Currently there are more treatments approved by the US Food and Drug Administration for individuals with mutation of the BRAF gene — including checkpoint inhibitors and targeted therapies — vs those with mutation of the NRAS gene. However, overall survival does not appear to be improved among patients with mutation of the BRAF gene compared with mutation of the NRAS gene due to the development of drug resistance to targeted therapies over time. No targeted therapies are currently approved for melanoma associated with mutation of NRAS. BRAF and MEK inhibitors are the preferred treatment for patients with mutation of BRAF, but checkpoint inhibitors are often added due to their ability to produce a more sustained response.5,6

Immunotherapy agents that target programmed death-1 (PD-1 checkpoint inhibitors) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4 inhibitors) are more likely to be used as first-line therapy for individuals who have BRAF-negative mutations or wild-type melanoma.5 PD-1 checkpoint inhibitors show some ag­e­-related variances, including better sustained results in patients aged >60 years due to a more favorable proinflammatory cancer microenvironment with fewer regulatory T cells and more CD8 T cells that kill tumors.5

As the patient in this case had no identifiable skin or mucosal lesions on examination, and her genetic testing was negative for an inheritable melanoma, it is likely her immune system either absorbed the original lesion or her years of cumulative ultraviolet (UV) sun exposure with a high nevi burden caused her melanoma. The patient had an additional mutation of TP53, which is seen in many late-stage cancers. TP53 mutation in melanoma is associated with increasing potential for angiogenesis, chemoresistance, and inhibition of apoptosis.5 The patient had a mutation of NRAS, where glutamine at position 61 is replaced by arginine, lysine, or leucine.4  


Compared with chemotherapy, the concept of immunotherapy is relatively new to most primary care clinicians. Both targeted therapies and checkpoint inhibitors have a unique set of complications because of their mechanisms of action. Combinations of therapies are more efficacious than monotherapies for the treatment of melanoma; however, these increase the risk of untoward side effects.  

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The patient was started on the PD-1 checkpoint inhibitor ipilimumab at 480 mg administered over 30 minutes and nivolumab, a CTLA-4 inhibitor, at 10 mg/kg administered over 90 minutes every 3 weeks. The patient was scheduled to receive 4 treatments with nivolumab and ipilimumab, and then transition to monthly ipilimumab to continue indefinitely until disease progression or development of toxic effects. The most common side effects of both drugs are chronic pruritic rash, which the patient developed, vitiligo, polyarthralgias, myositis, pericarditis, pneumonitis, adrenal insufficiency, thyroiditis, pituitary dysfunction, liver failure, renal failure, and colitis.7

External beam radiation (EBR) therapy was chosen to control pain from the vertebral metastases and to afford additional time for the immunotherapy to work. EBR is believed to prime the patient’s immune response when used with immunotherapies that target CTLA-4, potentially increasing overall survival.5 Prior to undergoing radiation, the patient was referred to an orthopedic surgeon who performed a vertebral biopsy and kyphoplasty to stabilize the vertebral fractures.8 

An endocrinologist was consulted because of the patient’s osteopenia, hypercalcemia of malignancy, and her prior lack of supplemental calcium and vitamin D intake. Her oncologist agreed to initiate zoledronic acid, a bisphosphonate, because of her vertebral metastatic fractures and because it could further minimize risk of tumor lysis syndrome.8 Additionally, when used with vitamin D, zoledronic acid can stabilize vertebral metastatic lesions specifically in patients with melanoma by reducing the number and size of bone metastases.8 A regimen of vitamin D 1000 IU daily, calcium 1500 mg daily, and zoledronic acid 4 mg intravenous every 4 weeks was initiated. 

The patient was evaluated monthly.  Laboratory assessment included a comprehensive metabolic panel; a complete blood count; and lactic dehydrogenase (LDH), thyroid-stimulating hormone, triiodothyronine, thyroxine, cortisol, and adrenocorticotrophic hormone levels. A normal LDH level has been associated with better overall survival in patients with metastatic melanoma as it is a direct measure of organ tissue damage.9 The patient was scheduled to undergo periodic PET and brain MRI scans to monitor for progression of her disease; 50% of patients with metastatic melanoma will eventually develop brain metastases and another 20% will develop liver metastases.5

There is no known cure for stage 4 melanoma. The goal of treatment is sustained response to immunotherapy and targeted therapies, and eventually a PET scan showing no evidence of disease. A diagnosis of melanoma carries a poor prognosis, and stage 4 melanoma has a 5-year survival rate of approximately 22.5%.5 However, patients receiving treatment with the newer PD-1 and CTLA-4 inhibitors have shown improved overall responses of up to 57%.5,10 Other therapies that have shown benefit in the treatment of melanoma include interleukin 2 (IL-2) therapy with or without adoptive cell therapy with tumor-infiltrating lymphocytes.5 Chemotherapy and IL-2 therapy are still used, although the response is not as robust as that seen with the newer immunotherapies and checkpoint inhibitors.1,5

Role of Primary Care NPs and PAs 

Primary care clinicians should be aware that melanoma is not just skin cancer. Genetic mutations, diffuse nevi, and chronic skin exposure to UV light (no matter the source) are all independent risk factors for melanoma. It can appear as completely invisible and go undetected on examination, and it can exist as a genetic mutation without any obvious skin lesion(s). Patients with melanoma have a 74% risk of passing the genetic mutation to their offspring.11 Genetic testing is available for familial melanoma; for those who test positive, the current recommendation remains skin and symptom surveillance and risk reduction.  Mutations in CDKN2A, BAP1 and MC1R genes are responsible for this non-sun-related genetic form of melanoma.5,11   

It is important to educate patients about the importance of annual skin checks as most melanomas arise from chronic, sustained UV exposure with visible abnormalities. Skin examinations should include the perineum as well other non-sun-exposed areas such as nails, hands, and feet because acral-lentiginous melanomas can be easily missed. Patients should also undergo routine eye examinations to detect uveal and choroidal melanoma, which may not be found until they have already metastasized.12 Because of the effectiveness of immunotherapy, melanoma is becoming a chronic illness, making it important to maintain health screenings.

Patients should be counseled to apply sunscreen products daily, wear 100% UVA and UVB sunglasses and UV-protected clothing and hats when outdoors, and avoid chronic sunlight exposure including tanning beds.

Non-estrogen-containing contraception methods should be recommended for any woman with metastatic disease who still ovulates. Estrogen-containing products including soy milk and phytoestrogens should be avoided due to risk of coagulopathies. Fertility-sparing measures should be a consideration for those with metastatic melanoma who want to have children.