Phase I Trial of a Selective c-MET Inhibitor ARQ 197 Incorporating Proof of Mechanism Pharmacodynamic Studies

Yap, Timothy A.; Olmos, David; Brunetto, André T.; Tunariu, Nina; Barriuso, Jorge; Riisnaes, Ruth; Pope, Lorna; Clark, J. W.; Futreal, Andrew; Germuska, Michael; Collins, David; deSouza, Nandita M.; Leach, Martin O.; Savage, Ronald E.; Waghorne, Carol; Chai, Feng; Garmey, Edward G.; Schwartz, Brian; Kaye, Stan B.; Bono, Johann S. de

doi:10.1200/jco.2010.31.0367

Cited by 175 publications

(157 citation statements)

References 36 publications

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“…An important issue relevant to the development of c-MET inhibitors is the identification of a molecular profile predictive [Schiller et al 2010]. Prior to this study, a phase I trial showed that 27% (14 out of 51 patients) of patients had stable disease for over 4 months [Yap et al 2011]. Based on these results, tivantinib has entered a randomized, double-blind, placebo-controlled phase III study in previously treated patients with metastatic NSCLC [DeJager, 2010].…”

Section: Plexins: Modulators Of C-met Activationmentioning

confidence: 99%

c-MET as a potential therapeutic target and biomarker in cancer

2011

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Abstract:The receptor tyrosine kinase c-MET and its ligand, hepatocyte growth factor (HGF), regulate multiple cellular processes that stimulate cell proliferation, invasion and angiogenesis. This review provides an overview of the evidence to support c-MET or the HGF/c-MET signaling pathway as relevant targets for personalized cancer treatment based on high frequencies of c-MET and/or HGF overexpression, activation, amplification in non-small cell lung carcinoma (NSCLC), gastric, ovarian, pancreatic, thyroid, breast, head and neck, colon and kidney carcinomas. Additionally, the current knowledge of small molecule inhibitors (tivantinib [ARQ 197]), c-MET/HGF antibodies (rilotumumab and MetMAb) and mechanisms of resistance to c-MET-targeted therapies are discussed.

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Section: Plexins: Modulators Of C-met Activationmentioning

confidence: 99%

c-MET as a potential therapeutic target and biomarker in cancer

2011

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confidence: 99%

“…3 One potential target in gastric cancer was identified as MET proto-oncogene (hepatocyte growth factor receptor) in preclinical studies. 1,4 As mutations in the kinase domain of MET gene are almost lacking in gastric carcinomas, 5 its activation has been mostly attributed to gene amplification. [6][7][8] Although earlier Japanese reports described MET gene amplification in approximately 20% of gastric cancers by comparative genomic in situ hybridization or southern blot analysis, [9][10][11][12][13] recent FISH analyses showed rare or no amplification in locally advanced gastric carcinomas.…”

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MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas

et al. 2013

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The establishment of better selection criteria for identifying sub-populations that may benefit from treatment is a key aspect of the development and success of targeted therapy. To investigate methods for assessing MET overexpression in gastric cancer, we conducted immunohistochemistry using a new anti-Total MET monoclonal antibody in a single-institution cohort of 495 patients. As antibody is directed against a membranous and/or cytoplasmic epitope, two interpretation methods were used: (1) membranous and cytoplasmic and (2) membranous alone. In selected 120 cases, copy number gain and mRNA expression levels were measured using quantitative real-time PCR. Further in situ hybridization confirmed the presence of MET gene amplification. Among the 495 gastric cancers, simultaneous membranous and cytoplasmic overexpression of MET was found in 108 cases (21.8%) and membranous alone overexpression was observed in 40 cases (8.1%). The highest correlation was observed in membranous and cytoplasmic staining of MET: MET expression scores correlated significantly with high MET mRNA levels (r ¼ 0.465, Po0.0001), increased copy number gain (r ¼ 0.393, P ¼ 0.000002) and amplification of MET gene. Moreover, patients with MET overexpression showed shorter overall survival (HR, 1.781; 95% CI, 1.324-2.395; Po0.001) and disease-free survival (HR, 1.765; 95% CI, 1.227-2.541; P ¼ 0.002) compared with patients without MET overexpression. However, membranous overexpression of MET did not highly correlate with mRNA level (r ¼ 0.274, P ¼ 0.002), copy number gain or survival (P40.05). We developed highly correlating interpretation methods of MET immunohistochemistry in gastric carcinomas. MET overexpression is an independent prognostic factor and could be a potential target and predictor of benefit for targeted therapy with MET inhibitors. Recently, the addition of trastuzumab to standard cytotoxic chemotherapy demonstrated significant survival benefit in HER2-positive gastric carcinomas. 2 Nevertheless, HER2 is positive in only a small portion of gastric cancer patients (7-20%); thus, more precise molecular segmentation is urgently needed. 3 One potential target in gastric cancer was identified as MET proto-oncogene (hepatocyte growth factor receptor) in preclinical studies. 1,4 As mutations in the kinase domain of MET gene are almost lacking in gastric carcinomas, 5 its

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“…As illustrated in Table 1, PD endpoints may include assessments of protein phosphorylation markers, measures of cellular proliferation/apoptosis, cell-cycle regulation biomarkers, and epigenetic changes (17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

Section: Serial Tumor Biopsiesmentioning

confidence: 99%

Pharmacodynamic Biomarkers: Falling Short of the Mark?

Gainor

Longo

Chabner

2014

Clinical Cancer Research

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In recent years, the clinical development of targeted therapies has been advanced by a greater understanding of tumor biology and genomics. Nonetheless, drug development remains a slow and costly process. An additional challenge is that targeted therapies may benefit only a subset of patients treatedtypically those patients whose tumors are dependent on the target of interest. Thus, there is a growing need for the incorporation of both predictive and pharmacodynamic (PD) biomarkers in drug development. Predictive biomarkers are important to help guide patient selection, while PD biomarkers can provide information on the pharmacologic effects of a drug on its target. PD studies may provide insights into proof of mechanism (i.e., Does the agent hit its intended target?) and proof of concept (i.e., Does hitting the drug target result in the desired biologic effect?). PD studies may also provide information on the optimal biologic dosing or scheduling of a targeted agent. Herein, we review PD endpoints in the context of targeted drug development in non-small cell lung cancer, highlighting some of the key challenges encountered to date. In doing so, we discuss recent experiences with repeat tumor biopsies, surrogate tissue analysis, alternative clinical trial designs (e.g., window-of-opportunity trials), circulating biomarkers, and mechanism-based toxicity assessments. The application of such technologies and biomarkers in early clinical trials may facilitate rational drug development, while enhancing our understanding of why certain targeted therapies succeed or fail.

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Phase I Trial of a Selective c-MET Inhibitor ARQ 197 Incorporating Proof of Mechanism Pharmacodynamic Studies

Abstract: ARQ 197 safely inhibited intratumoral c-MET signaling. Further clinical evaluation focusing on combination approaches, including an erlotinib combination in non-small-cell lung cancer, is ongoing.

Cited by 175 publications

References 36 publications

c-MET as a potential therapeutic target and biomarker in cancer

c-MET as a potential therapeutic target and biomarker in cancer

MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas

Pharmacodynamic Biomarkers: Falling Short of the Mark?

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