Introduction of melanoma

Melanoma is a type of skin cancer that develops when melanocytes (the cells responsible for the skin’s tan or brown colour) grow uncontrollably.¹ Compared to other types of skin cancers, melanoma is uncommon, however, melanoma is more critical as the possibility of spreading to other body parts is much higher.¹ Melanoma develops in melanocytes and can originate anywhere on the skin.¹ But it is more commonly seen in sun-exposed areas, such as the arms, legs, face and back.²

Conventional treatment options for melanoma

Surgery is the primary treatment method to remove the melanoma in all stages. To remove the melanoma, a wide local excision is made, and the melanoma along with the surrounding normal tissue is removed. In some cases, a skin graft may be taken from another part of the body to replace the removed tissue.³ 

Chemotherapy is a type of cancer treatment that uses drugs to halt the growth of cancer cells by killing them or preventing them from dividing. When chemotherapy drugs are taken orally or intravenously, they enter the bloodstream and reach the cancer cells throughout the body (also called systemic therapy).³ On the other hand, when chemotherapy is administered directly to a body cavity, an organ, or the cerebrospinal fluid, it mainly affects specific areas where there are cancer cells (regional chemotherapy).³ In some cases, chemotherapy is given after surgery to eliminate the remaining cancer cells and prevent the recurrence (adjuvant therapy).³

Radiotherapy is a cancer treatment that uses high-energy X-rays or other types of radiation to destroy cancer cells or prevent their growth.³ External radiation therapy sends radiation from outside the body to the affected area.³ This therapy is used for melanoma and is also used as palliative therapy to relieve symptoms.³

However, these treatment methods have disadvantages due to significant side effects since chemotherapy and radiation therapies tend to damage healthy tissues. Moreover, these treatments may have limited efficacy in the advanced stages. Surgery and radiotherapy are challenging to perform if the cancer metastasises. Thus, advanced treatment methods such as targeted therapy are necessary to increase the treatment options.

Genetic mutations in melanoma

Cancer is caused by mutations in our DNA that allow cells to grow uncontrollably and eventually invade surrounding tissue.⁴ Melanoma is one of the most commonly mutated carcinoma types, and its development is primarily due to exposure to ultraviolet light and other mutational factors.⁵ There are genomic subtypes of mutations, such as BRAF, mutant NRAS, mutant NF1, and triple-wildtype.⁵ 

BRAF mutations

BRAF mutation is the most common mutation in melanoma, and according to a study, about 40-50% of cutaneous melanoma patients have this mutation.⁵ 

NRAS mutations

The RAS family consists of three main proto-oncogenes, NRAS, KRAS, and HRAS, which modulate cell growth and apoptosis.⁵ Melanomas with NRAS mutations are considered aggressive, and the prognosis is poor.⁵ NRAS mutations are common in the skin without sun exposure.⁵

KIT mutations

KIT mutations are less common than the above mutations, and it is found in 1-3% of all melanomas.⁵ KIT mutations are found more commonly in the hand, feet, nails, mucosa,  and chronically sun-damaged skin.⁵

Targeted therapies for melanoma

Targeted therapy has been developed as an effective treatment option by inhibiting mutated signal pathways, such as the above-mentioned mutations, leading to the prevention of cell growth. Targeted therapy is a systemic treatment, and the drugs can circulate through the bloodstream, reaching all body parts.⁶ Thus, targeted therapy is also effective when cancers have metastasised and spread from the original part.⁶

BRAF inhibitors

BRAF inhibitors selectively inhibit the activity of mutated BRAF kinases, which leads to preventing the cascade signalling pathways, resulting in regulating cell proliferation.⁸ These drugs can be taken orally as the molecules are small.⁸ Currently, there are three approved BRAF inhibitors, as follows:

• Vemurafenib - selectively binds to the ATP-binding site of BRAF kinase and inhibits its activity, approved in 2011
• Dabrafenib - selectively binds and inhibits the activity of BRAF, approved in 2013
• Encorafenib - selective ATP-competitive RAF kinase inhibitor, approved in 2018

The brand names of these BRAF inhibitors are Zelboraf (vemurafenib), Taflinar (dabrafenib) and Braftovi (encorafenib).⁷ 

MEK inhibitors

MEK plays a key role in the regulation of cell growth, division and apoptosis (cell death).⁸ MEK can be overactivated by BRAF mutation and Ras mutation in Melanoma.⁸ Hence, MEK inhibitors inhibit the MEK, which is downstream of the signal pathway.⁸ 

Currently, there are two approved MEK inhibitors, which are the following,

• Trametinib (Mekinst) - Trametinib was the first approved MEK inhibitor by the FDA in 2013. A clinical study shows the efficacy of Trametinib in patients with BRAF V600E or V600K mutations⁸
• Cobimetinib (Cotellic) - Cobimetinib was approved by the FDA as an MEK inhibitor in 2015.⁹ This drug has a high selectivity against MEK, specifically MRK1⁹

KIT inhibitors

Although currently, there are no approved KIT inhibitors for the treatment of melanoma, they can be a treatment option.¹⁰ Clinical trials show the efficacy of KIT inhibitors in patients with KIT-mutated melanoma, such as ripretinib, imatinib, nilotinib, dasatinib and sunitinib.^10,11

Combination therapy

Combination therapy: BRAF and MEK inhibitors

Some clinical studies show better efficacy of BRAF and MEK combination therapy for melanoma with longer progression-free survival (PFS) compared to BRAF monotherapy, and it has become a standardised treatment method for melanoma.⁵ In addition, these combination therapies prevent the occurrence of resistance by targeting several signal pathways.⁵ The current approved BRAF + MEK combination therapies are dabrafenib + trametinib, vemurafenib + cobimetinib, and encorafenib + binibetinib.⁷

Combination therapy: BRAF/MEK inhibitors and immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) are an advanced treatment method used for many types of cancers, including melanoma.¹² In some cases, melanoma cancer cells produce checkpoint proteins that prevent the immune system from attacking the cancer cells in our body.¹² Recently, there were several clinical trials to evaluate the efficacy and the safety of ICIs + BRAF inhibitors + MEK inhibitors, which are the following

• COMBI-i Trial: spartalizumab (a type of ICI) + dabrafenib + trametinib¹³
• IMspire150 Trial: atezolizumab (a type of ICI) + vemurafenib + cobimetinib¹⁴
• KEYNOTE-022 Trial: pembrolizumab (a type of ICI) + dabrafenib + trametinib¹⁵

The efficacy of the combination therapies is under investigation. They can be new treatment options for melanoma.

Side effects of targeted therapy

Although side effects of targeted therapies compared to conventional cancer therapies are less harmful to normal cells, there are various side effects.¹⁶ Most side effects are reversible, and patients will recover from the side effects once they finish the treatments.¹⁷ The main side effects of targeted therapy are as follows,

• Skin problems
• High blood pressure
• Heart damage
• Autoimmune reactions
• Swelling
• Nausea and vomiting
• Mouth sores
• Shortness of breath, difficulty of breathing
• Cough
• Fatigue
• Headache
• Hair loss
• Allergic reaction
• Damage to the liver or kidneys
• Second cancers

Summary

Targeted therapy is a significant treatment option for melanoma with mutations of signal pathways, as they affect the specific site of the cancer cells. However, there are some challenges to overcome in terms of the occurrence of resistance and side effects. The combination use of several targeted therapies or the use of targeted therapies with other cancer treatment agents may show better efficacy and safety. However, further research and studies are necessary to evaluate them. Once it is validated, it will lead to improving the treatment of melanoma.