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Targeting signal transduction pathways in melanoma

Flaherty, K.T.

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doi: 10.1097/01.cmr.0000382784.44182.71
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Therapy for advanced melanoma has progressed slowly over the past three decades. The successful translation of therapies targeting signal transduction pathways that are activated by oncogenes in other cancers has provided a model for molecularly targeted therapy. KIT mutations and KIT inhibitors in gastrointestinal stromal tumors is a prime example. The identification of KIT mutations in a small subset of melanoma patients in 2005 provided an immediate opportunity to evaluate the relevance of KIT as a therapeutic target in melanoma using validated KIT inhibitors. Given the rarity of these patients, multicenter clinical trials have been slow to accrue, but responses have been observed with single-agent KIT inhibition in this population.

The identification of BRAF mutations in 2002 was the watershed event that turned the attention of the melanoma field to this concept. Seven years passed between the identification of BRAF mutations and the validation of this target in melanoma patients with a potent and specific BRAF inhibitor, PLX4032. In the first-in-human trial, 49 of 55 patients enrolled in the dose escalation portion of the study had metastatic melanoma. There was enrichment for patients with V600EBRAF mutations as many patients’ tumors were prospectively evaluated prior to study entry, particularly at the higher dose levels. An additional 32 patients with metastatic melanoma harboring BRAF mutations were enrolled at the maximum tolerated dose. Toxicity was clearly related to dose with increasing frequency and severity of rash, fatigue, and arthralgia at the highest doses. Efficacy was first clearly demonstrated at doses that produced drug exposure that was commensurate with that required to achieve tumor regression of V600EBRAF melanoma xenografts preclinically. Objective responses were observed in the vast majority of patients & FDG-PET scans revealed metabolic changes as early as two weeks into therapy. Selected patients underwent biopsy of superficial tumors for the purposes of confirming downregulation of Erk activation and Ki67. Updated data from the phase I/II trial will be presented. As single-agent trials are underway with the aim of establishing single-agent BRAF inhibition as a new standard of care for the BRAF mutated subpopulation, attention now turns to understanding mechanisms of resistance and rational combination approaches.

KIT and BRAF targeted therapies provide a new paradigm for matching therapy to somatic genetic changes identified prior to the initiation of therapy. NRAS mutations are known to occur in an additional 20% of melanomas, but represent a unique therapeutic challenge. Additional genetic discoveries may provide a basis of combinations of targeted therapy, in an effort to extend the early success of KIT and BRAF inhibitors in the subpopulations bearing mutations in these oncogenes.

© 2010 Lippincott Williams & Wilkins, Inc.