Double-Blind Randomized Phase II Study of the Combination of Sorafenib and Dacarbazine in Patients With Advanced Melanoma: A Report From the 11715 Study Group

McDermott, David F.; Sosman, Jeffrey A.; González, René; Hodi, F. Stephen; Linette, Gerald P.; Richards, Jon M.; Jakub, James W.; Beeram, Muralidhar; Tarantolo, Stefano; Agarwala, Sanjiv S.; Frenette, Gary; Puzanov, Igor; Cranmer, Lee D.; Lewis, Karl D.; Kirkwood, John M.; White, J. Michael; Xia, Chenghua; Patel, Kiran Klaus; Hersh, Evan M.

doi:10.1200/jco.2007.14.8288

Cited by 224 publications

(146 citation statements)

References 30 publications

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“…Considerable preclinical evidence has associated the BRAF V600E mutation with heightened sensitivity to pharmacologic inhibition of RAF or MEK kinases (4,5). Although early clinical trials of RAF and MEK inhibitors failed to show a substantial benefit (6,7), recent phase I studies of selective RAF inhibitors have shown promising results in patients with BRAF-mutant tumors (8,9). Thus, optimizing therapeutic efficacy while avoiding or bypassing the emergence of resistance to MAP kinase pathway inhibition will likely gain increasing importance in melanoma and other MAP kinasedriven cancers.…”

mentioning

confidence: 99%

MEK1 mutations confer resistance to MEK and B-RAF inhibition

Emery

Vijayendran

Zipser

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

577

509

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Genetic alterations that activate the mitogen-activated protein kinase (MAP kinase) pathway occur commonly in cancer. For example, the majority of melanomas harbor mutations in the BRAF oncogene, which are predicted to confer enhanced sensitivity to pharmacologic MAP kinase inhibition (e.g., RAF or MEK inhibitors). We investigated the clinical relevance of MEK dependency in melanoma by massively parallel sequencing of resistant clones generated from a MEK1 random mutagenesis screen in vitro, as well as tumors obtained from relapsed patients following treatment with AZD6244, an allosteric MEK inhibitor. Most mutations conferring resistance to MEK inhibition in vitro populated the allosteric drug binding pocket or ␣-helix C and showed robust (Ϸ100-fold) resistance to allosteric MEK inhibition. Other mutations affected MEK1 codons located within or abutting the Nterminal negative regulatory helix (helix A), which also undergo gain-of-function germline mutations in cardio-facio-cutaneous (CFC) syndrome. One such mutation, MEK1(P124L), was identified in a resistant metastatic focus that emerged in a melanoma patient treated with AZD6244. Both MEK1(P124L) and MEK1(Q56P), which disrupts helix A, conferred cross-resistance to PLX4720, a selective B-RAF inhibitor. However, exposing BRAF-mutant melanoma cells to AZD6244 and PLX4720 in combination prevented emergence of resistant clones. These results affirm the importance of MEK dependency in BRAF-mutant melanoma and suggest novel mechanisms of resistance to MEK and B-RAF inhibitors that may have important clinical implications.BRAF ͉ drug resistance ͉ MAP kinase ͉ melanoma A pproximately one-third of all cancers harbor genetic alterations that aberrantly upregulate mitogen-activated protein kinase (MAPK)-dependent signal transduction (1). In the MAPK pathway, RAS oncoproteins activate RAF, MEK, and ERK kinases to direct key cell proliferative and survival signals. When rendered constitutively active by genetic mutation, the MAP kinase pathway is believed to confer ''oncogene dependency'' (2), an excessive reliance on its dysregulated activity for tumor viability. Therefore, protein kinases within this signaling cascade offer promising targets for novel anticancer therapeutics.In melanoma, uncontrolled MAP kinase pathway activity is nearly ubiquitous and occurs most commonly through gain-offunction mutations involving codon 600 of the B-RAF kinase (3) (BRAF V600E ; 50-70% of cases). Considerable preclinical evidence has associated the BRAF V600E mutation with heightened sensitivity to pharmacologic inhibition of RAF or MEK kinases (4, 5). Although early clinical trials of RAF and MEK inhibitors failed to show a substantial benefit (6, 7), recent phase I studies of selective RAF inhibitors have shown promising results in patients with BRAF-mutant tumors (8, 9). Thus, optimizing therapeutic efficacy while avoiding or bypassing the emergence of resistance to MAP kinase pathway inhibition will likely gain increasing importance in melanoma and other MAP kinasedriven cancers.He...

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mentioning

confidence: 99%

MEK1 mutations confer resistance to MEK and B-RAF inhibition

Emery

Vijayendran

Zipser

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

577

509

View full text Add to dashboard Cite

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“…Systematic search of the literature de-novo: [458,481,483,[486][487][488][489][490][491][492][493][494][495][496][497][498][499][500][501] Strength of consensus: 85 % RCT = randomized clinical trial, Ipi = ipilimumab, gp100 = vaccine, HR = hazard ratio, CI = confidence Interval, vs. = versus, sign. = significant, n.s.…”

Section: Level Of Evidence 1bmentioning

confidence: 99%

Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma”

Pflugfelder

Kochs

Blum

et al. 2013

J Deutsche Derma Gesell

180

148

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“…34 In a phase II trial, oral sorafenib (400 mg twice a day) and IV dacarbazine (1000 mg/m 2 on day 1 of a 21-day cycle) showed a 50% improvement in progression-free survival as compared to placebo plus dacarbazine. 35 However, overall survival was not improved. Additional investigations are ongoing.…”

Section: Fibrohistiocytic Tumorsmentioning

confidence: 99%

Angiogenesis in cutaneous disease: Part II

Laquer

Hoang

Nguyen

et al. 2009

Journal of the American Academy of Dermatology

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This review will discuss the role of angiogenesis in specific cutaneous diseases. Scientific evidence now points to the role of angiogenesis in tumor development and many other cutaneous disorders. Angiogenesis is a complex process that involves angiogenic growth factors and inhibitors, many of which could be a potential target for pharmacologic intervention. Antiangiogenic agents have recently been applied to dermatologic diseases with promising efficacy. ( J Am Acad Dermatol 2009;61:945-58.)Learning objectives: After completing this learning activity, participants should be able to recognize cutaneous diseases where angiogenesis is likely to be an important factor, recognize scenarios where angiogenic therapy may be useful in conjunction with traditional therapies, and be able to use angiogenicmediating agents in the treatment of dermatologic disease.

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Double-Blind Randomized Phase II Study of the Combination of Sorafenib and Dacarbazine in Patients With Advanced Melanoma: A Report From the 11715 Study Group

Abstract: Sorafenib plus dacarbazine was well tolerated in patients with advanced melanoma and yielded an encouraging improvement in PFS. Based on these findings, additional studies with the combination are warranted in this patient population.

Cited by 224 publications

References 30 publications

MEK1 mutations confer resistance to MEK and B-RAF inhibition

MEK1 mutations confer resistance to MEK and B-RAF inhibition

Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma”

Angiogenesis in cutaneous disease: Part II

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