Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC.

Spigel, David R.; Ervin, Thomas J.; Ramlau, Rodryg; Daniel, D. B.; Goldschmidt, Jerome H.; Blumenschein, G. R.; Krzakowski, Maciej; Robinet, G.; Clément-Duchêne, Christelle; Govindan, Ramaswamy; Patel, Taral; Орлов, С. В.; Wertheim, M. S.; Zha, Jiping; Pandita, Ajay; Yu, Wei; Yauch, Robert L.; Patel, Premal H.; Peterson, Amy

doi:10.1200/jco.2011.29.15_suppl.7505

Cited by 160 publications

(140 citation statements)

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“…A global randomized, double-blind phase II study in which investigators compared MetMAb plus erlotinib with placebo plus erlotinib in the second-/third-line treatment of advanced non-small cell lung carcinoma (NSCLC) has been completed recently (10). In the MET-immunohistochemistry (IHC)-positive group (n = 65), MetMAb plus erlotinib resulted in a clinically and statistically significant improvement in both progression-free-survival (median, 2.9 vs. 1.5 months) and overall survival (median, 12.6 vs. 3.8 months).…”

Section: Viewsmentioning

confidence: 99%

Anti-MET Targeted Therapy Has Come of Age: The First Durable Complete Response with MetMAb in Metastatic Gastric Cancer

Yan

Patrick

2011

Cancer Discovery

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The MET/hepatocyte growth factor (HGF) signaling pathway plays important roles in oncogenesis and tumor progression in a variety of human cancers. MET/HGF drives an invasive signaling program that can be dysregulated in human cancers through a number of activating mechanisms, including mutations, overexpression, amplification, alternative splicing, and HGF ligand–induced autocrine/paracrine loop signaling. As a testimony of MET-targeting therapeutics is beginning to come to clinical fruition, Catenacci and colleagues report the first case of durable complete response under an anti-MET receptor monoclonal antibody, MetMAb, in a patient with chemotherapy-refractory, advanced gastric cancer metastatic to the liver, found to have high MET gene polysomy and remarkably high serum HGF level. Serum and tissue studies also revealed predictive biomarkers for therapeutic response to MET inhibition. Cancer Discovery; 1(7); 550–4. ©2011 AACR. Commentary on Catenacci et al., p. 573.

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Section: Viewsmentioning

confidence: 99%

Anti-MET Targeted Therapy Has Come of Age: The First Durable Complete Response with MetMAb in Metastatic Gastric Cancer

Yan

Patrick

2011

Cancer Discovery

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“…7,14,24 The establishment of selection criteria in identifying sub-populations that may benefit from treatment is a key aspect of further development of anti-MET monoclonal antibody (METMab) and hepatocyte growth factor/scatter factor monoclonal antibody treatment. 25 Recently, striking results using the METMab in combination with an EGFR inhibitor (erlotinib) have been reported in patients with non-small cell lung cancer (OAM4558g trial). 25 In that study, METMab increased progression-free survival in patients with high levels of MET expression by immunohistochemistry compared with the group receiving erlotinib alone.…”

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confidence: 99%

“…25 Recently, striking results using the METMab in combination with an EGFR inhibitor (erlotinib) have been reported in patients with non-small cell lung cancer (OAM4558g trial). 25 In that study, METMab increased progression-free survival in patients with high levels of MET expression by immunohistochemistry compared with the group receiving erlotinib alone. 26 Improvement in overall survival has also been reported in patients with advanced gastric adenocarcinoma in which treatment with the hepatocyte growth factor/scatter factor monoclonal antibody AMG102 (also known as rilotumumab) combined with chemotherapy was compared with chemotherapy alone.…”

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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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“…Their study designs are based on preclinical and early clinical response data showing the potential predictive value of specific molecular aberrations. Examples include PIK3CA-activating mutations and loss of PTEN expression and benefit with PI3K pathway inhibitors (15,16), synergistic antitumor activity with combination blockade of mTOR and IGF1R signaling (17,18), RAS/RAF mutations and response to PI3K pathway inhibitors plus MEK inhibitors (19)(20)(21), BRAF mutations linked to antitumor activity of selective BRAF inhibitors (22,23), and MET hyperactivation and benefit with MET/ HGF targeting agents (24,25).…”

Section: Introductionmentioning

confidence: 99%

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

Dienstmann

Serpico

Rodón

et al. 2012

Molecular Cancer Therapeutics

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Clinical experience increasingly suggests that molecular prescreening and biomarker enrichment strategies in phase I trials with targeted therapies will improve the outcomes of patients with cancer. In keeping with the exigencies of a personalized oncology program, tumors from patients with advanced chemorefractory colorectal cancer were analyzed for specific aberrations (KRAS/BRAF/PIK3CA mutations, PTEN and pMET expression). Patients were subsequently offered phase I trials with matched targeted agents (MTA) directed at the identified anomalies. During 2010 and 2011, tumor molecular analysis was conducted in 254 patients: KRAS mutations (80 of 254, 31.5%), BRAF mutations (24 of 196, 12.2%), PIK3CA mutations (15 of 114, 13.2%), KRAS and PIK3CA mutations (9 of 114, 7.9%), low PTEN expression (97 of 183, 53.0%), and high pMET expression (38 of 64, 59.4%). In total, 68 patients received 82 different MTAs: phosphoinositide 3-kinase (PI3K) pathway inhibitor (if PIK3CA mutation, n ¼ 10; or low PTEN, n ¼ 32), PI3K pathway inhibitor plus MEK inhibitor (if KRAS mutation, n ¼ 10; or BRAF mutation, n ¼ 1), second-generation anti-EGF receptor monoclonal antibodies (if wild-type KRAS, n ¼ 11), anti-hepatocyte growth factor monoclonal antibody (if high pMET, n ¼ 10), mTOR inhibitor plus anti-insulin-like growth factor-1 receptor monoclonal antibody (if low PTEN, n ¼ 5), and BRAF inhibitor (if BRAF mutation, n ¼ 3). Median time-to-treatment failure on MTA was 7.9 versus 16.3 weeks for their prior systemic antitumor therapy (P < 0.001). Partial response was seen in 1 patient [1.2%, PI3K inhibitor with PIK3CA mutation] and stable disease >16 weeks in 10 cases (12.2%). These results suggest that matching chemorefractory patients with colorectal cancer with targeted agents in phase I trials based on the current molecular profile does not confer a significant clinical benefit. Mol Cancer Ther; 11(9); 2062-71. Ó2012 AACR.

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Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC.

Cited by 160 publications

References 0 publications

Anti-MET Targeted Therapy Has Come of Age: The First Durable Complete Response with MetMAb in Metastatic Gastric Cancer

Anti-MET Targeted Therapy Has Come of Age: The First Durable Complete Response with MetMAb in Metastatic Gastric Cancer

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

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

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