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Erschienen in: Current Oncology Reports 5/2013

01.10.2013 | Melanoma (KB Kim, Section Editor)

MEK Inhibition in the Treatment of Advanced Melanoma

verfasst von: April K. S. Salama, Kevin B. Kim

Erschienen in: Current Oncology Reports | Ausgabe 5/2013

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Abstract

The RAS-RAF-MEK-ERK pathway is considered to be the most important signal transduction pathway in melanoma, and alterations in this pathway via various genetic mutations, such as BRAF and NRAS mutations, are known to be important drivers of melanomagenesis. As MEK is an essential intermediary kinase protein within this pathway, inhibition of MEK has been of a great interest as a molecular target therapy in melanoma. In fact, trametinib, a selective MEK inhibitor, has been shown to have a survival benefit over cytotoxic chemotherapy in patients with V600 BRAF-mutant metastatic melanoma, leading to the FDA approval for this patient population. MEK inhibitors may also be useful in treatment of advanced melanoma harboring other genetic mutations, such as NRAS and GNAQ/GNA11 mutations. Here, we review and discuss the preclinical and clinical data regarding MEK inhibitors and their role in the treatment of advanced melanoma.
Literatur
1.
Zurück zum Zitat Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199–206.PubMedCrossRef Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199–206.PubMedCrossRef
2.
Zurück zum Zitat Hodi FS, O'Day SJ, McDermott DF, et al. improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.PubMedCrossRef Hodi FS, O'Day SJ, McDermott DF, et al. improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.PubMedCrossRef
3.
Zurück zum Zitat •• Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16. ••This study demonstrated the survival advantage of vemurafenib over dacarbaizine in patients with metastatic melanoma harboring a V600E BRAF mutation.PubMedCrossRef •• Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16. ••This study demonstrated the survival advantage of vemurafenib over dacarbaizine in patients with metastatic melanoma harboring a V600E BRAF mutation.PubMedCrossRef
4.
Zurück zum Zitat • Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–65. This study demonstrated the survival advantage of dabrafenib, a selective BRAF inhibitor, over dacarbazine in patients with metastatic melanoma harboring a V600 BRAF mutation.PubMedCrossRef • Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–65. This study demonstrated the survival advantage of dabrafenib, a selective BRAF inhibitor, over dacarbazine in patients with metastatic melanoma harboring a V600 BRAF mutation.PubMedCrossRef
5.
Zurück zum Zitat Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26:3279–90.PubMedCrossRef Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26:3279–90.PubMedCrossRef
6.
Zurück zum Zitat •• Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54. This is the first report demonstrating the frequency of BRAF mutations and the functional relevance of V600E BRAF mutation in cancer, including melanoma.PubMedCrossRef •• Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54. This is the first report demonstrating the frequency of BRAF mutations and the functional relevance of V600E BRAF mutation in cancer, including melanoma.PubMedCrossRef
7.
Zurück zum Zitat Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135–47.PubMedCrossRef Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135–47.PubMedCrossRef
8.
Zurück zum Zitat Lee JH, Choi JW, Kim YS. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol. 2011;164:776–84.PubMedCrossRef Lee JH, Choi JW, Kim YS. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol. 2011;164:776–84.PubMedCrossRef
9.
Zurück zum Zitat McCubrey JA, Steelman LS, Chappell WH, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta (BBA) - Mol Cell Res. 2007;1773:1263–84.CrossRef McCubrey JA, Steelman LS, Chappell WH, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta (BBA) - Mol Cell Res. 2007;1773:1263–84.CrossRef
10.
Zurück zum Zitat Sharma A, Trivedi NR, Zimmerman MA, et al. Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res. 2005;65:2412–21.PubMedCrossRef Sharma A, Trivedi NR, Zimmerman MA, et al. Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res. 2005;65:2412–21.PubMedCrossRef
11.
Zurück zum Zitat Thomas NE. BRAF somatic mutations in malignant melanoma and melanocytic naevi. Melanoma Res. 2006;16:97–103.PubMedCrossRef Thomas NE. BRAF somatic mutations in malignant melanoma and melanocytic naevi. Melanoma Res. 2006;16:97–103.PubMedCrossRef
12.
Zurück zum Zitat Menzies AM, Haydu LE, Visintin L, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012;18:3242–9.PubMedCrossRef Menzies AM, Haydu LE, Visintin L, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012;18:3242–9.PubMedCrossRef
13.
Zurück zum Zitat Garnett MJ, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell. 2004;6:313–9.PubMedCrossRef Garnett MJ, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell. 2004;6:313–9.PubMedCrossRef
14.
Zurück zum Zitat Wilhelm SM, Carter C, Tang L, et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109.PubMedCrossRef Wilhelm SM, Carter C, Tang L, et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109.PubMedCrossRef
15.
Zurück zum Zitat Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009;27:2823–30.PubMedCrossRef Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009;27:2823–30.PubMedCrossRef
16.
Zurück zum Zitat Amaravadi RK, Schuchter LM, McDermott DF, et al. Phase II Trial of Temozolomide and Sorafenib in Advanced Melanoma Patients with or without Brain Metastases. Clin Cancer Res. 2009;15:7711–8.PubMedCrossRef Amaravadi RK, Schuchter LM, McDermott DF, et al. Phase II Trial of Temozolomide and Sorafenib in Advanced Melanoma Patients with or without Brain Metastases. Clin Cancer Res. 2009;15:7711–8.PubMedCrossRef
17.
Zurück zum Zitat Ott PA, Hamilton A, Min C, et al. A phase II trial of sorafenib in metastatic melanoma with tissue correlates. PLoS One. 2010;5:e15588.PubMedCrossRef Ott PA, Hamilton A, Min C, et al. A phase II trial of sorafenib in metastatic melanoma with tissue correlates. PLoS One. 2010;5:e15588.PubMedCrossRef
18.
Zurück zum Zitat Wilhelm SM, Adnane L, Newell P, et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7:3129–40.PubMedCrossRef Wilhelm SM, Adnane L, Newell P, et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7:3129–40.PubMedCrossRef
19.
Zurück zum Zitat • Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467:596–9. This is a report describing the clinical development and the mechanism of action of vemurafenib.PubMedCrossRef • Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467:596–9. This is a report describing the clinical development and the mechanism of action of vemurafenib.PubMedCrossRef
20.
Zurück zum Zitat Chapman PB, Hauschild A, Robert C et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. J Clin Oncol 30, 2012 (suppl; abstr 8502). Presented at the Amercian Society of Clinical Oncology Annual Meeting. Chicago, IL, USA; June 1–5, 2012. Chapman PB, Hauschild A, Robert C et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. J Clin Oncol 30, 2012 (suppl; abstr 8502). Presented at the Amercian Society of Clinical Oncology Annual Meeting. Chicago, IL, USA; June 1–5, 2012.
21.
Zurück zum Zitat Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–7.PubMedCrossRef Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–7.PubMedCrossRef
22.
Zurück zum Zitat McArthur GA, Ribas A, P. B. Chapman et al. Molecular analyses from a phase I trial of vemurafenib to study mechanism of action (MOA) and resistance in repeated biopsies from BRAF mutation–positive metastatic melanoma patients (pts). J Clin Oncol 29: 2011 (suppl; abstr 8502) 2011. McArthur GA, Ribas A, P. B. Chapman et al. Molecular analyses from a phase I trial of vemurafenib to study mechanism of action (MOA) and resistance in repeated biopsies from BRAF mutation–positive metastatic melanoma patients (pts). J Clin Oncol 29: 2011 (suppl; abstr 8502) 2011.
23.
Zurück zum Zitat Nathanson KL, A. Martin, R. Letrero et al. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor GSK2118436 (GSK436). J Clin Oncol 29: 2011 (suppl; abstr 8501). Nathanson KL, A. Martin, R. Letrero et al. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor GSK2118436 (GSK436). J Clin Oncol 29: 2011 (suppl; abstr 8501).
24.
Zurück zum Zitat Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209–21.PubMedCrossRef Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209–21.PubMedCrossRef
25.
Zurück zum Zitat Montagut C, Sharma SV, Shioda T, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68:4853–61.PubMedCrossRef Montagut C, Sharma SV, Shioda T, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68:4853–61.PubMedCrossRef
26.
Zurück zum Zitat Kaplan FM, Shao Y, Mayberry MM, Aplin AE. Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells. Oncogene. 2011;30:366–71.PubMedCrossRef Kaplan FM, Shao Y, Mayberry MM, Aplin AE. Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells. Oncogene. 2011;30:366–71.PubMedCrossRef
27.
Zurück zum Zitat Emery CM, Vijayendran KG, Zipser MC, et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A. 2009;106:20411–6.PubMedCrossRef Emery CM, Vijayendran KG, Zipser MC, et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A. 2009;106:20411–6.PubMedCrossRef
28.
Zurück zum Zitat Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968–72.PubMedCrossRef Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968–72.PubMedCrossRef
29.
Zurück zum Zitat Trunzer K, Pavlick AC, Schuchter L, et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol. 2013;31:1767–74.PubMedCrossRef Trunzer K, Pavlick AC, Schuchter L, et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol. 2013;31:1767–74.PubMedCrossRef
30.
Zurück zum Zitat •• Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14. This study demonstrated the survival advantage of trametinib over cytotoxic chemotherapeutic drugs in patients with metastatic melanoma harboring a BRAF mutation.PubMedCrossRef •• Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14. This study demonstrated the survival advantage of trametinib over cytotoxic chemotherapeutic drugs in patients with metastatic melanoma harboring a BRAF mutation.PubMedCrossRef
31.
Zurück zum Zitat Lorusso PM, Adjei AA, Varterasian M, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol. 2005;23:5281–93.PubMedCrossRef Lorusso PM, Adjei AA, Varterasian M, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol. 2005;23:5281–93.PubMedCrossRef
32.
Zurück zum Zitat Sebolt-Leopold JS, Dudley DT, Herrera R, et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med. 1999;5:810–6.PubMedCrossRef Sebolt-Leopold JS, Dudley DT, Herrera R, et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med. 1999;5:810–6.PubMedCrossRef
33.
Zurück zum Zitat Allen LF, Sebolt-Leopold J, Meyer MB. CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol. 2003;30:105–16.PubMedCrossRef Allen LF, Sebolt-Leopold J, Meyer MB. CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol. 2003;30:105–16.PubMedCrossRef
34.
Zurück zum Zitat Rinehart J, Adjei AA, Lorusso PM, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol. 2004;22:4456–62.PubMedCrossRef Rinehart J, Adjei AA, Lorusso PM, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol. 2004;22:4456–62.PubMedCrossRef
35.
Zurück zum Zitat Sebolt-Leopold J, Merriman R, Omer C. The biological profile of PD-0325901: a second generation analog of CI-1040 with improved pharmaceutical potential [abstract]. Presented at the American Association for Cancer Research Annual Meeting. Orlando, FL, USA; March 27–31, 2004. Sebolt-Leopold J, Merriman R, Omer C. The biological profile of PD-0325901: a second generation analog of CI-1040 with improved pharmaceutical potential [abstract]. Presented at the American Association for Cancer Research Annual Meeting. Orlando, FL, USA; March 27–31, 2004.
36.
Zurück zum Zitat Brown AP, Carlson TC, Loi CM, Graziano MJ. Pharmacodynamic and toxicokinetic evaluation of the novel MEK inhibitor, PD0325901, in the rat following oral and intravenous administration. Cancer Chemother Pharmacol. 2007;59:671–9.PubMedCrossRef Brown AP, Carlson TC, Loi CM, Graziano MJ. Pharmacodynamic and toxicokinetic evaluation of the novel MEK inhibitor, PD0325901, in the rat following oral and intravenous administration. Cancer Chemother Pharmacol. 2007;59:671–9.PubMedCrossRef
37.
Zurück zum Zitat LoRusso PM, Krishnamurthi SS, Rinehart JJ, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res. 2010;16:1924–37.PubMedCrossRef LoRusso PM, Krishnamurthi SS, Rinehart JJ, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res. 2010;16:1924–37.PubMedCrossRef
38.
Zurück zum Zitat Haura EB, Ricart AD, Larson TG, et al. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2010;16:2450–7.PubMedCrossRef Haura EB, Ricart AD, Larson TG, et al. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2010;16:2450–7.PubMedCrossRef
39.
Zurück zum Zitat Boasberg PD, Redfern CH, Daniels GA, et al. Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. Cancer Chemother Pharmacol. 2011;68:547–52.PubMedCrossRef Boasberg PD, Redfern CH, Daniels GA, et al. Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. Cancer Chemother Pharmacol. 2011;68:547–52.PubMedCrossRef
40.
Zurück zum Zitat Yeh TC, Marsh V, Bernat BA, et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007;13:1576–83.PubMedCrossRef Yeh TC, Marsh V, Bernat BA, et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007;13:1576–83.PubMedCrossRef
41.
Zurück zum Zitat Haass N, Smalley K, Sproesser K et al. The novel MEK1/2 inhibitor AZD6244 (ARRY-142886) inhibits the growth of melanomas harboring the BRAFV600E mutation in vitro and in vivo. Presented at the American Association for Cancer Research Annual Meeting. Los Angeles, CA, USA; April 14–18, 2007. Haass N, Smalley K, Sproesser K et al. The novel MEK1/2 inhibitor AZD6244 (ARRY-142886) inhibits the growth of melanomas harboring the BRAFV600E mutation in vitro and in vivo. Presented at the American Association for Cancer Research Annual Meeting. Los Angeles, CA, USA; April 14–18, 2007.
42.
Zurück zum Zitat • Adjei AA, Cohen RB, Franklin W, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008;26:2139–46. This study evaluated the safety of selumetinib and demonstrated the pharmacokinetic and pharmacodynamic effect of selumetinib for the first time in human.PubMedCrossRef • Adjei AA, Cohen RB, Franklin W, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008;26:2139–46. This study evaluated the safety of selumetinib and demonstrated the pharmacokinetic and pharmacodynamic effect of selumetinib for the first time in human.PubMedCrossRef
43.
Zurück zum Zitat Kirkwood JM, Bastholt L, Robert C, et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18:555–67.PubMedCrossRef Kirkwood JM, Bastholt L, Robert C, et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18:555–67.PubMedCrossRef
44.
Zurück zum Zitat Banerji U, Camidge DR, Verheul HM, et al. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res. 2010;16:1613–23.PubMedCrossRef Banerji U, Camidge DR, Verheul HM, et al. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res. 2010;16:1613–23.PubMedCrossRef
45.
Zurück zum Zitat Patel SP, Lazar AJ, Papadopoulos NE, et al. Clinical responses to selumetinib (AZD6244; ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma. Cancer. 2013;119:799–805.PubMedCrossRef Patel SP, Lazar AJ, Papadopoulos NE, et al. Clinical responses to selumetinib (AZD6244; ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma. Cancer. 2013;119:799–805.PubMedCrossRef
46.
Zurück zum Zitat Middleton MR, Dummer R, Gutzmer R et al. Phase II double-blind, randomized study of selumetinib (SEL) plus dacarbazine (DTIC) versus placebo (PBO) plus DTIC as first-line treatment for advanced BRAF-mutant cutaneous or unknown primary melanoma. J Clin Oncol 31, 2013 (suppl; abstr 9004). Middleton MR, Dummer R, Gutzmer R et al. Phase II double-blind, randomized study of selumetinib (SEL) plus dacarbazine (DTIC) versus placebo (PBO) plus DTIC as first-line treatment for advanced BRAF-mutant cutaneous or unknown primary melanoma. J Clin Oncol 31, 2013 (suppl; abstr 9004).
47.
Zurück zum Zitat Gilmartin AG, Bleam MR, Groy A, et al. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res. 2011;17:989–1000.PubMedCrossRef Gilmartin AG, Bleam MR, Groy A, et al. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res. 2011;17:989–1000.PubMedCrossRef
48.
Zurück zum Zitat • Infante JR, Fecher LA, Falchook GS, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:773–81. This article describes the safety, pharmacokinetic and pharmacodynamic data of trametinib in a phase I study.PubMedCrossRef • Infante JR, Fecher LA, Falchook GS, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:773–81. This article describes the safety, pharmacokinetic and pharmacodynamic data of trametinib in a phase I study.PubMedCrossRef
49.
Zurück zum Zitat • Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:782–9. This article describes preliminary clinical efficacy of trametinib in patients with advanced melanoma harboring various genetic mutations.PubMedCrossRef • Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:782–9. This article describes preliminary clinical efficacy of trametinib in patients with advanced melanoma harboring various genetic mutations.PubMedCrossRef
50.
Zurück zum Zitat •• Kim KB, Lewis K, Pavlick AC et al. A Phase II study of the MEK1/MEK2 inhibitor GSK1120212 in metastatic BRAF V600E or K mutant cutaneous melanoma patients previously treated with or without a BRAF inhibitor. Pigment Cell & Melanoma Research 2011; 24(5):1021 (Abst. LBA 1021–1023). This study reported that the clinical efficacy of trametinib in patients with advanced melanoma harboring V600E/K BRAF mutation who were previously treated with a BRAF inhibitor is only minimal. •• Kim KB, Lewis K, Pavlick AC et al. A Phase II study of the MEK1/MEK2 inhibitor GSK1120212 in metastatic BRAF V600E or K mutant cutaneous melanoma patients previously treated with or without a BRAF inhibitor. Pigment Cell & Melanoma Research 2011; 24(5):1021 (Abst. LBA 1021–1023). This study reported that the clinical efficacy of trametinib in patients with advanced melanoma harboring V600E/K BRAF mutation who were previously treated with a BRAF inhibitor is only minimal.
51.
Zurück zum Zitat Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24:4340–6.PubMedCrossRef Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24:4340–6.PubMedCrossRef
52.
Zurück zum Zitat Winski S, Anderson D, Bouhana K et al. MEK162 (ARRY-162), a Novel MEK 1/2 Inhibitor, Inhibits Tumor Growth Regardless of KRas/Raf Pathway Mutations. Presented at the Proc AACR-NCI-EORTC Symposium on Molecular Targets and Cancer Therapeutics, Berlin, Germany; Nov 16–19 2010. Winski S, Anderson D, Bouhana K et al. MEK162 (ARRY-162), a Novel MEK 1/2 Inhibitor, Inhibits Tumor Growth Regardless of KRas/Raf Pathway Mutations. Presented at the Proc AACR-NCI-EORTC Symposium on Molecular Targets and Cancer Therapeutics, Berlin, Germany; Nov 16–19 2010.
53.
Zurück zum Zitat Bendell J, Papadopoulos K, Jones S et al. A Phase 1 Dose-Escalation Study of MEK Inhibitor MEK162 (ARRY-438162) in Patients with Advanced Solid Tumors [abstr B243]. Presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, San Francisco, CA, USA; Nov 12–15, 2011. Bendell J, Papadopoulos K, Jones S et al. A Phase 1 Dose-Escalation Study of MEK Inhibitor MEK162 (ARRY-438162) in Patients with Advanced Solid Tumors [abstr B243]. Presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, San Francisco, CA, USA; Nov 12–15, 2011.
54.
Zurück zum Zitat •• Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14:249–56. This study demonstrated the clinical efficacy of MEK162 in patients with metastatic melanoma harboring a NRAS or BRAF mutation.PubMedCrossRef •• Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14:249–56. This study demonstrated the clinical efficacy of MEK162 in patients with metastatic melanoma harboring a NRAS or BRAF mutation.PubMedCrossRef
55.
Zurück zum Zitat Wong H, Vernillet L, Peterson A, et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin Cancer Res. 2012;18:3090–9.PubMedCrossRef Wong H, Vernillet L, Peterson A, et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin Cancer Res. 2012;18:3090–9.PubMedCrossRef
56.
Zurück zum Zitat Rosen L, LoRusso P, Ma WW et al. A first-in-human phase 1 study to evaluate the MEK 1/2 inhibitor GDC-0973 administered daily in patients with advanced solid tumors [abstract 4716]. Presented at the American Association for Cancer Research Annual Meeting. Orlando, FL, USA; April 2–6, 2011. Rosen L, LoRusso P, Ma WW et al. A first-in-human phase 1 study to evaluate the MEK 1/2 inhibitor GDC-0973 administered daily in patients with advanced solid tumors [abstract 4716]. Presented at the American Association for Cancer Research Annual Meeting. Orlando, FL, USA; April 2–6, 2011.
57.
Zurück zum Zitat Byron SA, Loch DC, Wellens CL, et al. Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status. Mol Cancer. 2012;11:75.PubMedCrossRef Byron SA, Loch DC, Wellens CL, et al. Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status. Mol Cancer. 2012;11:75.PubMedCrossRef
58.
Zurück zum Zitat Delord J, Houede N, Awada A et al. First-in-human phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the oral MEK-inhibitor AS703026 (two regimens [R]) in patients (pts) with advanced solid tumors [ abstr 2504]. Presented at the Amercian Society of Clinical Oncology Annual Meeting. Chicago, IL, USA; June 4–8, 2010. Delord J, Houede N, Awada A et al. First-in-human phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the oral MEK-inhibitor AS703026 (two regimens [R]) in patients (pts) with advanced solid tumors [ abstr 2504]. Presented at the Amercian Society of Clinical Oncology Annual Meeting. Chicago, IL, USA; June 4–8, 2010.
59.
Zurück zum Zitat Infante JR, G. S. Falchook, D. P. Lawrence et al. Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436) [abstr CRA8503]. Presented at the Amercian Society of Clinical Oncology Annual Meeting. Chicago, IL, USA; June 3–7, 2011. Infante JR, G. S. Falchook, D. P. Lawrence et al. Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436) [abstr CRA8503]. Presented at the Amercian Society of Clinical Oncology Annual Meeting. Chicago, IL, USA; June 3–7, 2011.
60.
Zurück zum Zitat •• Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703. This article describes the reduced frequency of the development of cutaneous squamous cell carcinoma/keratoacanthoma and the superior clinical efficacy of the combination of a BRAF inhibitor and a MEK inhibitor over a BRAF inhibitor alone.PubMedCrossRef •• Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703. This article describes the reduced frequency of the development of cutaneous squamous cell carcinoma/keratoacanthoma and the superior clinical efficacy of the combination of a BRAF inhibitor and a MEK inhibitor over a BRAF inhibitor alone.PubMedCrossRef
61.
Zurück zum Zitat Ribas A, Lewis K, Pavlick AC et al. Results of phase 1B combined BRAF and MEK inhibition with vemurafenib (vem) and GDC-0973 in patients (pts) with BRAFV600 advanced melanoma and establishing a phase III dose. Pigment Cell Melanoma Res 25:881 (abstract). Presented at the Society for Melanoma Research 2012 Congress. Hollywood, CA, United States; November 8–11, 2012. Ribas A, Lewis K, Pavlick AC et al. Results of phase 1B combined BRAF and MEK inhibition with vemurafenib (vem) and GDC-0973 in patients (pts) with BRAFV600 advanced melanoma and establishing a phase III dose. Pigment Cell Melanoma Res 25:881 (abstract). Presented at the Society for Melanoma Research 2012 Congress. Hollywood, CA, United States; November 8–11, 2012.
62.
Zurück zum Zitat Catalanotti F, Solit DB, Pulitzer MP et al. Phase II Trial of MEK Inhibitor Selumetinib (AZD6244, ARRY-142886) in Patients with BRAFV600E/K-Mutated Melanoma. Clin Cancer Res 2013. Catalanotti F, Solit DB, Pulitzer MP et al. Phase II Trial of MEK Inhibitor Selumetinib (AZD6244, ARRY-142886) in Patients with BRAFV600E/K-Mutated Melanoma. Clin Cancer Res 2013.
63.
Zurück zum Zitat Meng J, Dai B, Fang B, et al. Combination treatment with MEK and AKT inhibitors is more effective than each drug alone in human non-small cell lung cancer in vitro and in vivo. PLoS One. 2010;5:e14124.PubMedCrossRef Meng J, Dai B, Fang B, et al. Combination treatment with MEK and AKT inhibitors is more effective than each drug alone in human non-small cell lung cancer in vitro and in vivo. PLoS One. 2010;5:e14124.PubMedCrossRef
64.
Zurück zum Zitat Kwong LN, Costello JC, Liu H, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med. 2012;18:1503–10.PubMedCrossRef Kwong LN, Costello JC, Liu H, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med. 2012;18:1503–10.PubMedCrossRef
65.
Zurück zum Zitat Singh AD, Topham A. Incidence of uveal melanoma in the United States: 1973–1997. Ophthalmology. 2003;110:956–61.PubMedCrossRef Singh AD, Topham A. Incidence of uveal melanoma in the United States: 1973–1997. Ophthalmology. 2003;110:956–61.PubMedCrossRef
66.
Zurück zum Zitat Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599–602.PubMedCrossRef Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599–602.PubMedCrossRef
67.
Zurück zum Zitat Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363:2191–9.PubMedCrossRef Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363:2191–9.PubMedCrossRef
68.
Zurück zum Zitat Carvajal RD, Sosman JA, Quevedo F, Milhem MM, Joshua AM, Kudchadkar RR, et al. Phase II study of selumetinib versus temozolomide in gnaq/Gna11 mutant uveal melanoma. J Clin Oncol. 2013;31 Suppl; abstr CRA9003. Carvajal RD, Sosman JA, Quevedo F, Milhem MM, Joshua AM, Kudchadkar RR, et al. Phase II study of selumetinib versus temozolomide in gnaq/Gna11 mutant uveal melanoma. J Clin Oncol. 2013;31 Suppl; abstr CRA9003.
Metadaten
Titel
MEK Inhibition in the Treatment of Advanced Melanoma
verfasst von
April K. S. Salama
Kevin B. Kim
Publikationsdatum
01.10.2013
Verlag
Springer US
Erschienen in
Current Oncology Reports / Ausgabe 5/2013
Print ISSN: 1523-3790
Elektronische ISSN: 1534-6269
DOI
https://doi.org/10.1007/s11912-013-0336-2

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