After decades of no new treatment options for advanced melanoma, several drugs for unresectable stage III and IV disease and recurrent melanoma have been approved, including newer classes of drugs such as checkpoint inhibitors (anti-PD-1 and anti-CTLA-4 drugs) and signal transduction inhibitors (BRAF, MEK, and KIT inhibitors). Advanced practice registered nurses (APRNs) must be familiar with these newer agents and classes of drugs, especially the mutations that guide their use.

Mutations in Melonoma

One of the driving factors in deciding on treatment for unresectable or metastatic melanoma is the presence of certain gene mutations. According to Melinda L. Yushak, MD, MPH, an expert in melanoma, sarcoma, and predictive biomarkers and genetics testing from Emory University, “You generally find only one mutation in a patient, namely, BRAF (50%), NRAS (13.25%), MEK1 (6%), KIT (2.6%), CTNNB1 (2%–3%), GNA11 (2%), or GNAQ (1%)….All metastatic melanoma patients should be tested for actionable mutations.”

Specific mutation tests are available (e.g., the cobas 4800 BRAF V600 mutation test); however, more comprehensive testing can be achieved with next-generation sequencing (turnaround time of about 14 days), which can detect all the relevant mutations. The most critical mutation in melanoma is BRAF, and testing can change patient outcomes.

Determining a patient’s BRAF mutational status promptly and accurately at the time of initial diagnosis is crucial because it is currently the only reliable predictive biomarker that can influence the treatment of advanced melanoma.

Treatment Based on Mutations

According to the 2018 National Comprehensive Cancer Network guidelines on melanoma, first-line therapy for metastatic or unresectable disease should consist of either immunotherapy with anti-PD-1 monotherapy or nivolumab/ipilimumab combination.

Signal transduction inhibitors: If a tumor is positive for a BRAF V600 activating mutation, single-agent BRAF inhibitor therapy or combination therapy with BRAF/MEK inhibitors is recommended. BRAF/MEK inhibitor combination is preferred over monotherapy based on results from phase III trials (COMBI-d, COMBI-v, and CoBRIM) showing improved outcomes and similar toxicity.

Mutations in the BRAF gene, which occur in more than 60% of melanomas, can cause uncontrolled activation of the BRAF protein, initiating intracellular events that promote oncogenesis. Two BRAF inhibitors, vemurafenib and dabrafenib, are approved for use in metastatic melanoma with the BRAF V600E mutation.

MEK is a downstream therapeutic target in the MAPK pathway that regulates cellular proliferation. MEK inhibitors (trametinib and cobimetinib) are often used in combination with BRAF inhibitors as they have relatively low response rates as single agents. Two BRAF/MEK inhibitor combination regimens are approved for treatment of metastatic or unresectable disease: (a) dabrafenib and trametinib and (b) vemurafenib and cobimetinib.

Immune checkpoint inhibitors: Checkpoint inhibitors have shown to be effective regardless of BRAF mutation status. PD-1 inhibitors bind to PD-1 receptors on T cells, preventing them from binding to PD-L1 and ultimately releasing the immune system on cancer cells. The PD-1 inhibitors currently recommended as first-line therapy for metastatic and unresectable disease are single-agent pembrolizumab or nivolumab. Combination nivolumab plus ipilimumab, a CTLA-4 inhibitor, is an option as well, and all agents are listed as category 1 interventions. These are also options for second-line therapy in metastatic or unresectable disease.

Although combination nivolumab plus ipilimumab has shown better progression-free survival, it may cause more serious immune-mediated toxicities. Therefore, the decision to use monotherapy versus combination immunotherapy should be based on a patient’s overall health, medical history, concomitant therapies, comorbidities, and compliance concerns.

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