Review
The new paradigm of systemic therapies for metastatic melanoma

https://doi.org/10.1016/j.jaad.2017.04.1126Get rights and content

New treatments for metastatic melanoma work through distinct mechanisms: enhancing the immune response and blocking cellular proliferation. Agents that enhance the immune response include ipilimumab, pembrolizumb, and nivolumab; agents that block cellular proliferation include vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, and selumetinib. The translational impact of laboratory discoveries has revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients.

Section snippets

Immune checkpoints and their inhibition

A melanoma-specific immune response is generated when melanoma antigen on the major histocompatibility complexes of antigen-presenting cells (APCs) is presented to the T-cell receptors of T cells. The antigen-primed T cell becomes activated by engagement of its CD28 molecule with the costimulatory molecules CD80 and CD86 present on APCs (Fig 2). The resulting tight synapse between the T cell and APC leads to proliferation and survival of T cells that help eliminate tumor cells.1 The CTLA-4

Adverse events secondary to immune checkpoint inhibition

The common side effects are nonspecific and include fatigue, diarrhea, rash, and nausea. Immune-related adverse events (irAEs) have been commonly seen and involve a number of organ systems, including the gastrointestinal tract (colitis, hepatitis), skin (dermatitis), lung (pneumonitis), endocrine glands (hypophysitis, thyroid dysfunction), nervous system, and eyes (Table I).3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Dermatologic complications

Combined immune checkpoint inhibition: principle

Knowledge that blocking either of the 2 T-cell inhibitory checkpoints by monoclonal antibodies improved survival in MM patients and that these checkpoints are nonredundant led to the hypothesis that further improvement in survival might be achieved by combined blockade. Validated in preclinical studies, the first phase 1 study combined (concurrently or sequentially) ipilimumab and nivolumab treatments in unresectable stage III or IV melanoma. The results confirmed improved outcomes following

Targeted therapies

Genetic components of multiple cellular signaling pathways critical to maintaining cellular homeostasis by controlling key cellular functions of growth, proliferation, and cell death by apoptosis have been discovered. Mutations of genes encoding proteins of such pathways foster carcinogenesis by conferring uncontrolled cellular signaling for growth and proliferation. Targeted therapy involves control of tumor growth with small molecules designed to block the aberrant proteins of these signaling

BRAF inhibitors in combination with MEK inhibitors

Though BRAF inhibitors have high disease control rates, treatment failures following BRAF inhibitor monotherapy are common, with most patients developing tumor progression within 6-7 months. The tumor developing resistance to the BRAF inhibitor therapy is the main cause of treatment failure and is multifactorial.21, 54 Recent data shows that approximately two thirds of cases are caused by reactivation of oncogenic signaling via the MAPK pathway and the remainder by an MAPK-independent pathway.63

Treatment decision of a patient diagnosed with unresectable stage III or IV melanoma

The treatment options for patients with unresectable stage III or stage IV melanoma are expanding (Fig 4). A number of patient specific and disease factors are required to determine the best treatment option. These factors include treatment naïve status, previous use of immune therapy in the adjuvant setting, sites of metastasis, rate of tumor growth, tumor bulk, comorbidities including autoimmune diseases and their severities, performance status, age, serum LDH levels, and tumor PDL1 status.

Conclusion

Immune-based treatments and targeted therapies for MM have yielded promising results. Challenges still exist due to the toxicities that might limit treatment options in subsets of patients. While durable remissions are more likely with immune-based treatments, combined BRAF and MEK blockade can delay development of resistance and improve treatment outcomes.

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    Dr Volpe and Mr Klufas contributed to this work equally.

    Drs Hegde and Grant-Kels contributed to this work equally.

    Funding sources: Supported by Jane and Richard Lublin.

    Reprints not available from the authors.

    Conflicts of interest: None declared.

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