Advanced malignant melanoma treatment enters new era

Waikoloa, Hawaii - Treatment for metastatic melanoma has begun a dramatic renaissance with the development of novel immunotherapy strategies and targeted therapeutic approaches.

Becoming knowledgeable about these advances is important for dermatologists as their referrals open the gate for affected patients to receive the best possible care, says Michael Postow, M.D., who spoke at the 38^th Hawaii Dermatology Seminar held here.

“Until recently, chemotherapy and interleukin-2 were all that could be offered to patients with metastatic melanoma, but the efficacy of each of those approaches was limited. Therefore, metastatic melanoma was a fatal disease for most patients,” says Dr. Postow, assistant attending physician, melanoma-sarcoma oncology service, Memorial Sloan-Kettering Cancer Center, New York.

“Thanks to increased understanding of the activity of the immune system in cancer and of the genetics of melanoma, new therapies have been developed that are extending survival in more patients with metastatic disease. As dermatologists are at the frontline of care for melanoma patients, they need to understand recent treatment advances so they can communicate to patients the existing promise and ensure they receive optimal available care.”

Next: Immunotherapies available

Available immunotherapies

Immunotherapies for metastatic melanoma are monoclonal antibodies designed to block signals that inhibit the ability of the host immune system to eradicate cancerous cells. Intravenous ipilimumab (Yervoy, Bristol-Myers Squibb), which targets cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), is the first agent available in this class.

“Ipilimumab has shown benefit for prolonging survival of patients with metastatic melanoma, increasing the proportion of patients living for several years by about twofold compared with previously available therapy,” Dr. Postow says. “Unfortunately, the numbers who have long-term survival are still just a fraction of the total patient population, and so current research is aiming to identify features that will predict response and ways to increase the proportion of patients who benefit.”

Also within the immunotherapy category, there are several intravenous agents in development that are monoclonal antibodies targeting the programmed death-1 receptor (PD-1). The two farthest along in clinical trials are nivolumab (Bristol-Myers Squibb), and MK -3475 (Merck).

“Available data indicate that these treatments that target PD-1 result in sizeable tumor shrinkage in at least a third of patients with melanoma. In addition, the response to the anti-PD-1 agents seems to be durable, and this class appears to cause minimal side effects,” Dr. Postow says.

“Results from phase 3 studies are needed to determine what effect the PD-1 inhibitors have on extending survival. However, based on the promising efficacy and safety observed so far, I would encourage dermatologists to refer their patients with metastatic melanoma to a center participating in one of the PD-1 inhibitor trials,” he adds.

Targeted therapy for metastatic melanoma focuses primarily on patients with a BRAF mutation, who represent nearly 50 percent of the melanoma population. Currently, there are two approved BRAF inhibitors, vemurafenib (Zelboraf, Roche) and dabrafenib (Tafinlar, GlaxoSmithKline). Trametinib (Mekinist, GlaxoSmithKline), which inhibits mitogen-activated protein kinase enzymes (MEK), is also approved for the treatment of metastic melanoma in patients with a BRAF mutation. All three of these therapies are administered orally, and have been shown to be more effective than chemotherapy.

“These drugs have been game-changers for metastatic melanoma patients with a BRAF mutation. Unfortunately, the duration of benefit from BRAF inhibitor treatment is often limited,” Dr. Postow says.

“Therefore, current research is investigating strategies for extending the longevity of the response, including by combining BRAF inhibitors (such as dabrafenib) with MEK inhibitors (such as trametinib).

Next: Candidates for immunotherapy

Personalized approach

Current decisions on treatment for metastatic melanoma first take into account whether the patient has a BRAF mutation. Those who don’t are typically candidates for immunotherapy. In those with a BRAF mutation, consideration is given to symptom severity.

“In a patient with a BRAF mutation who is highly symptomatic, there may be a preference for initiating therapy with a BRAF inhibitor that will be most effective for shrinking the tumor, albeit at the expense of a less durable response,” Dr. Postow says. “In contrast, a patient with an asymptomatic metastasis detected on CT scan might consider immunotherapy that likely would provide a more long-lasting benefit. However, the pros and cons of each modality are discussed with the patient in order to make an informed decision.”

Maintaining skin health

Although treatment with the new immunotherapy agents and targeted therapies falls under the realm of medical oncologists, dermatologists are involved in the care of patients receiving these modalities due to their potential to cause dermatologic side effects. Skin rash can develop in patients treated with ipilimumab and the BRAF/MEK inhibitors. Patients treated with the BRAF inhibitors can also develop warty growths and are at increased risk for developing nonmelanoma skin cancers, particularly squamous cell carcinoma.

“As the use of these new strategies expands for the treatment of metastatic melanoma and other cancers, dermatologists can be expecting to see more patients on referral for adverse event management,” Dr. Postow says.

Disclosures: Dr. Postow has received research grant support from Bristol-Myers Squibb.

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