Treatment for melanoma with genetic mutations: a review

The authors reviewed current and future treatment options for melanoma patients with mutations (permanent changes) in various genes. 

In 40-60% of skin melanoma patients, BRAF genes are mutated. These genes are involved in cellular signaling and important protein function. These proteins are mainly MAPK and MEK proteins. In melanoma with BRAF mutations, these proteins remain permanently active. This results in uncontrolled growth of cancer cells. BRAF inhibitors are drugs that stop these cell signaling proteins in cancer cells containing mutations in the BRAF gene. BRAF inhibitors have shown significant improvements in the treatment of melanoma. However, patients often develop resistance to BRAF inhibitors. Therefore alternative treatment options are necessary for these patients and for patients who have mutations in other genes, such as NRAS.

A better understanding of the current and future treatment options for melanoma with various genetic mutations is required. 

The authors aimed to discuss current and future treatments for melanoma involving mutations in BRAF, NRAS and other genes.

Vemurafenib (Zelboraf) and dabrafenib (Tafinlar) are the two most common BRAF inhibitors. In a phase 3 clinical study overall survival (patients who were still alive after treatment) was compared between vemurafenib and chemotherapy treated patients. At 6 months, the overall survival was 84% in the vemurafenib group and 64% in the chemotherapy group. The response rate (how fast the tumor decreased in size) in the vemurafenib group was 48% compared to 5% in the chemotherapy group. However, in other phase 3 clinical trials, the progression free survival (time following treatment before the disease progressed) for both vemurafenib (5.3 months) and dabrafenib (5.1 months) was low. Patients who remained on either vemurafenib or dabrafenib following disease progression had an overall survival of 17.8 months. This was compared to 7 months in patients who stopped treatment after disease progression.

Combination therapy with BRAF and MEK inhibitors is another effective treatment option for patients who develop resistance to BRAF inhibitors. Trametinib (Mekinist) is a MEK inhibitor. In a phase 2 clinical trial, progression free survival and response rate were compared in patients treated with dabrafenib and a dabrafenib/ trametinib combination. The average progression free survival was 9.4 months in the combination group compared to 5.8 months in dabrafenib group. The response rate was 76% in the combination group compared to 54% in the dabrafenib group.

NRAS mutations are present in 20% of melanoma patients. This in turn affects MAPK and MEK proteins. A recently developed MEK inhibitor named MEK162 (ARRY-438162) has shown some promise in NRAS-mutated melanoma patients. In a phase 2 clinical trial, 20% of NRAS-mutated patients treated with MEK162 experienced either a complete response (tumor disappeared completely) or a partial disappearance of the tumor. For 43% of patients, no new tumors were detected. However, the average progression free survival was 3.7 months. 

The authors concluded that combination therapy with BRAF and MEK inhibitors would likely be the most effective treatment in melanoma with BRAF mutations. For NRAS-mutant melanoma, further research is needed to determine the most effective treatment.