PracticalDermatology

Melanoma, the deadliest form of skin cancer, is increasing in incidence worldwide. In the US, the lifetime probability that men will develop melanoma is one in 35; for women, one in 54.¹ Patients diagnosed with Stage I disease have a five-year survival rate of 90 percent, whereas median survival for patients diagnosed as Stage IV is less than a year. Impacting melanoma death rates will require better detection, increased capacity for evaluating lesions, and more effective treatments for patients with advanced disease.

Significant barriers exist to improving early detection. National practice guidelines do not include annual skin checks for the general population. Dermatologists are best at identifying suspicious lesions but lack the capacity to conduct widespread, routine evaluations.

Technological Innovations

Technology may improve detection and expand capacity. In 2011, the FDA approved MelaFind, a device that images lesions through a series of monochromatic filters. This technology generates a three-dimensional model of the lesion that is evaluated by a proprietary algorithm. A dermatologist can mark several lesions on a patient, then have a nurse or even a technician image those lesions. An evaluation is available within minutes and can serve as a guide for the physician.

Another company, Caliber I.D., has an in vivo confocal microscope specifically for use on the skin, allowing physicians to examine lesions at the cellular level real-time in the office. Other approaches look to genetic or proteomic patterns unique to melanoma. DermTech International has an adhesive strip product that is placed over a lesion and, when removed, retains some cells from the lesion. The strip is sent to a laboratory where genetic probes look for specific markers highly expressed in melanoma.

These and other technologies can potentially be used by health care providers other than dermatologists, allowing dermatologists to focus on those lesions that are, in essence, pre-screened. Still, widespread adoption of any of these systems remains uncertain.

Allan Halpern, MD, Chief, Dermatology Service of Memorial Sloan-Kettering Cancer Center, has stayed abreast of these exciting developments and notes that while bringing technology to bear on melanoma detection is very desirable, significant challenges remain.

“Automated systems like MelaFind have not been tested in routine clinical practice and it is not clear how they will affect biopsy rates. On the other hand, advanced imaging techniques like confocal microscopy require significant time and expertise,” Dr. Halpern notes. “Hopefully, additional clinical testing of automated instruments and logistical improvements of advanced imaging technologies will expedite diffusion into clinical practice.”

Once a lesion has been diagnosed as melanoma, physicians face new challenges. Based on depth and other criteria, the treatment team may conduct a sentinel node biopsy and, if the biopsy is positive, recommend lymphectomy and/or adjuvant therapy. In March 2013, the FDA approved Lymphoseek for use in identifying sentinel lymph nodes. This is a receptor-based radiolabel that binds to cells in the lymph node rather than washing it further downstream. Approved adjuvant therapy is limited to interferon, which offers modest improvement in relapse-free survival and no consistent improvement in overall survival. Important new trials are testing therapies—ipilimumab and vemurafenib— which, unlike interferon, have improved survival in more advanced disease.

Treatments for Advanced Disease

For years, doctors were limited to dacarbazine and interleukin 2 (IL-2) for treatment of advanced disease, neither of which had demonstrated improved survival in randomized trials. Now, treatment for unresectable Stage III or Stage IV disease is changing rapidly, as heralded by the approval in 2011 of ipilimumab and vemurafenib, both capable of improving overall survival. These two drugs represent the primary avenues of future exploration: immunotherapy and targeted therapy.

Recommendations for type of treatment are now influenced by molecular subtype. The identification of activating mutations in the MAP kinase pathway led to definitions of molecular subtypes and provided potential drug targets. The BRAF gene, first reported in 2002, harbors a single nucleotide transversion in approximately 50 percent of melanomas.² In smaller subsets of melanoma, other activating mutations include NRAS, c-KIT, and CDK4.

Vemurafenib blocks the function of BRAF, a step in the MAP kinase pathway. Response rates are approximately 50 percent, and overall survival is prolonged; however, resistance develops in a median of six months.^3,4 Another BRAF inhibitor, dabrafenib, is showing efficacy similar to vemurafenib. At least two drugs that block MEK, the step below BRAF in the MAP kinase pathway, are being developed. A number of compounds targeting other signaling pathways are in early development, thus the data is not sufficiently mature to determine their efficacy.

Ipilimumab blocks the T-cell checkpoint CTLA-4, thereby reactivating T-cells against melanoma. Response rates are relatively low at 11 percent; however, similar to IL-2, a subset of patients have prolonged survival.^5,6 Researchers are encouraged by studies involving another T-cell checkpoint, PD-1, or its ligand, PDL-1.⁷ Multiple companies are developing drugs that inhibit one of these targets, and early studies suggest some may have response rates as much as twice as high as ipilimumab, with less toxicity. Jeffery S. Weber, MD, PhD, Senior Member of the H. Lee Moffitt Cancer Center and Research Institute, has been involved with immunotherapy approaches to melanoma for his entire career and shares current enthusiasm about the new developments. “Melanoma clearly responds to immunotherapy,” says Dr. Weber. “Ipilimumab was a great advancement and now PD1 looks to be even better for patients.”

Other immunotherapy approaches include vaccine development and augmenting the activity of IL-2 with infusion of tumor infiltrating lymphocytes. Lymphocytes are removed from the patient and grown in the presence of tumor cells, in essence magnifying activation against their tumor prior to reinfusion.

The best chance of significant progress, however, is in combining two or more drugs, and a group of melanoma investigators recently formed the Melanoma Research Foundation Breakthrough Consortium for the purpose of accelerating progress in this area. Data indicate that combining multiple inhibitors of the MAP kinase pathway, e.g., BRAF and MEK inhibitors, can increase response rates, reduce side effects, and extend duration of response in patients with BRAF mutant melanoma. Laboratory data, and some small clinical studies, have shown that using a VEGF inhibitor, such as bevacizumab, in combination with either vemurafenib or ipilimumab, has at least an additive effect. Early stage studies are being launched to evaluate combinations of immunotherapeutics, e.g., IL-2 in combination with ipilimumab. As Dr. Lynn Schuchter, MD, Chief, Hematology/ Oncology, Abramson Cancer Center of the University of Pennsylvania, observes, “Combining drugs has proven successful in AIDS and tuberculosis. Now we are seeing similar promise become reality for people with melanoma.”

Accelerating Progress

As progress in the field of melanoma diagnosis and treatment continues to accelerate, dermatologists will increasingly need to stay abreast of technologies for evaluation of lesions, and they will need to ensure that medical oncologists in their referral network are aware of the importance of clinical trials—in the adjuvant and advanced disease setting, for initially diagnosed and relapsed patients.

Alison Martin, MD is Director, Medical Affairs, Melanoma Research Foundation. www.melanoma.org

1. American Cancer Society. Cancer Facts & Figures 2013, 2013. http://www.cancer.org/acs/groups/ content/@epidemiologysurveilance/documents/document /acspc-037130.pdf
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7. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-54.