Targeted Therapies in Melanoma

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Key points

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    Although melanoma bears one of the highest number of mutations per given DNA length among other malignancies, the most abundant mutations primarily affect 2 major signaling pathways.

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    Next-generation sequencing methodologies targeting a panel of cancer-related genes may better capture heterogeneity of melanoma and assist in treatment decisions.

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    Several genetic aberrations (mutations, copy number aberrations) can coexist within a particular melanoma, which may be of prognostic and therapeutic

Treating patients with malignant melanoma in the era of small molecule inhibitors

The approach to a patient with MM has dramatically changed since 2010 with the advent of small inhibitor therapies, especially for BRAF-mutant patients. In addition to factors such as patient performance status, tumor doubling time, ability to perform metastatectomy, comorbid factors, American Joint Committee on Cancer (AJCC) staging system guidelines, knowledge about the mutation status for at least BRAF, NRAS, and KIT is becoming the standard of care for prognostic14 and treatment reasons.

All 3 US Food and Drug Administration–Approved Targeted Therapies in Metastatic Melanoma are for Patients with BRAF-Mutant Melanoma

As of May 2013 there are 3 US Food and Drug Administration (FDA)-approved MAPKi for MM: the 2 BRAF inhibitors (BRAFi), vemurafenib and dabrafenib, and the first-in-class MEK inhibitor (MEKi), trametinib. Their approval was based on randomized, phase III trials in which each of the investigational agents was compared against dacarbazine for patients with unresectable BRAFV600E(K)-mutant MM.17, 18, 19 All important clinical endpoints were in favor of the investigational agents. Five key

Combinations Among Small Molecule Inhibitors

Concurrent suppression of BRAF plus MEK results in more potent and sustained suppression of ERK signaling, presumably owing to incomplete suppression of the MAPK pathway by either agent alone.25 In fact, treatment of patients with BRAFV600E,K-mutant MM with dabrafenib and trametinib (D+T) led to a higher incidence of complete antitumor responses.41 In line with this, the combination of D+T was associated with more prolonged, progression-free survival compared with dabrafenib alone in a

Treatment resistance

Based on the history of targeted therapies in other malignancies, resistance to targeted therapies in melanoma was highly expected. Several excellent reviews have been written for this important topic.52 In the case of BRAF-mutant melanoma, the most extensively studied subtype with respect to drug resistance, these mechanisms may or may not involve reactivation of the ERK signaling pathway. In fact, on most occasions BRAF-mutant, MAPKi-resistant melanoma remain “addicted” to MAPK signaling,

Discussion

Although great progress has been achieved toward finding effective treatments for patients with BRAF-mutant melanoma, therapeutic advances are only beginning to occur in RAS-mutant melanoma. The biology of melanomas that bear no oncogenic mutations for BRAF/RAS has only recently begun to be systematically investigated,57 but the subgroup that bears NF1 mutations, which is negative inhibitor of RAS signaling,58 suggests that an even greater proportion of melanomas than what was originally

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    This article is funded by NIH (P30-CA016086; NIHMS-ID: 651211).

    S.J. Moschos has served as consultant for Genentech, Amgen, and Merck. Dr R. Pinnamaneni has no conflict of interest.

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