A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens

Bennouna, Jaafar; Láng, István; Valladares‐Ayerbes, Manuel; Boér, Katalin; Adenis, Antoine; Escudero, P.; Kim, Tae You; Pover, G.; Morris, Clive; Douillard, Jean Yves

doi:10.1007/s10637-010-9392-8

Cited by 120 publications

(103 citation statements)

References 18 publications

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“…[18][19][20][21][22][23] Further, AZD6244 is a noncompetitive MEK inhibitor with preclinical antitumor activity in solid tumor models including hepatocellular, colon, myeloma, thyroid, pancreatic, melanoma, and breast cancers 19,20,41 and tested clinically in phase 1 24 and phase 2 trials of advanced, refractory colorectal, melanoma, and lung cancer. [25][26][27] AZD6244 has been examined in leukemia and myeloma models, [42][43][44] however to our knowledge, has never been tested in lymphoma.…”

Section: Discussionmentioning

confidence: 99%

“…[18][19][20][21][22][23] Furthermore, phase 1 and phase 2 solid tumor clinical trials have shown this agent to be well-tolerated and have encouraging clinical efficacy. [24][25][26][27] To our knowledge, minimal data are available on newer generation MEK inhibitors in lymphoma and moreover, this anti-MEK agent has never been examined in lymphoma. We sought to examine the mechanisms of action and cytotoxic effect of the novel 2nd generation MEK small molecule antagonist, AZD6244, in lymphoma cell lines, primary cells, and an in vivo human DLBCL xenograft model.…”

Section: Introductionmentioning

confidence: 99%

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The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

Bhalla

Evens

Dai

et al. 2011

Blood

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IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults accounting for nearly 35% of all non-Hodgkin lymphomas (NHL). Significant advances have been in the treatment of DLBCL, particularly with immunochemotherapy, however approximately 30%-40% of patients still die from this malignancy. In addition, short-and long-term toxicities of chemotherapy, including secondary malignancies and leukemias, continue to adversely impact the long-term prognosis of patients. Continued investigations of novel targeted therapeutic agents in DLBCL are warranted.The RAS/RAF/mitogen-activated protein kinase 1/2 (MEK1/2)/ extracellular signal-regulated kinase 1/2 (ERK1/2) plays a prominent role in cancer biology, including hematologic malignancies, in part through the regulation of cell growth and proliferation. [1][2][3][4][5] Activating mutations in RAS and RAF lead to aberrant activation of their downstream target, MEK1/2. Directly downstream of MEK1/2, ERK1 and ERK2 are intimately involved in transducing signals from growth factor receptors and cytokine receptors after ligand binding. 2 Furthermore, ERK is the only known catalytic substrate of MEK. 6 We and others have shown that the MEK/ERK signaling pathway is constitutively active in a large number of cancers, including hematologic malignancies. 3,4,[7][8][9] Moreover, the MEK/ERK signal transduction cascade has been shown to be susceptible to pharmacologic intervention. Thus, MEK has emerged as an attractive therapeutic target in cancer.The majority of preclinical, and especially clinical trial data studying MEK inhibitors to date have emerged largely from solid tumor studies. [10][11][12][13][14] We recently showed in preclinical studies that inhibition of ERK1/2 phosphorylation by 1st generation MEK and ERK inhibitors correlated with significant cell death in a lymphoma tumor model, 15 while others showed that sublethal concentrations of a 1st generation MEK antagonist potentiated the effect of sorafemib in lymphoma cells. 16 Furthermore, we recently demonstrated that MCT-1, an oncogene directly downstream of MEK/ ERK, is over-expressed in the majority of primary DLBCLs. 15 MCT-1 is known to colocalize with ERK1/2, while phosphorylation of MCT-1 protein by ERK is critical for stabilization of MCT-1 protein and for its functional ability to promote cell proliferation. 15,17 ARRY-142886 (AZD6244, selumetinib; Astra Zeneca) is a selective nonATP-competitive 2nd generation oral MEK inhibitor studied primarily in solid tumor studies with reported nanomolar activity against purified MEK1 enzyme. [18][19][20][21][22][23] Furthermore, phase 1 and phase 2 solid tumor clinical trials have shown this agent to be well-tolerated and have encouraging clinical efficacy. [24][25][26][27] To our knowledge, minimal data are available on newer generation MEK inhibitors in lymphoma and moreover, this anti-MEK agent has never been examined in lymphoma. We sought to examine the mechanisms of action and cytotoxic effect of the novel 2nd generation MEK sma...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

Bhalla

Evens

Dai

et al. 2011

Blood

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“…5, 6 Inhibitors of MEK have demonstrated efficacy against malignant tumors characterized by mutations in either RAS or Raf in preclinical models, and early development candidates including GSK1120212, 7 AZD6244, 8 and PD0325901 (2) 9 have further demonstrated evidence of activity in the clinical setting as well.…”

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confidence: 99%

Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973)

Rice

Aay

Anand

et al. 2012

ACS Med. Chem. Lett.

134

108

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The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials. KEYWORDS: MAPK pathway, MEK, cancer, kinase inhibitor, XL518, GDC-0973 T he MAPK cascade, or mitogen-activated protein kinase signal transduction pathway, is a mechanism commonly subject to dysregulation in cancer, and constitutive or highly upregulated signaling is a frequent hallmark of oncogenic transformation and progression. Controlled by activation of RAS at the cell surface interior, the subsequent stimulation of Raf and then MEK and ERK serves to regulate a range of key intracellular effectors associated with cell proliferation, 1 invasion, 2 angiogenesis, 3 and apoptotic resistance. 4 Mutated RAS is associated with almost one-third of human cancers, and a majority of malignant melanomas and papillary thyroid cancers harbor B-Raf mutations. 5,6 Inhibitors of MEK have demonstrated efficacy against malignant tumors characterized by mutations in either RAS or Raf in preclinical models, and early development candidates including GSK1120212, In some tumors, activation of both the RAS driven ERK/ MAPK cascade and the PI3K-Akt pathway is observed, resulting in degenerate and convergent oncogenic signals, and upregulation or constitutive PI3K pathway activation is associated with resistance to MEK inhibitor single agent treatment.10 Several combination approaches using inhibitors of mTor, PI3K, Akt, and Raf have more recently been validated in preclinical models and are being pursued clinically. Herein, the discovery of XL518 (GDC-0973) (1), a potent and selective MEK inhibitor, is described. XL518 is currently in early stage clinical testing as both a single agent and in combination with the class I PI3K inhibitor GDC-0941. 11Our goal at the outset was the identification of a potent and selective MEK inhibitor with sustained duration of efficacy suitable for qd dosing and an optimized safety profile relative to clinical precursors. The diphenylamine series disclosed by the Pfizer/Warner Lambert groups served as a starting point for our effort. A key aspect tha...

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“…Phase II and III trials of single agent trametinib have suggested efficacy in patients with BRAF-mutated melanoma who had not received previous BRAF inhibitor therapy [6] but not in those patients resistant to BRAF inhibition. In contrast, a series of phase II studies of other MEK inhibitors have shown limited evidence of efficacy in numerous settings, including treatment of cancers with high known incidence of dysregulated MAPK signalling [21][22][23][24][25] and selection of individuals with known BRAF-mutated tumours [26]. It is, therefore, likely that this class of agents will be used in rationally chosen combination therapy.…”

Section: Discussionmentioning

confidence: 99%

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

Jamieson

Griffin

Sludden

et al. 2016

European Journal of Cancer

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A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens

Abstract: AZD6244 showed similar efficacy to capecitabine in terms of the number of patients with a disease progression event and of progression-free survival. AZD6244 is currently undergoing evaluation in Phase II trials in combination with other chemotherapeutic agents.

Cited by 120 publications

References 18 publications

The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973)

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

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