Revolutionary New Drugs Offer Hope for Advanced Melanoma -

Sheila Krishna, M.D.

Melanoma is an increasingly common skin cancer that typically appears as a dark brown, black, or multi colored spot or growth on the skin. Melanoma occurs when melanocytes, or pigment producing cells, begin to grow out of control in the skin. The incidence of cutaneous, or skin based, melanoma has been increasing in all ages and genders and melanoma accounts for the majority of deaths related to skin cancer.

Melanoma is linked to exposure to ultraviolet rays from natural sunlight and tanning beds, which causes mutations in melanocytes that result in uncontrolled growth and proliferation. Melanoma can have an inherited component, and there are melanoma and atypical mole syndromes that are associated with other tumor types, such as breast or pancreatic cancer. Melanoma typically occurs on sun exposed areas but can occur in nearly any part of the body. Specifically, melanoma can be seen in the eyes, nails, lips, genitals, and central nervous system, and many of these tumors have signature mutations in their genetic composition.

Melanoma progresses thru a series of stages, which are dependent on the depth of the tumor at the time of diagnosis, along with other prognostic factors. Melanoma can be staged from 0-4 and the stage is dependent on tumor factors (thickness, ulceration), lymph node involvement, and spread to distant organs. As the extent of involvement increases, the cancer is staged at a higher number. A higher staged melanoma typically has a poorer prognosis.

Early stage melanoma (0-1) can be cured with surgical removal with appropriate margins and has an excellent long term prognosis of over 95%. For more advanced melanoma (stage 2 and higher), further staging is required with both surgical removal of the tumor and lymph node evaluation, often along with imaging and molecular testing. Melanomas that have lymph node or organ involvement, or that have specific molecular signatures, are considered advanced melanoma.

Treatment of advanced melanoma has undergone a revolution in the past several years. For many years, options were limited to surgery and conventional chemotherapy that had mixed results with respect to tumor progression and overall survival. The field of advanced melanoma has benefited greatly from an enhanced understanding of cancer gene expression and immune cell interactions. In recognition of the the magnitude of these advances, this seminal work was awarded the 2018 Nobel Prize in Medicine for its impact on the scientific community and on patient lives.

This history of advanced melanoma treatment began with conventional chemotherapy. Dacarbazine, an alkylating agent, was approved in 1974 as a treatment for metastatic melanoma but showed a dismal 5 year survival rate of only 2-6%. Temozolomide was then approved for treatment and while it showed an improved progression free survival, it did not improve overall mortality.

Immunotherapy began to be explored for the treatment of advanced melanoma during this time. Immunotherapy utilizes the immune system, which normally protects the body from infections, to recognize and halt tumor progression. An early attempt at immunotherapy was the use of interferons. Interferons are cytokines, or signaling molecules that are made by white blood cells. Interferons have important anti-tumor activities and activate immune cells such as T cells, B cells, and NK (natural killer) cells to help the body ward off cancer cells.

Interferon a-2b was approved by the FDA in 1995 as an adjuvant treatment of advanced melanoma. Interferon was found to significantly reduce the risk of melanoma recurrence and improve survival, but not all patients responded to the therapy. Side effects were also significant with this treatment.

In response to these data, interleukin 2 (IL-2) was explored for its role on the immune system and was approved for the treatment of advanced melanoma in 1998. IL-2 is a signalling molecule that enhances the production of T cells, specialized white blood cells, that can destroy melanoma cells, and it has shown an overall response of about 20%. IL-2 treatment includes serious side effects such as organ failure and cardiac arrhythmias.

The modern age of immunotherapy began in 2011, with the approval of ipilimumab ( Yervoy) for the treatment of advanced melanoma. Ipilimumab is an anti-CTLA4 antibody. CTLA-4 is what is known as a checkpoint inhibitor, which blocks the activation of T cells. Blocking T cell activation allows the body to tolerate tumor growth. By blocking CTLA-4, a blocker of T cell activation, ipilimumab allows T cells to proliferate and fight the melanoma. CTLA-4 inhibitors have been found to be highly effective and improve mortality in advanced melanoma. However, these medications also create non-specific inflammation of the skin, gut, liver, thyroid, and nervous system, that often requires treatment with steroids to minimize these effects.

The most current avenue of advanced melanoma immunotherapy involves the use of programmed cell death protein 1 (PD1) inhibitors. The PD1 receptor usually acts as an inhibitor of T cells and suppresses their activation. By inhibiting this inhibitor, T cells can freely proliferate and attack tumor cells. An early PD1 inhibitor was nivolumab ( Opdivo), which was approved in 2014 for the treatment of metastatic melanoma. Nivolumab is slightly more effective than ipilimumab, and has a similar side effect profile, and the combination of these two drugs showed superior results than either alone.

A newer anti-PD1-1 antibody named pembrolizumab ( Keytruda) was approved in 2015 and has been shown to have improved results and a better side effect profile than ipilimumab. Several clinical trials are ongoing, using nivolumab or pembrolizumab alone or in combination with chemotherapy, radiation, other immunotherapies, and targeted therapies.

Along with immunotherapy, targeted therapy has also been a promising area of research in the treatment of advanced melanoma. In contrast to immunotherapy, in which the immune system is activated to fight off the tumor, targeted therapy acts on specific mutations in the tumor. Approximately 70% of patients with melanoma harbor gene mutations in signaling pathways that lead to tumor growth. Improved identification of these genes and their role in melanoma growth has lead to the development of small molecule inhibitors of various points in this pathway.

A major target for melanoma growth is the BRAF protein. BRAF is a member of the potent MAPK signalling pathway that controls the growth of several tumors. The MAPK pathway is like a series of on and off switches that act in series to promote tumor growth. Mutations in BRAF permit continuous tumor growth, without being held in check by other cellular mechanisms. 50% of melanomas contain this mutated BRAF, which drives melanoma growth. Interestingly, many normal moles also contain BRAF mutations, so molecular testing must be taken in the context of other criteria. The specific BRAF mutation found in melanoma is termed the V600E mutation.

Vemurafenib ( Zelboraf) is a V600E BRAF inhibitor that was approved in 2011 for the treatment of advanced melanoma. Studies have shown that up to 90% of patients who receive this medication will experience tumor regression. Vemurafenib has also shown great promise in combination with classic chemotherapy or immunotherapies. Vemurafenib was followed by the development of dabrafenib-Tafinlar- in 2013, also for the treatment of advanced melanoma, and it has a similar mechanism of action.

While targeted therapies have lead to vastly improved response and survival rates, their use has been limited by the development of resistance mechanisms within the MAPK signalling pathway which will allow the tumor to continue to grow by bypassing BRAF. Combining BRAF inhibitors with MEK inhibitors helps to sidestep this issue, and specific MEK inhibitors have been developed to be used alone or in combination with BRAF inhibitors in the treatment of advanced melanoma.. Trametinib- Mekinist- a small molecule antibody against MEK, was approved in 2013 for the treatment of advanced melanoma with BRAF mutations. In 2015, cometinib ( Cotellic), a MEK inhibitor, was approved specifically for use in concert with vemurafenib for advanced melanoma and was shown to significantly improve progression of disease.

The field of advanced melanoma has seen a renaissance that now provides numerous treatment options for patients who once had very few. Research on immunotherapy and targeted therapies has yielded a host of treatments that offer durable results, and ongoing work continues to elucidate novel mechanisms of therapy. While the duration of therapy and long term safety of these medications is an ongoing area of research, the benefit and promise of these medications far exceeds their risks.

For advanced melanoma, cutting edge science continues to refine and improve therapies that lead to tumor regression and improved survival. Novel therapies continue to be developed and improved in clinical trials, along with new combinations of existing therapies that complement one another and boost survival. Along with early detection and surgical treatment of melanoma, new medical therapies for advanced melanoma offer hope and promise for patients and their families.

References

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Luke JJ, Hodi FS. Ipilimumab, vemurafenib, dabrafenib, and trametinib: synergistic competitors in the clinical management of BRAF mutant malignant melanoma. Oncologist. 2013 Jun;18(6):717-25.

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