for a rare skin cancer called Merkel cell carcinoma (MCC), avelumab (Bavencio®) is an intravenously infused checkpoint blockade therapy. These drugs block certain molecules that inhibit or “check” T-cell production to prevent excessive and potentially dangerous inflammatory and autoimmune reactions under normal circumstances. Cancer cells can keep these checkpoints active, preventing the release of T cells that would combat the cancer, but checkpoint blockade therapies can inhibit them and release the T cells.

Avelumab blocks a checkpoint called programmed death-ligand 1 (PD-L1), a molecule that binds to another molecule called PD-1 (programmed death-1) on tumor cells. Together these two molecules form a complex that inhibits T-cell activation. By blocking PD-L1, avelumab prevents it from binding with PD-1, thereby releasing massive amounts of T cells to fight MCC that has spread (metastasized). It was the first drug approved for metastatic MCC and today is one of just two available treatments, along with the checkpoint inhibitor pembrolizumab (Keytruda^®), which blocks PD-1.

Avelumab is approved for the treatment of adults and pediatric patients age 12 and older with metastatic MCC. Its approval was based on data from a clinical trial in which 33 percent of the patients experienced complete or partial shrinkage of their tumors. The responses lasted more than six months in 86 percent of responding patients and more than 12 months in 45 percent of responding patients.

Using synthetic versions of natural immune system chemicals, or by inhibiting proteins that suppress immune functions, immunotherapies boost the immune system’s ability to fight disease. Approved by the FDA in 2018, cemiplimab-rwlc (Libtayo®) is an intravenously infused checkpoint blockade therapy. These drugs have made giant strides in treating advanced melanomas and other cancers. Cemiplimab is the first checkpoint blockade therapy — in fact, the first treatment of any kind —approved in the U.S. for advanced squamous cell carcinoma (SCC) of the skin (also known as cutaneous squamous cell carcinoma, or cSCC). The medication is also the first immunotherapy approved in the U.S. for treating patients with advanced basal cell carcinoma (BCC). By blocking a protein receptor called PD-1 (programmed death-1), which, under normal circumstances, keeps the immune system in check, this drug releases massive amounts of T cells to fight the cancer.

Cemiplimab is approved for patients who have metastatic SCC and those who have locally advanced, inoperable SCC for whom curative surgery or radiation are not options. Approval was based on the combined data from a phase 2 study and a phase 1 study, which found that out of a combined 108 patients, more than 47 percent responded to the drug, with 4 percent experiencing a complete response (complete remission). Some patients who had failed other therapies had complete responses, including one patient with metastases to the brain. Only three responders had their disease advance.

In February 2021, the U.S. Food and Drug Administration (FDA) approved cemiplimab for treating patients with advanced basal cell carcinoma (BCC) previously treated with a hedgehog pathway inhibitor (HHI) or for whom an HHI is not appropriate. Full approval was granted for patients with locally advanced BCC and accelerated approval was granted for patients with metastatic BCC.

This combination of two drugs taken by mouth, cobimetinib (Cotellic®) and vemurafenib (Zelboraf®), is in a class of treatments known as targeted therapies, which, along with immunotherapies, have been making giant strides in the treatment of advanced melanoma. In patients with stage IV melanoma, these targeted therapies are for those who have a cancer-producing version of the BRAF gene. About half of all melanoma patients have this defective gene. Normally, BRAF controls skin cell growth, but the defective version essentially becomes stuck in the “on” position, leading to out-of-control growth of cancer cells.

The FDA approved this combination therapy in 2015 for patients with stage IV inoperable or metastatic melanoma, pairing the BRAF blocker vemurafenib with the drug cobimetinib, which blocks a protein called MEK. As with patients on two other BRAF-MEK targeted combination therapies, dabrafenib-trametinib and encorafenib-binimetinib, those on this combination therapy have slower disease progression and live longer on average than those on vemurafenib, dabrafenib or encorafenib alone. Cobimetinib is used only in combination with vemurafenib, not as an individual therapy. In general, the combined targeted therapies are having such success that they have replaced the single-therapy targeted regimens as frontline therapies.

The most common serious side effect of vemurafenib, dabrafenib and encorafenib, and their combinations, is the formation of nonmelanoma skin cancers, especially squamous cell carcinomas. Most are small or superficial and can be treated effectively. These side effects occur less frequently with the combination therapies than with the monotherapies.

Taken by mouth, this drug is one of a class of treatments known as targeted therapies, which, along with immunotherapies, have been making giant strides in the treatment of advanced melanoma. In patients with stage IV melanoma, these targeted therapies for those who have a cancer-producing version of the BRAF gene. About half of all melanoma patients have this defective gene. Normally, BRAF controls skin cell growth, but the defective version essentially becomes stuck in the “on” position, leading to out-of-control growth of cancer cells.

The FDA approved this oral BRAF inhibitor for advanced melanoma patients in 2013. Like its predecessor, vemurafenib, dabrafenib blocks the BRAF protein, turning off cancerous growth in many patients for months or even years. While it increases the length of time before patients’ disease starts to advance again, as well as length of survival, in most patients the melanoma eventually develops resistance to the drug, and the disease begins to advance again. Drugs such as trametinib, cobimetinib and binimetinib, which target an enzyme called MEK, further delay progression of the disease, and drugs combining them with dabrafenib, vemurafenib and encorafenib, respectively, are improving outcomes. In fact, today the combination drugs have become the frontline choices for targeted therapy. (See Dabrafenib-Trametinib, Combination; Cobimetinib-Vemurafenib, Combination; and Encorafenib-Binimetinib, Combination.)

The most common serious side effect of vemurafenib, dabrafenib and encorafenib, as well their combinations, is the formation of nonmelanoma skin cancers, especially squamous cell carcinomas. Most are small or superficial and can be treated effectively. These side effects occur less frequently with the combination therapies than with the monotherapies.

This combination of two drugs taken by mouth, dabrafenib (Tafinlar®) and trametinib (Mekinist®), is part of a class of treatments known as targeted therapies, which, along with immunotherapies, have been making giant strides in the treatment of advanced melanoma. In patients with stage IV melanoma, these targeted therapies are designed exclusively for those who have a defective, cancer-producing version of the BRAF gene. About half of all melanoma patients have this defective gene. Normally, BRAF controls skin cell growth, but the defective version essentially becomes stuck in the “on” position, leading to out-of-control growth of cancer cells.

The FDA approved this combination therapy in 2014 for patients with stage IV inoperable or metastatic melanoma, pairing the BRAF blocker dabrafenib with the drug trametinib, which blocks another protein called MEK. This combination therapy has produced some of the best results ever achieved for stage IV melanoma. As with patients on two other targeted combination therapies, cobimetinib-vemurafenib and encorafenib-binimetinib, those on this combination therapy have slower disease progression and live longer on average than those on vemurafenib or dabrafenib alone.

In general, trametinib today is used only in combination with dabrafenib, not as an individual therapy. In fact, the combination targeted therapies are achieving such superior results that they have essentially eliminated the use of the single-drug targeted therapies.

In 2018, the FDA also approved the use of combination dabrafenib-trametinib as an adjuvant treatment for patients with BRAF V600E-positive or V600K-positive stage III melanoma following complete removal of the primary tumor. The approval was based on the results of the COMBI-AD trial, the first randomized study ever of combination BRAF-MEK inhibition as a melanoma adjuvant therapy, published in The New England Journal of Medicine. In the study, the combination reduced the risk of disease recurrence or death by 53 percent compared with placebo for patients with BRAF-mutant stage III melanoma. After a median follow-up of 2.8 years, the three-year recurrence-free survival rate with dabrafenib-trametinib was 58 percent compared with 39 percent for the placebo arm. Early data on overall survival showed that 86 percent of patients in the combination arm were still alive at three years, versus 77 percent in the placebo arm.

In 2020, researchers published updated results from the COMBI-AD trial, now including five-year analysis. The combination treatment reduced the risk of disease relapse or death by 49 percent compared with placebo for patients with BRAF-mutant stage III melanoma at five years, and the recurrence-free survival rate was 52 percent compared with 36 percent for the placebo arm.

Adjuvant therapies are strategies that enhance the effectiveness of a primary treatment such as surgery, with the goal of delaying recurrence and extending overall survival. The hope is that by using this medicine before the cancer reaches stage IV, spreading throughout the body, it will provide even greater benefits for patients and save more lives.

The most common serious side effect of vemurafenib, dabrafenib and encorafenib, as well as their combinations, is the formation of nonmelanoma skin cancers, especially squamous cell carcinomas. Most are small or superficial and can be treated effectively. These side effects occur less frequently with the combination therapies than with the monotherapies.

This topical gel combining hyaluronic acid, a chemical found naturally in the body, with the nonsteroidal anti-inflammatory drug diclofenac can be effective against precancerous actinic keratoses (AKs) for people whose skin is sensitive to 5-fluorouracil. Recent research found that a formula of 3 percent diclofenac twice a day successfully eliminated AKs in organ transplant patients, who are highly susceptible to AKs and skin cancers. It also effectively prevented invasive squamous cell skin carcinoma. Treatment typically continues for two to three months. The most common side effects include mild to moderately severe skin reactions, such as dermatitis, rash, itching, dry skin, scaling or other skin irritations, and sometimes nausea and stomach irritations. There is minimal risk of scarring.

This combination of two drugs taken by mouth, encorafenib (Braftovi®) and binimetinib (Mektovi®), is the newest addition to a class of treatments known as targeted therapies, which along with immunotherapies have made giant strides in the treatment of advanced melanoma. In patients with stage IV melanoma, these targeted therapies are designed exclusively for those who have a defective, cancer-producing version of a gene called BRAF. About half of all melanoma patients have this defective gene. Normally, BRAF controls skin cell growth, but the defective version essentially becomes stuck in the “on” position, leading to out-of-control growth of cancer cells.

The FDA approved this combination therapy in 2018 for patients with stage IV inoperable or metastatic melanoma, pairing the BRAF blocker encorafenib with the drug binimetinib, which blocks another protein called MEK. The drugs are used only in combination. The therapy has produced some of the best results ever achieved for stage IV melanoma. As with patients on two other targeted combination therapies, vemurafenib-cobimetinib and dabrafenib-trametinib, those on this therapy have slower disease progression and longer overall survival than those on vemurafenib or dabrafenib alone. In fact, the combination targeted therapies are achieving such superior results that they have essentially eliminated the use of the single-drug targeted therapies.

This combination therapy was approved based on results from the phase 3 COLUMBUS trial, which demonstrated that it doubled median progression-free survival (PFS) compared to vemurafenib alone (14.9 months versus 7.3 months, respectively), and preliminary results show that it also doubles overall survival (OS) compared with vemurafenib alone (33.6 months versus 16.9 months). PFS for this combination was slightly better than for the preexisting combinations vemurafenib-cobimetinib and dabrafenib-trametinib. It is also the first targeted treatment to demonstrate over 30 months median OS in a phase 3 trial. The most common side effects are fatigue, diarrhea, nausea, vomiting, abdominal pain and arthralgia.

The most common serious side effect of vemurafenib, dabrafenib and encorafenib, as well as the combination therapies they are part of, is the formation of nonmelanoma skin cancers, especially squamous cell carcinomas. Most are small or superficial and can be treated effectively. These side effects occur less frequently with the combination therapies than with the monotherapies.

This topical cream stimulates the immune system to produce interferon, a chemical that attacks cancerous and precancerous cells. It is especially effective for “field therapy,” treating areas of skin with multiple lesions. Available in different strengths, it is usually applied two or three times a week for several weeks or months to treat people with multiple precancerous actinic keratoses. This immunotherapy is also FDA-approved to treat superficial basal cell carcinoma, rubbed gently into the tumor five times a week for six weeks or longer, with cure rates between 80 and 90 percent. It is used off-label (without FDA approval) for the treatment of some superficial squamous cell carcinomas. The most common side effects are flaking, itching, swelling, redness and other skin irritations, sometimes accompanied by diarrhea, sinus infections and headaches. There is minimal risk of scarring.

Using synthetic versions of natural immune system chemicals, or by inhibiting proteins that block immune functions, immunotherapies boost the immune system’s ability to fight disease. This older form of immunotherapy, infused intravenously or injected subcutaneously or intramuscularly as an adjuvant treatment for high-risk stage II and stage III melanoma patients, helps to keep melanomas from recurring and advancing. Synthetically derived from natural immune system interferons, it has been found to give patients a longer period before recurrence, but its ability to extend overall survival has proven more controversial, varying from study to study.

Interferon alfa-2b is used less today as a frontline therapy because of the success of newer immunotherapies and targeted therapies. However, it is sometimes used as an additional or follow-up therapy after the frontline therapies have been administered.

Adjuvant therapies are strategies that enhance the effectiveness of a primary treatment such as surgery, with the goal of delaying recurrence and extending overall survival. The hope is that by using this medicine before the cancer reaches stage IV, spreading throughout the body, it will provide even greater benefits for patients and save more lives.

Using synthetic versions of natural immune system chemicals, or by inhibiting proteins that block immune functions, immunotherapies boost the immune system’s ability to fight disease. This older form of immunotherapy, injected intravenously and subcutaneously, was the first immunotherapy approved by the FDA to treat stage IV metastatic melanoma. It has been found to delay recurrence and increase survival in some patients, with about 6 percent of patients achieving complete remission. The technique is used less today because of the success of newer immunotherapies and targeted therapies.

Using synthetic versions of natural immune system chemicals, or by inhibiting proteins that block immune functions, immunotherapies boost the immune system’s ability to fight disease. This intravenously infused drug, FDA-approved in 2011, was the first checkpoint blockade therapy approved for stage IV melanoma patients. By blocking a protein receptor known as CTLA-4 that, under normal circumstances, keeps the immune system in check, ipilimumab releases waves of helpful T cells to fight melanoma. Ipilimumab has substantially increased the life span of many patients, some of whom are considered cured. However, the drug can produce serious side effects, requiring some patients to stop the therapy. Ipilimumab is no longer a frontline stand-alone therapy for stage IV melanoma, as drugs that block a different protein receptor, PD-1, have proven more effective. It is, however, still a frontline therapy for stage IV in combination with nivolumab (Opdivo®), one of the PD-1 blockers. (See Nivolumab-Ipilimumab, Combination.)

In 2015, the FDA approved use of ipilimumab for stage III melanoma patients as well, specifically those with lymph node metastases whose primary tumors have been completely removed. For these patients, it was approved as an adjuvant therapy — a medicine that enhances the effectiveness of a primary treatment such as surgery, with the goal of delaying recurrence and extending overall survival. The hope was that by using this medicine before the cancer reaches stage IV, spreading throughout the body, it would provide even greater benefits for patients and save more lives.

In 2017, however, nivolumab was approved for stage III patients as well, replacing ipilimumab as a frontline adjuvant therapy because of its superior results and lower toxicity. Then, in early 2019, pembrolizumab (Keytruda®), another PD-1 blocker, was also approved for stage III patients, again superseding ipilimumab as a frontline adjuvant therapy because of superior results and lower toxicity.

Adjuvant therapies are strategies that enhance the effectiveness of a primary treatment such as surgery, with the goal of delaying recurrence and extending overall survival. The hope is that by using such a medicine before the cancer reaches stage IV, spreading throughout the body, it will provide even greater benefits for patients and save more lives.

In February 2024, the FDA granted accelerated approval to lifileucel (Amtagvi), a cellular therapy for adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody and, if the melanoma is BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor.   

Tumor infiltrating lymphocytes (TILs) are naturally occurring immune cells that can recognize unique tumor markers on cancer cells in the body and attack and kill them. Called tumor-derived autologous T cell immunotherapy, this treatment is designed to enhance the patient’s own TILs outside the body and then deliver them back to the patient to attack the cancer cells. 

Safety and efficacy were evaluated in a global, multicenter, multicohort, open-label, single-arm trial in patients with unresectable or metastatic melanoma who had previously been treated with at least one systemic therapy. The objective response rate (ORR), based on 73 patients, was 31.5%. 

This drug-device combo uses a hepatic delivery system (HDS) to deliver a high dose of the chemotherapy drug melphalan directly to the liver for patients with metastatic uveal melanoma (mUM), cancer that originates in the tissue of the eyes. It’s approved for patients who have liver metastases affecting less than 50 percent of the liver that can’t be surgically removed and no extrahepatic disease (disease outside the liver), or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues or lung that can be surgically removed or treated with radiation. 

Its 2023 approval is significant because it’s the first liver-directed treatment for mUM, and approximately 90 percent of mUM cases include liver metastases, with liver failure being a common cause of death in this patient population.   

In the phase 3 FOCUS study, 91 patients with liver lesions were treated every 6 to 8 weeks for up to six treatments. The response rate was 36 percent with 7.7 percent having a complete response and 28.6 percent experiencing a partial response for an average of 14 months. A total of 73.6 percent of patients experienced disease control, which means their cancer did not shrink or grow.  

There is a boxed warning for toxicity and bone marrow suppression, which can lead to anemia, neutropenia or thrombocytopenia. Other serious side effects may include liver injury, hemorrhage and blood clots, which occurred in 5 percent or fewer patients. 

Using synthetic versions of natural immune system chemicals, or by inhibiting proteins that block immune functions, immunotherapies boost the immune system’s ability to fight disease. In 2014, the FDA approved two intravenously infused therapies for stage IV patients, nivolumab (Opdivo®) and pembrolizumab (Keytruda®). These immune checkpoint inhibitors blockade therapies (also known as checkpoint blockade immunotherapy) have had unprecedented success in treating advanced melanomas. By blocking a protein receptor known as PD-1, which, under normal circumstances, helps keep the immune system in check, these drugs release massive amounts of T cells to fight the melanoma.

The FDA approved both drugs as frontline therapies, meaning they can be used before any other treatments for stage IV melanoma patients. Studies have shown that both nivolumab and pembrolizumab are safer than the checkpoint inhibitor ipilimumab, with fewer serious side effects, and are significantly more effective in fighting off melanoma and lengthening lives.

In December 2017 and 2019, respectively, the FDA approved the use of nivolumab and then pembrolizumab as adjuvant therapies — medicines that enhance the effectiveness of a primary treatment such as surgery — for stage III patients with lymph node metastases whose primary tumors have been completely removed.

The research leading to approval of adjuvant nivolumab showed greater than 66 percent recurrence-free survival (RFS) at 18 months with nivolumab, compared with 52 percent RFS with the checkpoint immunotherapy ipilimumab. It also showed a 35 percent reduction in the risk of recurrence or death with nivolumab compared with ipilimumab. Serious side effects were also significantly lower with nivolumab than with ipilimumab (about 14 percent of cases versus 46 percent). Consequently, nivolumab (along with pembrolizumab) has replaced ipilimumab as a frontline adjuvant therapy for stage III melanoma. 

In 2023, the FDA approved nivolumab as an adjuvant treatment (meaning after the main treatment, such as surgery, to reduce the chance of the cancer coming back) for patients 12 years and older with completely resected stage IIB and stage IIC melanoma. This is a significant development because, typically, within five years of diagnosis, one-third of patients with surgically resected stage IIB and nearly one-half of patients with surgically resected IIC have a recurrence of melanoma. In the phase 3 trial, nivolumab reduced the risk of recurrence, new primary melanoma or death by 58 percent compared to the placebo. At one year, the RFS was 89 percent versus 79 percent for the placebo. 

Using synthetic versions of natural immune system chemicals, or by inhibiting proteins that block immune functions, immunotherapies boost the immune system’s ability to fight disease. In late 2015, the FDA approved this intravenously infused immunotherapy, combining the drugs nivolumab (Opdivo®) and ipilimumab (Yervoy®) for patients with metastatic or inoperable melanoma. Both are checkpoint blockade therapies, which have had unprecedented success in treating advanced melanomas. Ipilimumab blocks a protein receptor called CTLA-4 and nivolumab blocks a similar receptor called PD-1, both of which, under normal circumstances, keep the immune system in check. By blocking these receptors, the combination therapy releases waves of T cells to fight melanoma.

This regimen was approved based on research demonstrating a major reduction in disease progression with the combination therapy compared with ipilimumab alone. About 50 percent of patients have responded to the combination therapy, many going into complete remission. The combination treatment is also slightly more effective than nivolumab alone, though with a higher risk of serious side effects than nivolumab alone. Oncologists today are getting better at controlling or mitigating these adverse effects, and patients have to decide with their doctors whether nivolumab alone (nivolumab monotherapy) or the combination therapy is preferable for them. Pembrolizumab, another anti-PD-1 monotherapy, is another frontline option comparable to nivolumab monotherapy.

Previously, combination nivolumab-ipilimumab therapy could be used only after ipilimumab alone or if targeted therapy had been tried unsuccessfully. But in 2016, the FDA approved combination nivolumab-ipilimumab as a frontline therapy, meaning it can now be used for advanced melanoma before any other treatments.

In March 2022, the FDA approved a combination immunotherapy treatment (Opdualag®) consisting of nivolumab and relatlimab for patients with previously untreated, inoperable melanoma. The two medications are administered in the same intravenous infusion. Both are immune checkpoint inhibitors, which means they block receptors on cells that would otherwise prevent the immune system from attacking cancer cells.

Relatlimab blocks a receptor called LAG-3, and is the first approved medication to target this receptor. Nivolumab (Opdivo®), which was first approved for the treatment of stage IV melanoma in 2014, blocks a receptor called PD-1. Since 2014, nivolumab has also been approved as an adjuvant treatment for surgically removed stage III melanoma and for the treatment of metastatic or inoperable melanoma in combination with ipilimumab (Yervoy®), an immune checkpoint inhibitor that blocks the protein receptor CTLA-4. 

Approval of the combination of nivolumab plus relatlimab is based on data from a clinical trial of more than 700 patients with previously untreated stage III or IV inoperable or metastatic melanoma. About half of the patients in the trial received nivolumab monotherapy, while the other half received the combination of relatlimab and nivolumab. Patients on the combination had statistically significant improvement in progression-free survival over patients on nivolumab alone.

Using synthetic versions of natural immune system chemicals, or by inhibiting proteins that block immune functions, immunotherapies boost the immune system’s ability to fight disease. In 2011, the FDA approved this subcutaneously injected variation of high-dose interferon alfa-2b, synthetically derived from natural immune system interferons, as an adjuvant therapy to treat stage III melanoma patients. Through pegylation, the process of attaching polyethylene glycol molecules to (or amalgamating them into) a therapeutic vehicle, this drug may give patients a longer period before recurrence than interferon alfa-2b. Like that earlier drug, however, pegylated interferon has not been definitively proven to extend lives. It is considered a second-line or complementary therapy to the checkpoint blockade immunotherapies and targeted therapies.

Adjuvant therapies are strategies that enhance the effectiveness of a primary treatment, such as surgery, with the goal of delaying recurrence and extending overall survival. The hope is that by using such a medicine before the cancer reaches stage IV, spreading throughout the body, it will provide even greater benefits for patients and save more lives.

Using synthetic versions of natural immune system chemicals, or by inhibiting proteins that block immune functions, immunotherapies boost the immune system’s ability to fight disease. In 2014, the FDA approved pembrolizumab (Keytruda®), as well as nivolumab (Opdivo®), intravenously infused medications called checkpoint blockade therapies that have had unprecedented success in treating advanced melanomas. By blocking a protein receptor called PD-1 (programmed death-1), which, under normal circumstances, helps keep the immune system in check, both these drugs release massive amounts of T cells to fight the melanoma.

The FDA first approved both drugs as frontline therapies for stage IV melanomas, meaning they can be used before any other treatments for stage IV patients.

In 2018, the FDA granted accelerated approval to pembrolizumab for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC), a rare but dangerous skin cancer. The FDA based its approval on a multicenter clinical trial of 50 adult and pediatric patients with recurrent or advanced disease who had not received prior systemic therapy. Fifty-six percent of patients responded to the drug, with 24 percent going into complete remission. Among the 28 patients who responded, 96 percent had response durations of greater than six months and 54 percent had response durations of greater than 12 months. Median progression-free survival was 16.8 months.

Pembrolizumab is one of three FDA-approved treatments for advanced MCC, along with immune checkpoint inhibitors avelumab (Bavencio®) and retifanlimab-dlwr (Zynyz™). Clinical trials are exploring additional possible treatments for MCC. 

In February 2019, the FDA granted approval to pembrolizumab for the adjuvant treatment of stage III melanoma (melanoma that has metastasized to the lymph nodes) after tumor removal. Adjuvant therapies are strategies that enhance the effectiveness of a primary treatment, such as surgery, with the goal of delaying recurrence of cancer and extending overall survival. The 2019 approval was based on phase 3 research demonstrating that pembrolizumab significantly prolonged recurrence-free survival (RFS) in patients with resected, high-risk stage III melanoma. Pembrolizumab joined the checkpoint blockade inhibitor nivolumab (Opdivo^®) and the combination targeted therapy dabrafenib-trametinib (Tafinlar^®-Mekinist^®) as the frontline adjuvant therapies for stage III melanoma.

In December 2021, the FDA granted approval to pembrolizumab for the adjuvant treatment of stage IIB or IIC melanoma (melanoma with a deep or ulcerated primary tumor) after tumor removal in patients 12 and older. Stage IIB and IIC melanoma have the same risk of recurrence or death as stage IIIA and IIIB melanoma. The approval is based on phase 3 research demonstrating a significant improvement in recurrence-free survival. Pembrolizumab reduced the risk of recurrence or death for patients in this study by 35 percent. This approval essentially doubles the number of melanoma patients eligible for adjuvant PD-1 therapy.

In June 2020, the FDA approved pembrolizumab for the treatment of recurrent or metastatic squamous cell carcinoma (SCC) of the skin, also known as cutaneous squamous cell carcinoma (cSCC), that is not curable by radiation or surgery. Approval was based on a phase 2 clinical trial, which found that for 105 patients, 34 percent experienced some positive response, including 4 percent who experienced a complete response. Among the 36 responding patients, 69 percent had ongoing responses of six months or longer. Patients receiving pembrolizumab may have received other therapies before being treated with pembrolizumab; 87 percent of patients had had one or more prior therapies and 74 percent of patients had prior radiation therapy.

In July 2021, the FDA expanded the approval of pembrolizumab to include treatment of locally advanced cSCC not curable by surgery or radiation. The approval was also based on phase 2 clinical trial data, with 50 percent of the 54 patients enrolled experiencing some positive response to treatment, and 37 percent of those responses lasting 12 months or longer. Twenty-two percent of patients had received one or more prior therapies, with 63 percent having received prior radiation therapy.

Using synthetic versions of natural immune system chemicals, or by inhibiting proteins that suppress immune functions, immunotherapies boost the immune system’s ability to fight disease. In March 2023, the FDA granted accelerated approval to retifanlimab-dlwr as a treatment for adults with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC). 

Retifanlimab-dlwr is an intravenously infused immune checkpoint inhibitor. By blocking a protein receptor called PD-1 (programmed death-1), which, under normal circumstances, helps keep the immune system in check, the treatment releases massive amounts of T cells to fight the cancer. 

The safety and efficacy of this treatment were based on data from the POD1UM-201 trial that evaluated retifanlimab-dlwr (Zynyz™) in adults with metastatic or recurrent locally advanced MCC who had not received previous systemic therapy for the disease. These patients showed an objective response rate of 52 percent. Continued approval for this drug for this use may be contingent on verification and description of clinical benefit in confirmatory trials.  

In 2015 the FDA approved this medicine, taken by mouth, for patients with locally advanced basal cell carcinomas (BCCs) whose tumors have recurred following surgery or radiation therapy, or who are not candidates for surgery or radiation therapy. The second of two medications approved in the past few years for rare, advanced forms of BCC (the first was vismodegib), it works by blocking abnormal signals that promote cancerous growth.

Like vismodegib, sonidegib can cause severe birth defects, so both male and female patients should use effective contraception. Other potential side effects include serious musculoskeletal problems and muscle pain and spasms.

Using synthetic versions of natural immune system chemicals, or by inhibiting proteins that block immune functions, immunotherapies boost the immune system’s ability to fight disease. In late 2015, the FDA approved this new type of immunotherapy for stage III and IV melanoma patients who have recurring skin or lymph node lesions that cannot be completely removed by surgery. The drug, often shortened to T-VEC, is the first oncolytic virus therapy approved for melanoma. An oncolytic virus is one that specifically targets, infects and kills cancer cells. T-VEC, injected directly into tumors, is a version of the herpes simplex virus that has been genetically modified to infect cancer cells but not healthy cells. It also secretes an immune-boosting protein that can strengthen the body’s immune response against melanoma. In clinical trials, T-VEC modestly delayed disease progression for patients with advanced disease. While benefits to date are limited, the excitement is that oncolytic virus therapy has opened up a promising new avenue for treatment. T-VEC is also being used in conjunction with other therapies to enhance results. And a recent study shows that T-VEC used as a neoadjuvant therapy (before surgery) can increase relapse-free survival and overall survival.

Uveal melanoma, also called ocular melanoma, grows in the dark melanin pigment in the uveal tract of the eye, which includes the iris. While rare, this type of cancer can be aggressive, and patients may lose the vision in their affected eye. If not treated, uveal melanoma may spread and become life-threatening.

In January 2022, the FDA approved tebentafusp-tebn (Kimmtrak®), the first medication for unresectable or metastatic uveal melanoma and the first drug of its class, as a T-cell receptor therapeutic, to be approved.

The medication is for adult patients with uveal melanoma that has spread to other parts of the body or can’t be removed with surgery. It is an immunotherapy treatment designed to mobilize and activate the T cells of the patient’s own immune system to fight the melanoma tumor cells in the eye.

Tirbanibulin (Klisyri^®) is a topical medication used to treat actinic keratosis on the face or scalp. Prescribed as a 1% ointment, tirbanibulin is applied directly on the treatment area once daily for five days as a field-directed therapy, treating areas of the skin affected by actinic keratosis and not just individual lesions.

Tirbanibulin is a microtubule inhibitor. Microtubules are key structural elements of cells, and by blocking their construction, tirbanibulin eventually leads to apoptosis, or cell death. Side effects in trials were generally mild, and can include application-site pain and itching.

Taken by mouth, this drug is one of a class of treatments known as targeted therapies, which along with immunotherapies have been making giant strides in the treatment of advanced melanoma. In patients with stage IV melanoma, these targeted therapies are designed exclusively for those who have a defective, cancer-producing version of the BRAF gene. About half of all melanoma patients have this defective gene. Normally, BRAF controls skin cell growth, but the defective version essentially becomes stuck in the “on” position, leading to out-of-control growth of cancer cells.

In 2011, vemurafenib (Zelboraf®) became the first targeted therapy approved to inhibit the defective BRAF gene in advanced melanoma patients, stopping the cancerous growth without harming normal cells. Vemurafenib often rapidly eliminates tumors and has been found to slow down disease progression and increase life span in many patients for months or even years, but in most patients the melanoma eventually develops resistance to the drug, and the disease begins to advance again.

Drugs that block an enzyme called MEK further delay progression of the disease, and drugs combining MEK blockers with vemurafenib or the two other BRAF blockers dabrafenib and encorafenib, are improving outcomes. (See Cobimetinib-Vemurafenib, Combination, Dabrafenib-Trametinib, Combination and Encorafenib-Binimetinib, Combination.) The most serious side effect of vemurafenib, dabrafenib and binimetinib is the formation of nonmelanoma skin cancers, especially squamous cell carcinomas. Most are small or superficial and can be treated effectively. These side effects are less frequent with the combination targeted therapies. Vemurafenib is no longer used as a stand-alone targeted therapy because of the success of the combination therapies.

Vismodegib (Erivedge®) was the first of two medications (the second was sonidegib) approved in the past few years for rare, advanced forms of basal cell carcinoma (BCC). Both are taken by mouth. Vismodegib was approved in 2011 for very rare cases of metastatic or locally advanced BCC for which other treatments, such as surgery or radiation, are not options. Both vismodegib and sonidegib work by blocking abnormal signals that promote cancerous growth. Due to a risk of birth defects, women who are pregnant or may become pregnant should not use vismodegib. Other side effects include hair loss, muscle spasms and loss of the sense of taste.