Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies

SIMPLE SUMMARY: Immunotherapies and molecularly targeted therapies have drastically changed the therapeutic approach for unresectable advanced or metastatic melanoma. The majority of melanoma patients have benefitted from these therapies; however, some patients acquire resistance to them. Novel combinations of immunotherapies and molecularly targeted therapies may be more efficient in treating these patients. In this review, we discuss various combination therapies under pre-clinical and clinical development which can reduce toxicity, enhance efficacy, and prevent recurrences in patients with metastatic melanoma. ABSTRACT: Melanoma possesses invasive metastatic growth patterns and is one of the most aggressive types of skin cancer. In 2021, it is estimated that 7180 deaths were attributed to melanoma in the United States alone. Once melanoma metastasizes, traditional therapies are no longer effective. Instead, immunotherapies, such as ipilimumab, pembrolizumab, and nivolumab, are the treatment options for malignant melanoma. Several biomarkers involved in tumorigenesis have been identified as potential targets for molecularly targeted melanoma therapy, such as tyrosine kinase inhibitors (TKIs). Unfortunately, melanoma quickly acquires resistance to these molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been employed and have been shown to improve the prognosis of melanoma patients compared to monotherapy. This review discusses several combination therapies that target melanoma biomarkers, such as BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K. Several of these regimens are already FDA-approved for treating metastatic melanoma, while others are still in clinical trials. Continued research into the causes of resistance and factors influencing the efficacy of these combination treatments, such as specific mutations in oncogenic proteins, may further improve the effectiveness of combination therapies, providing a better prognosis for melanoma patients.