The prevalence and incidence of melanoma has increased exponentially in the past 20 years. Nevertheless, with significant advances in medicine over the past decade, almost 85% of melanoma patients have a good prognosis owing to early diagnosis and prompt management.
Prior to advancements in the currently employed modes of therapy such as targeted therapy and immunotherapy, the primary agents used for treatment of melanoma was chemotherapy drugs such as dacarbazine. However, these therapies are far from ideal for patients due to their poor therapeutic benefits and associated adverse effects in advanced stages of melanoma.
In order to find alternative treatment modalities, researchers focused on studies that strived to understand the underlying pathophysiology of melanoma.
As researchers noticed the differences in the pattern of melanoma lesions in areas that were chronically exposed to sun against nonexposed areas, they shifted their attention towards genetic mutations resulting from damage by the sun’s harmful UV rays.
Genomic sequencing of patients with chronic exposure to the sun versus those with limited sun exposure found unique mutation patterns in those with chronic sun exposure. This eventually resulted in the discovery of MAPK pathway which in turn led to the identification of BRAF and NRAS as the major gene mutations responsible for melanoma.
With this newfound understanding of melanoma, targeted therapies were developed which was found to be significantly superior to chemotherapy in terms of both survival and adverse effects.
Drugs such as vemurafenib, trametinib and dabrafenib that targeted BRAF mutations underwent clinical trials, which reported these agents to have profound albeit temporary responses in melanoma patients. Significant reduction in tumor burden was reported for short periods in advanced cases of melanoma.
Further studies focused on combination therapy using BRAF and MEK inhibitory drugs. This combination treatment resulted in overwhelming inhibition of MAPK pathway. With these groundbreaking findings, the US FDA approved trametinib drug in 2013 and combination drug therapy with dabrafenib/trametinib in 2015 for treatment of melanoma.
Additionally, combining immunotherapy with targeted therapy resulted in even better prognosis in melanoma cases.
Immunotherapy for melanoma is done using monoclonal antibodies Ipilimumab that inhibit CTLA-4, and Pembrolizumab/Nivolumab that inhibit PD-1 receptors.
In patients with advanced stage melanoma, the first study that examined the effects of immunotherapy was conducted using low-dose Ipilimumab which reported an overall 11% improvement in overall survival. Follow-up of this study combined a slightly higher dosage of ipilimumab with the chemotherapeutic drug dacarbazine but found no increase in benefits with the higher dosage or the combination therapy. Hereafter, low dose ipilimumab was approved for treatment of melanoma. Ipilimumab was associated with some symptoms of toxicity such as hepatitis, diarrhea, hypophysitis and rash in almost 30% of treated cases.
Subsequent studies that compared ipilimumab with pembrolizumab found the latter to be associated with greater one-year survival benefits as well as lower rates of adverse effects. Henceforth, the US FDA approved pembrolizumab as a treatment modality for melanoma in 2014 as a second-line treatment drug but it was upgraded as a first-line treatment drug in 2015.
Further studies that employed combined therapy with ipilimumab and nivolumab in melanoma patients proved to be highly beneficial but was also associated with increased rates of adverse toxic symptoms. Currently, FDA recommends using combination immunotherapy of ipilimumab and nivolumab as a first-line treatment for melanoma
Over the past decade, profound achievements have been accomplished in the treatment of melanoma, a condition that just 10 years back was akin to a death sentence due to its extremely poor prognosis.
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