Randomized Phase II Trial of Onartuzumab in Combination With Erlotinib in Patients With Advanced Non–Small-Cell Lung Cancer

Spigel, David R.; Ervin, Thomas J.; Ramlau, Rodryg; Daniel, Davey B.; Goldschmidt, Jerome H.; Blumenschein, George R.; Krzakowski, Maciej; Robinet, G.; Godbert, B.; Barlési, Fabrice; Govindan, Ramaswamy; Patel, Taral; Орлов, С. В.; Wertheim, M. S.; Yu, Wei; Zha, Jiping; Yauch, Robert L.; Patel, Premal H.; Phan, See; Peterson, Amy

doi:10.1200/jco.2012.47.4189

Cited by 449 publications

(408 citation statements)

References 18 publications

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“…This statement was evidence based and supported by 7 studies, 107e113 comprising 1 MA, 107 1 phase II randomized controlled trial, 109 1 PCS, 110 and 4 RCSs. 108,111e113 All included studies were assessed for quality and none were found to have methodologic flaws that would raise concerns about the studies' finding (SDC Table 18).…”

Section: Lindeman Et Al 140mentioning

confidence: 89%

“…107 A frequently used commercially available antibody, particularly in clinical trials, is the CONFIRM anti-total MET (SP44) rabbit monoclonal primary antibody (Ventana Medical Systems, Tucson, Arizona) directed against a membranous and cytoplasmic epitope of MET. 109 At the time of publication, it remains unclear whether total MET or phosphoMET protein overexpression represents a reliable indicator of MET activation. Both MET IHC and FISH are not predictive of efficacy of onartuzumab combined with erlotinib in advanced NSCLC patients.…”

Section: Lung Cancer Molecular Testing Guideline Updatementioning

confidence: 99%

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Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

Aung

Donald

Ellison

et al. 2014

The Journal of Molecular Diagnostics

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Context: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. Objective: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update. Design: The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. Results: Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. Conclusions: The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of

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Section: Lindeman Et Al 140mentioning

confidence: 89%

Section: Lung Cancer Molecular Testing Guideline Updatementioning

confidence: 99%

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

Aung

Donald

Ellison

et al. 2014

The Journal of Molecular Diagnostics

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“…Recently, the need for biomarkers when targeting the HGF/cMET pathway has become apparent, with the finding that patients with NSCLC with low Met expression do worse when receiving onartuzumab (a monoclonal antibody targeting Met) + erlotinib than erlotinib + placebo [95]. It was proposed by Spigel and colleagues that abstract 4005).…”

Section: A Requirement For Biomarkersmentioning

confidence: 99%

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

Moran-Jones

2016

Mol Diagn Ther

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Survival rates for ovarian cancer have remained relatively stable for the past two decades, despite advances in surgical techniques and cytotoxic chemotherapeutics, indicating a requirement for better therapies. One pathway currently proposed for targeting is the HGF/cMET pathway. Up-regulated in a number of tumour types, cMET is a tyrosine kinase receptor expressed on epithelial cells. In ovarian cancer, it has been identified as highly expressed in the four major subtypes, with expression estimates ranging from 11-68% of cases. HGF, the only known ligand for cMET, is found at high levels in both serum and ascites in women with ovarian cancer, and proposed to induce both migration and metastasis. However, clinically validated biomarkers are not yet available for either HGF or cMET, preventing a clear understanding of the true rate of over-expression, or its correlation with prognosis.

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“…Clinical development of onartuzumab was pursued in NSCLC before gastric cancer. A randomized phase II trial with relapsed NSCLC patients revealed that onartuzumab together with the EGFR TKI erlotinib conferred a better PFS and OS compared with erlotinib alone in MET-positive cases, which were defined prospectively as those in which more than 50 % of tumor cells were positive for MET expression by immunohistochemistry [58]. In contrast, a detrimental effect of the combination therapy compared with erlotinib alone was observed in MET-negative patients.…”

Section: Targeting Of the Hgf-met Axis By Monoclonal Antibodiesmentioning

confidence: 99%

MET-targeted therapy for gastric cancer: the importance of a biomarker-based strategy

Kawakami

Okamoto

2015

Gastric Cancer

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The MET protooncogene encodes the receptor tyrosine kinase c-MET (MET). Aberrant activation of MET signaling occurs in a subset of advanced malignancies, including gastric cancer, and promotes tumor cell growth, survival, migration, and invasion as well as tumor angiogenesis, suggesting its potential importance as a therapeutic target. MET can be activated by two distinct pathways that are dependent on or independent of its ligand, hepatocyte growth factor (HGF), with the latter pathway having been attributed mostly to MET amplification in gastric cancer. Preclinical evidence has suggested that interruption of the HGF-MET axis either with antibodies to HGF or with MET tyrosine kinase inhibitors (TKIs) has antitumor effects in gastric cancer cells. Overexpression of MET occurs frequently in gastric cancer and has been proposed as a potential predictive biomarker for anti-MET therapy. However, several factors can trigger such MET upregulation in a manner independent of HGF, suggesting that gastric tumors with MET overexpression are not necessarily MET driven. On the other hand, gastric cancer cells with MET amplification are dependent on MET signaling for their survival and are thus vulnerable to MET TKI treatment. Given the low prevalence of MET amplification in gastric cancer (approximately 8 %), testing for this genetic change would substantially narrow the target population but it might constitute a better biomarker than MET overexpression for MET TKI therapy. We compare aberrant MET signaling dependent on the HGF-MET axis or on MET amplification as well as address clinical issues and challenges associated with the identification of appropriate biomarkers for MET-driven tumors.

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Randomized Phase II Trial of Onartuzumab in Combination With Erlotinib in Patients With Advanced Non–Small-Cell Lung Cancer

Abstract: Onartuzumab plus erlotinib was associated with improved PFS and OS in the MET-positive population. These results combined with the worse outcomes observed in MET-negative patients treated with onartuzumab highlight the importance of diagnostic testing in drug development.

Cited by 449 publications

References 18 publications

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

MET-targeted therapy for gastric cancer: the importance of a biomarker-based strategy

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