Hot Topic Update: Advanced Melanoma
The landscape for treating advanced melanoma is evolving rapidly. Since 2011, in the United States 11 new treatments have been approved for the treatment of metastatic melanoma, and dermatologists must become familiar with these, stated Allan C. Halpern, MD, Memorial Sloan Kettering Cancer Center, New York, USA.
Regarding the prevention of melanoma, Dr. Halpern urged dermatologists to continue to actively support the American Academy of Dermatology initiative for legislation to restrict the use of tanning beds to persons over 18 years old, and to require any person using a tanning bed to sign an acknowledgement of risk certification.
Population-based screening for melanoma is not recommended by the US Preventive Services Task Force, because of the lack of sufficient data on which to base a recommendation. However, screening is recommended for persons at high risk, including those >55 years old,and persons with moles, atypical moles, or a family history of melanoma. In the US, melanoma-related mortality is increasing in men over 55 and women over 65 years old.
The diagnosis of melanoma is changing. Digital dermoscopy is improving diagnostic accuracy, providing the capacity to document and follow lesions over time. Patient-driven screening is increasing, because of public health messaging, with patients taking photos of questionable spots/moles on their skin for assessment by the dermatologist. Indeed, dermatoscopes for the consumer market are now available that attach to the Smart phone (exhibited at AAD 2016). Teledermatology will increase, said Dr. Halpern, noting there are now nearly 260 dermatology Apps available. The increasing quality of these Apps that is anticipated over the next 5 years will increase patient-driven screening and increase the numbers seeking care by a dermatologist for suspected lesions. Dermatologists must consider how they will add value within this changing paradigm, he noted, and this may be through 3-D total body scans or reflectance confocal microscopy, among other measures.
The new treatments for advanced melanoma fall into two main categories: pathway-targeted therapies and immunotherapy. These pathway-targeted therapies were made possible by key discoveries regarding the role of the BRAF in the MAP kinase pathway. About 40% of patients with melanoma have a BRAF mutation, and the mutation is in the same location in nearly all of these patients, providing an effective treatment target. Further the combination of a BRAF inhibitor and a MEK inhibitor has a synergistic effect providing even greater improvements, and some of the side effects associated with a BRAF inhibitor are reduced.
Effective immunotherapy was made possible because of the identification of immune checkpoints, specifically, cytotoxic T lymphocyte antigen (CTLA)-4, programmed cell death (PD)-1, and programmed cell death ligand (PD-L1). Inhibitors of these checkpoints remove the breaks from the immune system, allowing for increased immune system activity and subsequent anticancer effects.
Ipilimumab, a CTLA-4 inhibitorthat increases T-cell activation and cytokine secretion, was the first novel immunotherapy to prolong progression-free survival (PFS) in melanoma, with about 20% of patients having a durable response to treatment. The PD-1 blocker nivolumab improves PFS, and the combination of ipilimumab plus nivolumabprovides even greater improvement. In the Checkmate 067 study, this combination improved PFSto 11.5 months, compared with 2.9 months and 6.9 months alone, respectively. However, with the combination treatment there are substantial cutaneous side effects, including rash and vitiligo.
Immune-related side effects with this class of drug include diarrhea, colitis, and death, along with skin-related effects. Dermatologists should anticipate seeing more patients with cutaneous reactions that are side effects to the new anti-PD-1 lung cancer drug that is now available in the United States. Recognizing and managing these toxicities will improve patient quality of life and prevent unnecessary dose reduction or treatment discontinuation.