Metastatic Melanoma Therapeutics: Advances in Treatment Options

Metastatic Melanoma Therapeutics

Melanoma is a type of skin cancer that develops from melanocyte cells which produce melanin pigment in the skin. While melanoma makes up only 1% of skin cancer cases, it causes a large majority of skin cancer deaths due to its ability to spread to other parts of the body. When melanoma spreads from the skin to other organs, it is called metastatic melanoma. For decades, there were very limited options for treating metastatic melanoma with chemotherapy providing little benefit. However, over the past 10-15 years there have been major advances in targeted therapies and immunotherapies that have transformed the treatment landscape for metastatic melanoma.

Targeted Therapies

One of the major breakthroughs was the discovery of targeted therapies that inhibit specific mutated genes that drive melanoma growth and progression. About 50% of melanomas have a mutation in the BRAF gene which leads to uncontrolled cell growth and division. In 2011, the FDA approved vemurafenib (Zelboraf), the first BRAF inhibitor targeted therapy for metastatic melanoma patients with the BRAF V600E mutation. Vemurafenib more than doubled median progression-free and overall survival compared to chemotherapy. Another BRAF inhibitor, dabrafenib (Tafinlar), was approved in 2013 and showed similar benefits. While very effective initially, resistance often emerges which limits the long term benefit of BRAF inhibitors alone. Combining a BRAF inhibitor with a MEK inhibitor to inhibit downstream signaling pathways increased progression-free survival further. Currently approved options include the combination of dabrafenib plus trametinib or vemurafenib plus cobimetinib. Targeted therapies revolutionized treatment for the roughly 50% of metastatic melanoma patients whose tumors carry BRAF mutations.

Immunotherapies

Another major development came from immunotherapies that activate the body's own immune system to recognize and destroy cancer cells. In 2011, the CTLA-4 blocking antibody ipilimumab (Yervoy) became the first immunotherapy approved for Metastatic Melanoma Therapeutics based on improved overall survival compared to a gp100 vaccine in a phase III trial. However, side effects can be severe as it disinhibits the immune system's natural brakes. In 2014, the PD-1 blocking antibodies pembrolizumab (Keytruda) and nivolumab (Opdivo) were approved based on response rates over ipilimumab alone and better tolerability. PD-1 inhibitors have since become the backbone of melanoma treatment due to higher and more durable response rates than ipilimumab of around 40-50%. Alone or in combination with other therapies like targeted agents, immunotherapies have provided unprecedented long term control and even cure of metastatic disease for many patients.

Immunotherapy Combinations

More recent research has explored combining immunotherapies or adding them to targeted therapies to improve outcomes even further. Studies demonstrated that sequential treatment with a BRAF/MEK inhibitor followed by anti-PD-1 therapy achieved higher response rates than either approach alone. This led to approval of the combination of binimetinib, encorafenib and pembrolizumab in 2021. There is also ongoing exploration of combining different immunotherapies like ipilimumab plus nivolumab. In a phase III trial, this combination improved survival versus nivolumab alone. However, greater toxicities require close patient monitoring. Looking ahead, newer immunotherapies targeting additional checkpoints like LAG-3 and TIM-3 are in development that may provide alternatives for patients resistant to current options. With the right combination of therapies tailored to each patient's specific tumor, the goal of metabolically "curing" melanoma by achieving a sustained remission may become a reality for more individuals.

Other Treatment Approaches

For patients where immunotherapy and targeted therapy options are limited due to tumor genetics or progression on earlier lines, additional approaches are being studied. Oncolytic virus therapy aims to destroy cancer cells by using viruses that preferentially target and lyse tumor tissue. Talimogene laherparepvec (Imlygic) was approved in 2015 based on a phase III trial showing improved durable response rates compared to granulocyte-macrophage colony-stimulating factor. Ongoing research also evaluates the use of oncolytic viruses in combination with checkpoint inhibitors. For rare melanoma subtypes like mucosal or acral melanomas where targeted therapies often do not apply, new treatments are still urgently needed. Investigational therapies include EP4 receptor antagonists which may enhance chemotherapy response and tumor-infiltrating lymphocyte (TIL) cell therapy where T cells are extracted from a patient's own tumor, grown in vitro and infused back into the patient to induce an anticancer immune response. With continued research, further progress is expected in broadening treatment options for all stages of melanoma.

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