A Phase II Study of PD-0325901, an Oral MEK Inhibitor, in Previously Treated Patients with Advanced Non–Small Cell Lung Cancer

Haura, Eric B.; Ricart, Alejandro D.; Larson, Timothy; Stella, Philip J.; Bazhenova, Lyudmila; Miller, Vincent A.; Cohen, Roger B.; Eisenberg, Peter D.; Selaru, Paulina; Wilner, Keith D.; Gadgeel, Shirish M.

doi:10.1158/1078-0432.ccr-09-1920

Cited by 215 publications

(158 citation statements)

References 26 publications

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“…However, a phase II clinical trial in advanced non-small cell lung cancer was negative for its primary endpoint, with no patients achieving partial or complete responses (23,24). These studies highlight the possibility that MEK inhibitors, as with PI3K pathway inhibitors, may need to be developed with alternate scheduling, appropriate patient selection criteria, or be combined with other rationally determined inhibitors to be clinically successful.…”

Section: Discussionmentioning

confidence: 99%

“…One limitation of the clinical development of PD-0325901 is that prolonged exposure can cause diarrhea and ocular toxicity (23)(24)(25); therefore, using the compound at a minimally effective dose rather than the maximum-tolerated dose may improve tolerability. This schedule was well tolerated, causing no weight loss over the treatment period (data not shown).…”

Section: Combined Inhibition Of Pi3k/mtor (Pf-04691502) and Mek (Pd-0mentioning

confidence: 99%

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In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

Kinross

Brown

Kleinschmidt

et al. 2011

Molecular Cancer Therapeutics

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The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is commonly dysregulated in human cancer, making it an attractive target for novel anticancer therapeutics. We have used a mouse model of ovarian cancer generated by Kras G12D activation and Pten deletion in the ovarian surface epithelium for the preclinical assessment of a novel PI3K/mTOR inhibitor PF-04691502. To enable higher throughput studies, we developed an orthotopic primary transplant model from these mice and evaluated therapeutic response to PF-04691502 using small-animal ultrasound and FDG-PET imaging. PF-04691502 inhibited tumor growth at 7 days by 72% AE 9. FDG-PET imaging revealed that PF-04691502 reduced glucose metabolism dramatically, suggesting FDG-PET may be exploited as an imaging biomarker of target inhibition by PF-04691502. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), were also dramatically inhibited following PF-04691502 treatment. However, as a single agent, PF-04691502 did not induce tumor regression and the long-term efficacy was limited, with tumor proliferation continuing in the presence of drug treatment. We hypothesized that tumor progression was because of concomitant activation of the mitogenactivated protein kinase pathway downstream of Kras G12D expression promoting cell survival and that the therapeutic effect of PF-04691502 would be enhanced by combinatory inhibition of MEK using PD-0325901. This combination induced striking tumor regression, apoptosis associated with upregulation of Bim and downregulation of Mcl-1, and greatly improved duration of survival. These data suggest that contemporaneous MEK inhibition enhances the cytotoxicity associated with abrogation of PI3K/mTOR signaling, converting tumor growth inhibition to tumor regression in a mouse model of ovarian cancer driven by PTEN loss and mutant K-Ras.

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Section: Discussionmentioning

confidence: 99%

Section: Combined Inhibition Of Pi3k/mtor (Pf-04691502) and Mek (Pd-0mentioning

confidence: 99%

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

Kinross

Brown

Kleinschmidt

et al. 2011

Molecular Cancer Therapeutics

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“…[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.…”

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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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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“…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%

“…Combination therapy with trametinib/dabrafenib and cobimetinib/vemurafenib for the treatment of BRAF-mutation positive melanoma has been shown to improve overall survival, and both these combinations are now licensed [8,12,27]. It has been suggested that resistance to MEK inhibition may occur via up regulation of AKT signalling and that combination therapy with both MEK and PI3K inhibitors may be beneficial [24,26], and investigations into this combination therapy continue [28]. The use of MEK inhibitors in combination with docetaxel has been investigated in phase II studies in melanoma [29] and NSCLC with indications that KRAS mutant NSCLC may be sensitive to the combination [30] and a phase III trial is underway to test the efficacy of the combination [31].…”

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 Study of PD-0325901, an Oral MEK Inhibitor, in Previously Treated Patients with Advanced Non–Small Cell Lung Cancer

Cited by 215 publications

References 26 publications

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

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

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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