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The Rapid Emergence of Novel Therapeutics in Advanced Malignant Melanoma.

John L, Cowey CL - Dermatol Ther (Heidelb) (2015)

Bottom Line: These findings have facilitated a rapid emergence of novel therapeutics for the disease with multiple FDA approvals in the last several years.The drugs vemurafenib, trametinib, and dabrafenib, which inhibit the commonly mutated BRAF pathway, have been approved based on improvements in survival outcomes.Agents that block immune checkpoints on lymphocytes allowing for immune cell activity against melanoma have also been approved based on improved survival outcomes such as ipilimumab and nivolumab.

View Article: PubMed Central - PubMed

Affiliation: Baylor-Sammons Cancer Center, Texas Oncology, P.A., Dallas, TX, USA.

ABSTRACT
For decades, no cancer therapy had been shown to improve average survival in metastatic melanoma. Two critical events have occurred, the discovery of melanoma driver mutation subsets and the discovery of immune checkpoint inhibitors, which have allowed for the development of modern, effective therapies. These findings have facilitated a rapid emergence of novel therapeutics for the disease with multiple FDA approvals in the last several years. The drugs vemurafenib, trametinib, and dabrafenib, which inhibit the commonly mutated BRAF pathway, have been approved based on improvements in survival outcomes. Agents that block immune checkpoints on lymphocytes allowing for immune cell activity against melanoma have also been approved based on improved survival outcomes such as ipilimumab and nivolumab. Pembrolizumab, another immune checkpoint inhibitor, has also been approved based on the response rate and duration of response in a phase 1 trial. Further agents and combinations of approved agents are positioned to possibly further increase this tally of approved drugs. This review will discuss recently approved novel agents and select drugs in development in advanced melanoma.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram showing select signaling pathways in melanoma. With activating BRAF mutations present in 50% of melanoma tumors and NRAS mutations present in approximately 20%, the MAP kinase pathway (RAS-RAF-MEK-ERK) plays an important role in the majority of melanomas. However, other pathways also can contribute to pathogenesis and resistance to BRAF and MEK inhibition, such as activation of the PI3K pathway and signaling through COT and CDK4
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Fig1: Schematic diagram showing select signaling pathways in melanoma. With activating BRAF mutations present in 50% of melanoma tumors and NRAS mutations present in approximately 20%, the MAP kinase pathway (RAS-RAF-MEK-ERK) plays an important role in the majority of melanomas. However, other pathways also can contribute to pathogenesis and resistance to BRAF and MEK inhibition, such as activation of the PI3K pathway and signaling through COT and CDK4

Mentions: The molecular biology of melanoma is complicated with numerous mutations present and a variety of pathways impacted (Fig. 1). However, there are common driver mutations present at high frequencies that allow for a molecularly targeted approach. Critical to highlighting these common targetable mutation events was the work of Davies et al. in 2002 when they reported a high frequency of BRAF gene mutation (now known to be present in approximately 50% of melanomas), leading to the theory that the BRAF serine/threonine kinase could represent a commonly applicable therapeutic target [4]. In about 80–90% of mutated BRAF tumors, an activating V600E missense mutation is present, while about 10–20% of BRAF mutant tumors have V600K, V600D, and V600R mutations [5]. These activating mutations result in constitutive activation of the MAP (mitogen-activated protein) kinase pathway resulting in unchecked cell proliferation.Fig. 1


The Rapid Emergence of Novel Therapeutics in Advanced Malignant Melanoma.

John L, Cowey CL - Dermatol Ther (Heidelb) (2015)

Schematic diagram showing select signaling pathways in melanoma. With activating BRAF mutations present in 50% of melanoma tumors and NRAS mutations present in approximately 20%, the MAP kinase pathway (RAS-RAF-MEK-ERK) plays an important role in the majority of melanomas. However, other pathways also can contribute to pathogenesis and resistance to BRAF and MEK inhibition, such as activation of the PI3K pathway and signaling through COT and CDK4
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4580658&req=5

Fig1: Schematic diagram showing select signaling pathways in melanoma. With activating BRAF mutations present in 50% of melanoma tumors and NRAS mutations present in approximately 20%, the MAP kinase pathway (RAS-RAF-MEK-ERK) plays an important role in the majority of melanomas. However, other pathways also can contribute to pathogenesis and resistance to BRAF and MEK inhibition, such as activation of the PI3K pathway and signaling through COT and CDK4
Mentions: The molecular biology of melanoma is complicated with numerous mutations present and a variety of pathways impacted (Fig. 1). However, there are common driver mutations present at high frequencies that allow for a molecularly targeted approach. Critical to highlighting these common targetable mutation events was the work of Davies et al. in 2002 when they reported a high frequency of BRAF gene mutation (now known to be present in approximately 50% of melanomas), leading to the theory that the BRAF serine/threonine kinase could represent a commonly applicable therapeutic target [4]. In about 80–90% of mutated BRAF tumors, an activating V600E missense mutation is present, while about 10–20% of BRAF mutant tumors have V600K, V600D, and V600R mutations [5]. These activating mutations result in constitutive activation of the MAP (mitogen-activated protein) kinase pathway resulting in unchecked cell proliferation.Fig. 1

Bottom Line: These findings have facilitated a rapid emergence of novel therapeutics for the disease with multiple FDA approvals in the last several years.The drugs vemurafenib, trametinib, and dabrafenib, which inhibit the commonly mutated BRAF pathway, have been approved based on improvements in survival outcomes.Agents that block immune checkpoints on lymphocytes allowing for immune cell activity against melanoma have also been approved based on improved survival outcomes such as ipilimumab and nivolumab.

View Article: PubMed Central - PubMed

Affiliation: Baylor-Sammons Cancer Center, Texas Oncology, P.A., Dallas, TX, USA.

ABSTRACT
For decades, no cancer therapy had been shown to improve average survival in metastatic melanoma. Two critical events have occurred, the discovery of melanoma driver mutation subsets and the discovery of immune checkpoint inhibitors, which have allowed for the development of modern, effective therapies. These findings have facilitated a rapid emergence of novel therapeutics for the disease with multiple FDA approvals in the last several years. The drugs vemurafenib, trametinib, and dabrafenib, which inhibit the commonly mutated BRAF pathway, have been approved based on improvements in survival outcomes. Agents that block immune checkpoints on lymphocytes allowing for immune cell activity against melanoma have also been approved based on improved survival outcomes such as ipilimumab and nivolumab. Pembrolizumab, another immune checkpoint inhibitor, has also been approved based on the response rate and duration of response in a phase 1 trial. Further agents and combinations of approved agents are positioned to possibly further increase this tally of approved drugs. This review will discuss recently approved novel agents and select drugs in development in advanced melanoma.

No MeSH data available.


Related in: MedlinePlus