Clinical Review

Advanced Melanoma: First-line Therapy

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References

How is melanoma diagnosed?

Detailed discussion about diagnosis and staging will be deferred in this review of treatment of advanced melanoma. In brief, melanoma is best diagnosed by excisional biopsy and histopathology. Staging of melanoma is done according to the American Joint Committee on Cancer’s (AJCC) Cancer Staging Manual, 8th edition, using a TNM staging system that incorporates tumor thickness (Breslow depth); ulceration; number of involved regional lymph nodes; presence of in-transit, satellite, and/or microsatellite metastases; distant metastases; and serum lactate dehydrogenase level.14

Case Continued

The patient undergoes a wide excisional biopsy of the right scalp lesion, which is consistent with malignant melanoma. Pathology demonstrates a Breslow depth of 2.6 mm, 2 mitotic figures/mm2, and no evidence of ulceration. He subsequently undergoes wide local excision with 0/3 sentinel lymph nodes positive for malignancy. His final staging is consistent with pT3aN0M0, stage IIA melanoma.

He is seen in follow-up with medical oncology for the next 3.5 years without any evidence of disease recurrence. He then develops symptoms of vertigo, diplopia, and recurrent falls, prompting medical attention. Magnetic resonance imaging (MRI) brain reveals multiple supratentorial and infratentorial lesions concerning for intracranial metastases. Further imaging with computed tomography (CT) chest/abdomen/pelvis reveals a right lower lobe pulmonary mass with right hilar and subcarinal lymphadenopathy. He is admitted for treatment with intravenous dexamethasone and further evaluation with endobronchial ultrasound-guided fine-needle aspiration of the right lower lobe mass, which reveals metastatic melanoma. Given the extent of his intracranial metastases, he is treated with whole brain radiation therapy for symptomatic relief prior to initiating systemic therapy.

What is the general approach to first-line treatment for metastatic melanoma?

The past decade has brought an abundance of data supporting the use of immunotherapy with immune checkpoint inhibitors or molecularly targeted therapy with combined BRAF/MEK inhibitors in the first-line setting.4-8 After the diagnosis of metastatic melanoma has been made, molecular testing is recommended to determine the BRAF status of the tumor. Immunotherapy is the clear choice for first-line therapy in the absence of an activating BRAF V600 mutation. When a BRAF V600 mutation is present, current evidence supports the use of either immunotherapy or molecularly targeted therapy as first-line therapy.

To date, there have been no prospective clinical trials comparing the sequencing of immunotherapy and molecularly targeted therapy in the first-line setting. An ongoing clinical trial (NCT02224781) is comparing dabrafenib and trametinib followed by ipilimumab and nivolumab at time of progression to ipilimumab and nivolumab followed by dabrafenib and trametinib in patients with newly diagnosed stage III/IV BRAF V600 mutation–positive melanoma. The primary outcome measure is 2-year OS. Until completion of that trial, current practice regarding which type of therapy to use in the first-line setting is based on a number of factors including clinical characteristics and provider preferences.

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