Melanoma, the deadliest form of skin cancer, can spread from the primary site on the skin to other organs in the body. This stage of melanoma is called metastatic or advanced melanoma. While treatment options have improved significantly in recent years, metastatic melanoma remains difficult to treat and often leads to poor patient outcomes.

Conventional Chemotherapy

For many years, conventional chemotherapy was one of the only treatment options available for metastatic melanoma. Chemotherapy utilizes cytotoxic drugs that work throughout the body to damage cancer cells and stop their growth and spread. However, chemotherapy has limited effectiveness against melanoma.

Dacarbazine, an alkylating chemotherapy drug, was the standard first-line treatment for metastatic melanoma for decades. Unfortunately, dacarbazine only produces objective response rates of around 15-20% with minimal improvement in overall survival. Immunotherapies like high-dose interleukin-2 can induce complete responses in a small subset of patients but are also associated with significant toxicity.

Clearly, chemotherapy alone was insufficient for metastatic melanoma. Newer targeted therapies and immunotherapies have since revolutionized treatment. However, chemotherapy still has a role in some treatment algorithms, often in combination with other agents.

Targeted Therapies

Targeted therapies interfere with specific molecules involved in melanoma growth and progression. Some targeted therapies work by inhibiting the BRAF protein, which is abnormal in around 50% of melanomas due to a V600 mutation.

Vemurafenib was the first FDA-approved BRAF inhibitor for metastatic melanoma. It produced overall response rates of around 50% but many patients eventually develop resistance. Dabrafenib is another BRAF inhibitor with similar efficacy. Combining a BRAF inhibitor with a MEK inhibitor such as trametinib can delay resistance and improve outcomes compared to BRAF inhibition alone.

For patients without a BRAF mutation, immunotherapy remains the primary treatment approach. However, newer targeted therapies are also in development for wild-type disease. C-KIT inhibitors like imatinib may benefit a small subset of patients with C-KIT mutations. Angiogenesis inhibitors that target new blood vessel growth, such as nivolumab plus ipilimumab, are also being studied.

Immunotherapies

The advent of immunotherapy has revolutionized the treatment landscape for metastatic melanoma. Immunotherapies aim to boost the body's own immune response against cancer cells. Major immunotherapy classes explored for melanoma include:

- Checkpoint inhibitors: These drugs relieve brakes on the immune system by blocking checkpoints like CTLA-4 and PD-1/PD-L1. Ipilimumab was the first FDA-approved checkpoint inhibitor for melanoma. Pembrolizumab and nivolumab target PD-1 and have stronger efficacy. Combining ipilimumab and nivolumab can produce extended survival benefit compared to monotherapy.

- Cancer vaccines: Therapies like talimogene laherparepvec aim to stimulate an immune response against tumor antigens. As a first-in-class oncolytic virus therapy, talimogene laherparepvec showed survival benefit when combined with ipilimumab.

- Immunomodulators: Agents like high-dose interleukin-2 directly stimulate immune cells. Although toxic, IL-2 can induce durable complete remissions in a small proportion.

Today, most newly diagnosed Metastatic Melanoma Therapeutics patients receive a checkpoint inhibitor or chemo-immunotherapy combination as the standard of care. While immunotherapy has significantly improved outcomes, durable responses remain elusive for many. Combination strategies and sequenced therapy approaches continue evolving.

Emerging Treatment Landscape

While current options have paved the way, the treatment landscape continues advancing rapidly. Many novel therapies are under investigation that may further improve outcomes:

- Next-gen checkpoint inhibitors: Monoclonal antibodies targeting alternate checkpoints like LAG-3, TIM-3, and IDO are in clinical trials. Combining these "cold" tumors may augment responses.

- Cellular therapies: Chimeric antigen receptor (CAR) T-cell therapies genetically engineer patient T-cells to target tumor antigens like NY-ESO-1. Early CAR-T data shows promise but toxicity remains a challenge.

- Oncolytic viruses: Armed oncolytic viruses simultaneously kill tumor cells and stimulate immunity. New viruses are being developed with enhanced targeting and arming capabilities.

- Neoantigen vaccines: Personalized vaccines target patient-specific neoantigens to induce stronger, longer-lasting immune responses than traditional antigens.

- Multi-targeted inhibitors: Combining different targeted agents like BRAF/MEK inhibitors or agents blocking parallel pathways holds potential synergy.

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