METGastric: A phase III study of onartuzumab plus mFOLFOX6 in patients with metastatic HER2-negative (HER2-) and MET-positive (MET+) adenocarcinoma of the stomach or gastroesophageal junction (GEC).

Shah, Manish A.; Bang, Yung‐Jue; Lordick, Florian; Tabernero, Josep; Chen, Meng; Hack, Stephen P.; Phan, See‐Chun; Shames, David S.; Cunningham, David

doi:10.1200/jco.2015.33.15_suppl.4012

Cited by 85 publications

(61 citation statements)

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“…The validity of MET as a therapeutic target in EGC has been questioned based on recent negative Phase III studies targeting this pathway in EGC(9, 10). However, these studies were not conducted specifically in the MET -amplified EGC population, and the majority of patients treated had MET protein overexpression only.…”

Section: Discussionmentioning

confidence: 99%

“…MET encodes a receptor tyrosine kinase (RTK), which is typically activated by its ligand, hepatocyte growth factor (HGF), and signals through downstream pathways involved in oncogenesis(8). Although clinical efforts to target the MET pathway in EGC patients harboring MET protein overexpression have yielded disappointing results(9, 10), there is evidence that MET -amplification (as opposed to protein overexpression only) may be a true oncogenic driver in EGC. MET -amplified EGC cell lines display exquisite sensitivity to MET inhibitors(11), and patients with MET -amplified EGC have experienced tumor shrinkage after treatment with small molecule MET inhibitors or monoclonal antibodies against MET(12, 13).…”

Section: Introductionmentioning

confidence: 99%

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Molecular Heterogeneity and Receptor Coamplification Drive Resistance to Targeted Therapy inMET-Amplified Esophagogastric Cancer

et al. 2015

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MET inhibition is effective in some MET-amplified esophagogastric cancer (EGC) patients, but understanding acquired and de novo resistance mechanisms will be critical to improving therapy. We identified KRAS mutation as a novel cause of acquired resistance in a patient after a two-year response to MET inhibitor. We also observed that 40–50% of MET-amplified EGC patients harbor co-amplification of HER2 and/or EGFR concurrently in the same tumor cells, which can drive de novo resistance. One patient with concurrent MET and HER2-amplification was refractory to HER2 blockade, but responded to combined MET/HER2 inhibition. We also found striking heterogeneity in MET-amplification between distinct metastatic lesions and primary tumors in individual EGC patients. In these patients, MET inhibition led to mixed responses and disease progression through outgrowth of non-MET-amplified clones, which could be monitored in circulating tumor DNA. Thus, receptor co-amplification and molecular heterogeneity may be key drivers of clinical resistance in MET-amplified EGC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Heterogeneity and Receptor Coamplification Drive Resistance to Targeted Therapy inMET-Amplified Esophagogastric Cancer

et al. 2015

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“…On the other hand, despite early evidence of predictive value of anti-Met therapy for tumors that overexpress Met (irrespective of GCN/amplification status), 21,23 two recent phase III trials, RILOMET-1 (with rilotumumab anti-HGF antibody) and METGastric (with onartuzumab anti-Met antibody), both failed to meet their primary endpoints in “Met-positive” patients, as determined by two different IHC methods. 26,37 Although it is quite plausible that Met inhibition, in the setting of Met overexpression lacking amplification, is not sufficient to improve outcome (i.e., a negative prognostic biomarker is not by default also a positive predictive biomarker to a targeted therapy), there is also potential that the positivity criteria was too lenient. The phase I patient that responded to onartuzumab monotherapy, 23 was later found to have expression at 526.93 amol/ug.…”

Section: Discussionmentioning

confidence: 99%

MET tyrosine kinase receptor expression and amplification as prognostic biomarkers of survival in gastroesophageal adenocarcinoma

Catenacci

Ang

Liao³

et al. 2016

Cancer

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Background MET gene amplification and Met protein overexpression may be associated with poor prognosis. MET/Met status is typically determined with fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Targeted proteomics uses mass spectrometry-based selected-reaction-monitoring (SRM) to accurately quantitate Met expression. FISH, IHC, and SRM analyses were compared to characterize the prognostic value of MET/Met in gastroesophageal adenocarcinoma (GEC). Methods Samples from 447 GEC patients were analyzed for MET gene amplification (FISH) and Met protein expression (IHC and SRM). Cox proportional hazards models and Kaplan-Meier estimates were applied to explore relationships between Met, overall survival (OS) and clinical/pathologic characteristics. Spearman’s rank coefficient assessed the correlation between parameters. Results Patients with MET-amplified tumors had worse OS (MET/CEP7 FISH ratio ≥2 (hazard ratio [HR] 3.13; 95% CI 1.84-5.33), MET gene copy number ≥5 (HR 2.51; 95% CI 1.45-4.34), or ≥10% of cells ≥15 copies (HR 4.28; 95% CI 2.18-8.39). Similar observations were made with Met protein overexpression, by IHC (≥25% tumor cell membrane, ≥1+ intensity) (HR 1.39; 95% CI 1.04-1.86) or SRM (≥400 amol/μg) (HR 1.76; 95% CI 1.06-2.90). Significant correlation was observed between MET FISH/Met IHC, MET FISH/Met SRM, and Met IHC/Met SRM; only MET FISH and Met SRM were independent negative prognostic biomarkers in multivariate analyses. Conclusions MET amplification/overexpression, assessed by multiple methods, were associated with worse prognosis in univariate analyses. However, only MET amplification by FISH and Met expression by SRM were independent prognostic biomarkers. Compared with IHC, SRM may provide added benefit towards informed decisions about Met-targeted therapy.

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“…Despite solid preclinical evidence and promising phase 1/2 clinical trial results [43][44][45][46], several approaches to address RTK-related signaling pathways like EGFR, cMET/HGF, and mTOR failed in recent phase 3 studies [47][48][49][50][51]. This failure demonstrates our incomplete understanding of oncogenic pathways in gastric cancer.…”

Section: Growth Factor-related Signaling Pathways Beyond Her2mentioning

confidence: 84%

Insights into next developments in advanced gastric cancer

Obermannová

Lordick

2016

Current Opinion in Oncology

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METGastric: A phase III study of onartuzumab plus mFOLFOX6 in patients with metastatic HER2-negative (HER2-) and MET-positive (MET+) adenocarcinoma of the stomach or gastroesophageal junction (GEC).

Cited by 85 publications

References 0 publications

Molecular Heterogeneity and Receptor Coamplification Drive Resistance to Targeted Therapy inMET-Amplified Esophagogastric Cancer

Molecular Heterogeneity and Receptor Coamplification Drive Resistance to Targeted Therapy inMET-Amplified Esophagogastric Cancer

MET tyrosine kinase receptor expression and amplification as prognostic biomarkers of survival in gastroesophageal adenocarcinoma

Insights into next developments in advanced gastric cancer

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