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The recent increase in the number of molecular-targeted agents for non-small cell lung carcinoma and the corresponding target genes has led to the demand for the simultaneous testing of multiple genes. Although gene panels that use next-generation sequencing (NGS) are ideal for this purpose, conventional panels require a high tumor content, and biopsy samples often do not meet this requirement. We developed a new NGS panel, called a compact panel, to accommodate biopsy samples without restricting tumor content. The panel was characterized by high sensitivity, with detection limits for mutations of 0.14%, 0.20%, 0.48%, 0.24%, and 0.20% forEGFRexon 19 deletion, L858R, T790M,BRAFV600E, andKRASG12C, respectively. Mutation detection also had a high quantitative ability, with correlation coefficients ranging from 0.966 to 0.992. The threshold for fusion detection was 1%. The panel exhibited good concordance with the approved tests. Identity rates are as follows:EGFRpositive, 100% (95% confidence interval, 95.5-100);EGFRnegative, 90.9 (82.2-96.3);BRAFpositive, 100 (59.0-100);BRAFnegative, 100 (94.9-100);KRASG12C positive, 100 (92.7-100);KRASG12C negative, 100 (93.0-100);ALKpositive, 96.7 (83.8-99.9);ALKnegative, 98.4 (97.2-99.2);ROS1positive, 100 (66.4-100);ROS1negative, 99.0 (94.6-100);METpositive, 98.0 (89.0-99.9);METnegative 100 (92.8-100);RETpositive, 93.8 (69.8-100);RETnegative, 99.8 (94.9-100). The analytical performance showed that the compact panel could handle various types of biopsy samples obtained by routine clinical practice without requiring strict pathological monitoring, as in the case of conventional NGS panels.

Ectodomain shedding unleashes the aggressive nature of the MET oncogene product. Using specific C- and N-terminal MET antibodies (D1C2 and A2H2-3), MET protein status (i.e., no MET, decoy MET, transmembranous C-terminal MET with or without the ectodomain) was investigated in oral squamous cell carcinoma. For the cancers showing transmembranous C-terminal MET, the impact of ectodomain shedding on prognosis was investigated. To examine ectodomain shedding, reduced lysates of oral squamous cell carcinoma cell lines were immunoblotted using D1C2 and an ELISA was performed on culture media using A2H2-3. In addition, reduced lysates of fresh frozen tissues of 30 oral squamous cell carcinoma were immunoblotted using D1C2 and immunohistochemistry was performed on corresponding formalin-fixed paraffin-embedded tissues using both antibodies on parallel sections. To examine MET protein status, differences between membranous D1C2 and A2H2-3 immunoreactivities were scored using parallel tissue microarray sections representing 156 oral squamous cell carcinoma. The prognostic value of ectodomain shedding was examined using Cox regression analysis for disease-free survival and overall survival. Ectodomain shedding was observed in all cell lines, 43% (n = 13) of fresh frozen and 50% (n = 15) of formalin-fixed paraffin-embedded cancers (27% overlap, n = 8). The tissue microarray showed no MET in 23% (n = 36), decoy MET in 9% (n = 14), and transmembranous C-terminal MET in 68% (n = 106) of examined cancers. Within the latter group, ectodomain shedding occurs in 36% (n = 38) of the cases and is independently associated with poor disease-free survival (HR = 2.41; 95% CI, 1.35–4.30 and P = 0.003)—though not overall survival (HR = 1.64; 95% CI, 0.92–2.94 and P = 0.095)—after correcting for factors known to influence survival. In conclusion, MET ectodomain shedding occurs in transmembranous C-terminal MET positive oral squamous cell carcinoma and is independently associated with disease-free survival. These findings might aid in designing companion diagnostics for targeted therapies directed against MET.

ObjectiveMET positivity is independently associated with survival in oral squamous cell carcinoma (OSCC). Since MET is a known orchestrator of invasive tumor growth, we investigated its association with LNM in early oral tongue squamous cell carcinoma (OTSCC). As it is recommended by the NCCN to use tumor depth of invasion (DOI) in making decisions on elective neck dissection (END), the results obtained for MET positivity were aligned with those for DOI > 4 mm. The cutoff value used in our institution.MethodsTumor samples from patients who underwent primary tumor resection and neck dissection between 1995 and 2013, were collected from the archives of the Leiden and Erasmus University Medical Center. Immunohistochemistry with D1C2 was performed to identify MET negative (< 10% uniform positivity) and MET positive (≥ 10% uniform positivity) cancers. ROC curve analysis and the Chi-squared test were used to investigate the association of MET positivity with LNM (pN+ and occult). Binary logistic regression was used to investigate the association of MET positivity with LNM.ResultsForty-five (44.1%) of the 102 cancers were MET positive. Ninety were cN0 of which 20 were pN+ (occult metastasis). The remaining 12 cancers were cN+, of which 10 were proven pN+ and 2 were pN0. MET positivity was associated with LNM with a positive predictive value (PPV) of 44.4% and a negative predictive value (NPV) of 82.5% for pN+. For the occult group, the PPV was 36.8% and the NPV was 88.5%. Regression analysis showed that MET positivity is associated with pN+ and occult LNM (p-value < 0.05).ConclusionMET positivity is significantly associated with LNM in early OTSCC, outperforming DOI. The added value of MET positivity could be in the preoperative setting when END is being considered during the initial surgery. For cases with DOI ≤ 4 mm, MET positivity could aid in the clinical decision whether regular follow-up, watchful waiting, or END is more appropriate. Realizing that these preliminary results need to be independently validated in a larger patient cohort, we believe that MET positivity could be of added value in the decision making on END in early OTSCC.

PURPOSE MET dysregulation is an oncogenic driver in non–small-cell lung cancer (NSCLC), as well as a mechanism of TKI (tyrosine kinase inhibitor) resistance in patients with epidermal growth factor receptor ( EGFR)–mutated disease. This study was conducted to determine safety and preliminary efficacy of the combination EGFR and MET inhibitors as a strategy to overcome and/or delay EGFR-TKI resistance. METHODS A standard 3 + 3 dose-escalation trial of capmatinib in combination with erlotinib in patients with MET-positive NSCLC was used. Eighteen patients in the dose-escalation cohort received 100-600 mg twice daily of capmatinib with 100-150 mg daily of erlotinib. There were two dose-expansion cohorts. Cohort A included 12 patients with EGFR-mutant tumors resistant to TKIs. Cohort B included five patients with EGFR wild-type tumors. The primary outcome was to assess safety and determine the recommended phase II dose (RP2D) of the combination. RESULTS The most common adverse events of any grade were rash (62.9%), fatigue (51%), and nausea (45.7%). Capmatinib exhibited nonlinear pharmacokinetics combined with erlotinib, while showing no significant drug interactions. The RP2D was 400 mg twice daily capmatinib tablets with 150 mg daily erlotinib. The overall response rate (ORR) and DCR in dose-expansion cohort A was 50% and 50%, respectively. In cohort B, the ORR and disease control rate were 75% and 75%. CONCLUSION Capmatinib in combination with erlotinib demonstrated safety profiles consistent with prior studies. We observed efficacy in specific patient populations. Continued evaluation of capmatinib plus EGFR-TKIs is warranted in patients with EGFR activating mutations.

Amy O’Donnell,1 Sanjai Rao,2 Ibrahim Turkoz,3 Srihari Gopal,3 Edward Kim1 1Janssen Scientific Affairs, LLC, Titusville, NJ, USA; 2Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; 3Janssen Research and Development, LLC, Titusville, NJ, USACorrespondence: Ibrahim TurkozJanssen Research and Development, LLC, Titusville, NJ, USATel +1 609-730-7719Fax +1 609-730-3232Email iturkoz@its.jnj.comPurpose: Paliperidone palmitate once every 3 months (PP3M) is indicated in adults with schizophrenia adequately treated with once-monthly paliperidone palmitate (PP1M) for at least 4 months, in whom the last two consecutive doses are the same. The decision of when to transition to PP3M is based on the patient’s symptom status while receiving PP1M.Patients and Methods: In a double-blind relapse–prevention study (NCT01529515), patients who met Positive and Negative Syndrome Scale (PANSS) score stabilization criteria after 4 months of PP1M were eligible for transition to PP3M; those who continued to meet stabilization criteria after 12 weeks following an open-label PP3M dose were randomized to receive PP3M or placebo. We compared (post hoc) PANSS, Clinical Global Impression–Severity (CGI-S), and Personal and Social Performance (PSP) scores during the pre-randomization, open-label phase in patients in randomized versus non-randomized groups using analysis of variance or chi-square tests.Results: Of 506 patients enrolled, 305 were randomized. After 4 months’ PP1M treatment, PANSS and CGI-S scores were significantly lower and PSP scores significantly higher in randomized patients versus non-randomized patients (least squares means [95% CI]: 57.1 [55.7, 58.6] vs 62.2 [60.0, 64.3], 2.9 [2.8, 3.1] vs 3.3 [3.1, 3.4], and 67.0 [65.7, 68.3] vs 64.5 [62.6, 66.4], respectively); changes from baseline between groups differed significantly (all P ≤ 0.009).Conclusion: Confirming adequate stabilization with PP1M prior to transitioning to PP3M is critical in maximizing treatment response; clinicians should consider transitioning patients to PP3M only if patients respond well to PP1M for at least 4 months and their last two consecutive doses are the same.Keywords: treatment outcome, administration and dosage, neuropsychiatric symptoms, psychosocial functioning, stabilization, long-acting injectable antipsychotic

Background Overcoming resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with KRAS wildtype (WT) metastatic colorectal cancer (mCRC) could help meet the needs of patients with limited treatment options. Methods In this phase 1b study, patients with N/KRAS WT, MET-positive mCRC who had progressed following anti-EGFR mAb treatment received escalating oral doses of capmatinib (150, 300, and 400 mg) twice daily plus weekly intravenous cetuximab (at the approved dose). The primary objective was to establish a recommended dose for expansion (RDE) of capmatinib in combination with cetuximab. Safety, preliminary activity, pharmacokinetics, and pharmacodynamics were also explored. Results Thirteen patients were enrolled. No patients experienced a dose-limiting toxicity at investigated doses; the RDE was established as capmatinib 400 mg twice daily plus cetuximab. All patients experienced adverse events (AEs) suspected to be related to the study treatment. Five patients (38.5%) reported study-drug–related AEs of grade 3/4 in severity. No patients achieved a complete or partial response according to RECIST v1.1; however, tumor shrinkage of 29–44% was observed in 4 patients. Conclusions Capmatinib plus cetuximab was well tolerated. Preliminary signs of activity were observed. Further investigation is warranted to obtain efficacy data and refine predictive biomarkers of response. Clinical trial registration NCT02205398.

Background: Results from previous studies indicated that lung cancer patients harboring EGFR sensitizing mutations may receive unfavorable outcomes from immunotherapy. The present study aims to investigate the landscape of PD-L1 expression in lung cancer harboring driver oncogene mutations except EGFR mutations. Methods: Tissue samples were subjected to NGS in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab for driver oncogene mutations and PD-L1 expression. Results: A total of 22143 lung cancer patients were selected, there are 2120 patients have the driver oncogene mutation, including 1115 (5.04%) ALK positive cases,498 (2.25%) MET positive cases,239(1.08%) RET positive cases,182(0.82%) BRAF positive cases, 72 (0.33%) ROS1 positive cases and 14 (0.03%) NTRK positive cases. Among all the driver oncogene mutation patients, 481 patients have been collected tumor tissue, and the PD-L1 expression have been tested by FDA-approved 22C3 antibodies. Among all the driver oncogene mutation cases assessed PD-L1 expression (n=481), low PD-L1 expression levels ( Conclusion: Our study supported that NSCLC patients harboring sensitizing oncogenic mutations may potentially benefit from anti-PD-1/L1 especially for those with positive indicators of immunotherapy with strong positive PD-L1 expression. Citation Format: Ningbo Liu, Fuyu Gong. The landscape of PD-L1 expression in lung cancer harboring driver oncogene mutations except EGFR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 454.

Introduction. Ethylene glycol (EG) and methanol (MET) exposuresare rare but can cause significant morbidity and mortality.Though frequently treated similarly, EG and MET exposures havecharacteristics that are not well differentiated in the literature. Wesought to describe the clinical characteristics of EG and MET exposures,confirmed with quantitative serum levels. Methods. An IRB-approved retrospective review of the Universityof Kansas Health System Poison Control Center database from July2005 to July 2015 identified all EG/MET exposures evaluated ata health care facility. Initial measurements were EG/MET levels,serum pH, serum creatinine, anion gap, serum ethanol level, maxanion gap, max osmolar gap, therapy performed (hemodialysis,fomepizole, ethanol) and death. Results. The search identified 75 cases, with 59 cases having onlydetectable EG levels and 15 cases having only detectable MET levels.The average EG level was 126 mg/dL (range 5 - 834). The averagedetectable methanol level was 78 mg/dL (range 5 - 396). The averagemaximum anion gap of the EG positive group was 20 mEq/L (range8 - 35). The average maximum anion gap of the MET positive groupwas 14 mEq/L (range 6 - 34). One death was reported in the EG positivegroup, with an initial level of 266 mg/dL. Conclusions. In this study of EG/MET exposures, EG exposureswere more common than MET exposures, but they had similardemographics, laboratory findings, and interventions. Continuedstudies are warranted to characterize these uncommon exposuresfurther. Kans J Med 2018;11(3):67-69.

Capmatinib is an oral, ATP‐competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose‐escalation results for capmatinib in advanced MET‐positive solid tumor patients and dose expansion in advanced non‐lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose‐limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c‐MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose‐expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near‐complete immunohistochemically determined phospho‐MET inhibition (H‐score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high‐level MET GCN (GCN ≥6) and MET‐overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479)., MET dysregulation is an important newly established molecular driver of tumorigenesis in various cancers and is recognized as a negative prognostic factor. The findings of this study provide the recommended phase 2 dose (RP2D) of capmatinib and also safety and efficacy data in selected expansion cohorts treated at the RP2D.

Background MET is a tyrosine kinase receptor for the hepatocyte growth factor, and its overexpression is a poor prognostic factor in gastric carcinomas. Programmed death-ligand 1 (PD-L1) is an important biomarker of immunotherapy and is frequently positive in microsatellite instability-high (MSI-H) gastric carcinomas. In lung cancers, MET activation up-regulates PD-L1 expression. In this study, we investigated expression of MET and PD-L1 in MSI-H gastric carcinoma and the effects on prognosis. Methods MET and PD-L1 (SP142) immunohistochemistry was performed in 73 gastric carcinomas with MSI-H. In cases with MET overexpression, we performed fluorescent in situ hybridization (FISH). PD-L1 expression was calculated from both tumor cells (2+ and 3+ in > 10% of tumor cells was defined as PD-L1TC+) and immune cells (positive in >5% immune cells was PD-L1IC+), and also used a combined positive score (CPS; number of PD-L1 staining cells relative to all viable tumor cells; > 1 was PD-L1+). Results In 73 MSI-H gastric carcinomas, MET overexpression was observed in 11 cases (15.1%). In all 11 cases with MET overexpression,MET amplification was not found. MET overexpression was not related to any of clinico-pathological variables and PD-L1 expression. However, the PD-L1 CPS tended to be higher in tumors that were MET positive. Although MET overexpression alone was not a prognostic indicator, combined MET overexpression/PD-L1 predictive models showed that patients with MET+/PD-L1+ showed the best prognosis for overall survival as compared to other groups. Conclusion MET overexpression was observed in 15% of MSI-H gastric carcinomas and was associated with high level expression of PD-L1.

Background Preliminary data from TATTON (NCT02143466, a multi-arm, multi-drug combination study) suggested that adding savolitinib (AZD6094, HMPL-504, volitinib), a potent and highly selective MET TKI, to osimertinib, a 3rd generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), which selectively inhibits EGFR TKI sensitising (EGFRm) and T790M resistance mutations, may overcome MET-driven resistance to EGFR TKIs. We present updated data from TATTON Part B and data from Part D, for the first time. Methods Pts were ≥18 years (Japan ≥20 years), mainly Asian, with locally advanced/metastatic, MET-positive, EGFRm NSCLC and disease progression on prior therapy. Pts enrolled based on MET status by local fluorescent in-situ hybridisation (MET gene copy ≥5 or MET/CEP7 ratio ≥2), next-generation sequencing or immunohistochemistry (+3 in ≥ 50% of tumour cells), with retrospective central confirmation. Pts in Part B received osimertinib 80 mg + savolitinib 600 mg or 300 mg orally (PO) once daily (QD). Pts in Part D received osimertinib 80 mg + savolitinib 300 mg PO QD, were T790M negative and had received no prior 3rd generation EGFR TKI. Primary endpoints: safety and tolerability; secondary endpoints included objective response rate and progression-free survival. Results In Parts B (N = 138) and D (N = 42); Grade ≥3 AEs reported by 57% and 38%, respectively; serious AEs reported by 45% and 26%, respectively. AEs possibly related to treatment, led to discontinuation of savolitinib in 38 (28%) vs 9 (21%) and osimertinib in 14 (10%) vs 2 (5%), for Parts B and D, respectively. Efficacy data: Table. Table . LBA2 Efficacy endpoints Part B Part D Endpoint Previously treated with a 3G EGFR TKI No prior 3G EGFR TKI, T790M-negative No prior 3G EGFR TKI, T790M-positive Total No prior 3G EGFR TKI, T790M-negative Best response n = 69 n = 51 n = 18 n = 138 n = 36 * ORR † , n (%) [95% CI] 21 (30) [20–43] 33 (65) [50–78] 12 (67) [41–87] 66 (48) [39–56] 23 (64) [46–79] PFS n = 69 n = 51 n = 18 n = 138 n = 42 Median PFS, months 5·4 9·0 11·0 7·6 9·1 [95% CI] [4·1–8·0] [5·5–11·9] [4·0–NR] [5·5–9·2] [5·4–12·9] Total events, n (%) 43 (62) 33 (65) 10 (56) 86 (62) 17 (40) * Best response data are for patients who had an opportunity to have two follow-up scans. † All confirmed responses were partial response. Conclusions Our results support that osimertinib + savolitinib may overcome MET-driven resistance to EGFR TKIs, and warrant further exploration of the osimertinib 80 mg + savolitinib 300 mg combination in the SAVANNAH (NCT03778229) and ORCHARD (NCT03944772) studies. Clinical trial identification NCT02143466. Editorial acknowledgement Laura Crocker, BMedSci, of iMed Comms, an Ashfield Company, funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure J. Han: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Research grant / Funding (self): ONO; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Takeda. L.V. Sequist: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Janssen; Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Merrimack Pharmaceuticals; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): LOXO; Honoraria (self), Research grant / Funding (institution): Blueprint Medicines; Honoraria (self), Research grant / Funding (institution): Genentech. M. Ahn: Honoraria (self), Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Ono Pharmaceutical, Roche; Advisory / Consultancy: Takeda, Alpha Pharmaceutical. B.C. Cho: Research grant / Funding (institution): Novartis, Bayer, AstraZeneca, Mogam Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD; Advisory / Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono Pharmaceutical, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, and MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc, Gencurix Inc, Bridgebio Therapeutics; Licensing / Royalties, Patent with royalties paid: Champions Oncology. H. Yu: Advisory / Consultancy: AstraZeneca; Research grant / Funding (institution): AstraZeneca, Lilly, Pfizer, Daiichi, Novartis, Astellas. S. Kim: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. J.C. Yang: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, MSD, Pfizer, Novartis, Bristol-Myers Squibb, Ono Pharmaceuticals; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, Bristol-Myers Squibb, Ono Pharmaceuticals, Daiichi Sankyo, Hansoh, Takeda, Blueprint. M. Cantarini: Shareholder / Stockholder / Stock options, Full / Part-time employment, Full time Contractor: AstraZeneca. R.B. Verheijen: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: Aduro Biotech. A. Mellemgaard: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Frewer: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. X. Ou: Full / Part-time employment, Full time Contractor: AstraZeneca. G. Oxnard: Honoraria (self): Chugai Pharma, Bio-Rad, Sysmex, Guardant Health, Foundation Medicine; Advisory / Consultancy: AstraZeneca, Inviata, Takeda, Loxo, Ignyta, DropWorks, GRAIL, Illumina, Janssen; Licensing / Royalties, Patent pending: DFCI.

MET and its sole ligand, hepatocyte growth factor (HGF), are promising targets in gastric and gastroesophageal junction cancer. We evaluated whether MET protein expression or MET gene amplification is prognostic for overall survival (OS) in Chinese patients with advanced gastric or gastroesophageal junction cancer. Archival formalin-fixed, paraffin-embedded tumor samples from patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancer enrolled in clinical trials at Peking University Cancer Hospital from 2008 to 2010 were assessed for MET and phospho-MET (p-MET) expression by immunohistochemistry and MET amplification by FISH. MET-positive expression was defined as membrane protein staining in ≥25% of tumor cells. MET amplification was defined as MET:centromere 7 ratio >2.0. We tested the association of MET status with clinical characteristics and OS, and also evaluated the association between expression and amplification. One hundred sixty-eight patients were eligible. Of the evaluable samples, 53 of 137 (39%) were MET positive, eight of 134 (6%) were p-MET positive, and eight of 113 (7%) were MET amplified. Neither MET expression nor MET amplification were associated with clinical characteristics, except Lauren classification (P = 0.04); MET amplification was associated with diffuse type. No significant OS difference was observed between MET-positive and MET-negative populations, regardless of first-line chemotherapy received. In 95 evaluable patients, MET expression was significantly associated with MET amplification (P < 0.001); all MET-amplified tumor samples showed some MET expression. In 96 evaluable patients, p-MET positivity was significantly associated with MET amplification (P < 0.001). Further evaluation in larger and independent sample sets is warranted to confirm our findings. Mol Cancer Ther; 14(11); 2634–41. ©2015 AACR.

OBJECTIVE: We aimed to assess MET intratumoral heterogeneity and its potential impact on biomarker-based patient selection as well as potential surrogate biomarkers of MET activation. METHODS: Our study included 120 patients with non-squamous Non-small-cell Lung Cancer (nsNSCLC), of which 47 were incorporated in tissue microarrays (TMA). Four morphologically distinct tumor areas were selected to assess MET heterogeneity. MET positivity by immunohistochemistry (IHC) was defined as an above-median H-score and by +2/+3 staining intensity in >50% of tumor cells (Metmab criteria). MET FISH positivity was defined by MET/CEP7 ratio ≥ 2.0 and/or MET ≥ 5.0. MET staining pattern (cytoplasmic vs. membranous) and mesenchymal markers were investigated as surrogates of MET activation. RESULTS: Median MET H-score was 140 (range 0-400) and 47.8% of patients were MET positive by Metmab criteria. Eight cases (6.8%) were MET FISH positive and showed higher H-scores (p = 0.021). MET positivity by IHC changed in up to 40% of cases among different tumor areas, and MET amplification in 25-50%. Cytoplasmic MET staining and positivity for vimentin predicted poor survival (p = 0.042 and 0.047, respectively). CONCLUSIONS: MET status is highly heterogeneous among different nsNSCLC tumor areas, hindering adequate patient selection for MET-targeted therapies. MET cytoplasmic staining and vimentin might represent surrogate markers for MET activation. This work was supported by RD12/0036/0051 /FEDER, PI13/00140/FEDER, a grant from Fundacio Marato de TV3. Ref.666/C/2013 and 2014 SGR 740. the “Xarxa de Bancs de tumors sponsored by Pla Director d’Oncologia de Catalunya (XBTC).” JA is recipient of intensification programme ISCIII.

ABSTRACT Aims: ID1 is an important component of the MET–SRC signaling pathway, which is a regulator of cell migration and invasion. We hypothesized that the ALK/MET inhibitor crizotinib inhibits migration via MET–SRC–ID1, rather than ALK. Materials & methods: We used ALK fusion-positive and -negative lung cancer cell lines; crizotinib, PHA-665752, and saracatinib, and stable transfection with shMET. We performed western blotting for p-ALK, ALK, p-MET, MET, p-SRC, SRC and ID1, and quantitative real-time PCR for ID1. Results: Crizotinib decreased p-MET, p-SRC and ID1 levels in ALK- and or MET-positive cell lines and inhibited cell migration. Knockdown of MET was comparable with the effect of crizotinib. Conclusion: The effects of crizotinib on ID1 expression and cancer cell migration were associated with the presence of activated MET, rather than ALK fusion.

Importance Dysregulation of the mesenchymal-epithelial transition (MET) signaling pathway is associated with poor prognosis in gastroesophageal adenocarcinoma (GEC). We report results of METGastric, a phase 3 trial of the MET inhibitor onartuzumab plus standard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, MET-positive, advanced GEC. Objective To determine whether the addition of onartuzumab to first-line fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improves efficacy compared with mFOLFOX6 plus placebo in HER2-negative, MET-positive GEC. Design, Setting, and Participants Randomized, double-blind, multicenter trial conducted from November 2012 to March 2014. Patients were 18 years or older with an adenocarcinoma of the stomach or gastroesophageal junction with metastatic disease not amenable for curative therapy. Tumor samples were centrally tested for MET expression using Ventana anti-Total c-MET (SP44) rabbit monoclonal antibody, HER2 status, and Lauren histologic subtype. MET-positive tumors were defined as at least 50% of tumor cells showing weak, moderate, and/or strong staining intensity (MET 1+/2+/3+, respectively) by immunohistochemistry. Interventions Patients with HER2-negative, MET-positive GEC were enrolled and randomized 1:1 to receive mFOLFOX6 with or without onartuzumab (10 mg/kg). Main Outcomes and Measures Co–primary end points: overall survival in the intent-to-treat (ITT) population and in patients with MET 2+/3+ GEC. Secondary end points: progression-free survival (PFS), overall response rate (ORR), and safety. Results Enrollment was stopped early due to sponsor decision, which was agreed with an independent data monitoring committee. At the data cutoff (April 25, 2014) there were 562 patients in the ITT population (n = 283 placebo plus mFOLFOX6 [median age, 58 y; 65% male]; n = 279 onartuzumab plus mFOLFOX6 [median age, 60 y; 67% male]); 109 (38.5%) and 105 (37.6%) of the ITT population were MET 2+/3+, respectively. Addition of onartuzumab to mFOLFOX6 did not significantly improve OS, PFS, or ORR vs placebo plus mFOLFOX6 in the ITT (OS hazard ratio [HR], 0.82; 95% CI, 0.59-1.15; P = .24; PFS HR, 0.90; 95% CI, 0.71-1.16; P = .43; ORR, 46.1% vs 40.6%) or MET 2+/3+ populations (OS HR, 0.64; 95% CI, 0.40-1.03; P = .06; PFS HR, 0.79; 95% CI, 0.54-1.15; P = .22; ORR, 53.8% vs 44.6%). Safety was as expected for onartuzumab. Conclusions and Relevance Addition of onartuzumab to first-line mFOLFOX6 did not significantly improve clinical benefits in the ITT or MET 2+/3+ populations. Trial Registration clinicaltrials.gov Identifier:NCT01662869

ABX9xx is a bispecific Centyrin targeting the Met-EGFR axis, an emerging cancer treatment paradigm. Centyrins are small, chemically simple proteins based on a human FN3 domain that can be engineered to have high affinity for a selected target and are easily linked to form multi-specific binders. The standard of care for patients with EGFR mutant non-small cell lung cancer (NSCLC) is treatment with small molecule tyrosine kinase inhibitors (TKI) including recently approved third generation molecules (ie. osimertinib). Despite initial promising responses with TKIs, most patients regress within 12-14 months due to resistance. A predominant resistance mechanism dependent on Met amplification and signaling has been described from both in vitro experiments and clinical data. Targeting Met and EGFR with a bispecific ligand blocking inhibitor that attenuates intracellular signaling may provide a significant efficacy advantage and reduced side effect profile compared to small molecule TKI combinations. Exploiting the potential for avidity on tumor tissue, a bispecific ligand blocking inhibitor of Met and EGFRis also anticipated to provide improved selectivity for tumor tissue that overexpress both receptors compared to normal tissue with lower receptor expression. To enable sustained exposure while maintaining small size for good tumor penetration, ABX9xx includes a domain comprising an albumin binding Centyrin. ABX9xx activity on Met, EGFR and downstream signaling proteins was confirmed on several lung cancer cell lines in vitro including those carrying clinically observed mutations in Met and EGFR. ABX9xx inhibited EGFR phosphorylation independent of EGFR mutational status with higher potency than osimertinib. In addition, ABX9xx inhibited Met phosphorylation with higher potency than Crizotinib, an ALK inhibitor with cross reactivity to Met, currently used to treat Met positive patients. The pharmacokinetic properties of ABX9xx in animal models suggest a suitable dosing paradigm in patients. Together the data provides a strong rationale for advancing ABX9xx into clinical development for NSCLC and other cancers where EGFR and MET are drivers of tumor progression. Citation Format: Russ Addis, Robert Kolakowski, Swapnil Kulkarni, Josh Gorsky, Rebecca Meyer, Karyn ONeil. ABX9xx: A bispecific centyrin that synergizes to attenuate intracellular signaling in Met/EGFR positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4830.

Introduction The phase II JO28638 study evaluated first-line onartuzumab plus erlotinib in patients with MET-positive advanced, metastatic, or post-operative recurrent non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The study was stopped following termination of the global METLung study (OAM4971g), which showed lack of efficacy in the onartuzumab/erlotinib arm. We present immature efficacy and safety data from JO28638. Materials and Methods Chemotherapy-naive patients aged ≥ 20 years were enrolled. Patients received onartuzumab (15 mg/kg every 3 weeks) plus erlotinib (150 mg once daily) until progression or unacceptable toxicity. The co-primary endpoints were investigator (INV)-assessed progression-free survival (PFS) and safety. Secondary endpoints: overall response rate (ORR), disease control rate (DCR), overall survival (OS), duration of response (DOR), and pharmacokinetics. Exploratory biomarker analyses were also conducted. Results 61 patients received treatment. Median age was 67 years and most patients had stage IV NSCLC (71%), MET-IHC score 2 (87%), and exon 19 deletion EGFR mutation (53%). Median PFS (INV) was 8.5 months (95% confidence interval [CI] 6.8–12.4); median OS was 15.6 months (95% CI 15.6–not evaluable); ORR was 68.9% (95% CI 55.7–80.1); median DOR was not reached; DCR was 88.5% (95% CI 77.8–95.3). Pharmacokinetics were similar to previous studies. All patients experienced an adverse event (AE); 26 patients discontinued treatment due to AEs; no grade 5 AEs were reported. No significant correlation was found between biomarkers and efficacy outcomes. Conclusion The results presented are inconclusive due to the early termination of the study.

Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P

Despite the promising results from initial studies, there are significant limitations in the application of MET-targeted therapy in gastric cancer. Intrinsic resistance is one of the major obstacles. The aim of this study is to identify the responsible receptor tyrosine kinases (RTKs) that determine the unresponsiveness of MET inhibitor in MET-positive gastric cancer. through an RNA-interference-based functional screen targeting most human RTKs, we identified that activation of the fibroblast growth factor receptor 2 (FGFR2) and recepteur d'origine nantais (RON) pathways attenuated MET inhibitor-induced suppression of cell proliferation and migration. Notably, in the two forms of RON pathway activation, only upregulation of short-form RON (sf-RON), but not stimulation of full length RON with macrophage stimulating protein, conferred MET inhibitor resistance in vitro and in vivo. Furthermore, the profile of the gastric cancer samples observed that sf-RON was frequently upregulated in MET-positive gastric cancer. Our findings indicate that activation of the sf-RON signaling pathway represents a novel mechanism underlying MET inhibitor unresponsiveness. A combination strategy with drugs targeting both RON and MET pathways is believed to improve the efficacy of MET-targeted therapy.

Approximately 5%-22% of non-small cell lung cancer (NSCLC) patients with secondary resistance to EGFR TKIs had evidence of amplification of the Met oncogene. This dysregulation of Met signaling was implicated in the proliferation and eventual metastasis of NSCLC, and therefore represents an attractive target for anticancer drug development. Currently, there are a number of clinical trials for Met targeted small molecule and monoclonal antibody therapies. Immunohistochemistry (IHC) analysis of the Met protein will be very important for these Met targeted therapies and requires a highly specific antibody to prevent false positives. To develop a highly specific monoclonal antibody against Met for IHC analysis in NSCLC, we generated 97 monoclonal antibodies. IHC evaluation showed that 8 of the antibodies had suitable performance in Met positive NSCLC patient tissues. The 8 Met monoclonal antibodies were further tested on a high density protein microarray chip containing 17,000 human proteins. The microarray a...

In 2014, outcomes for patients with advanced gastric cancer remain extremely poor with a high level of unmet need regarding effective therapeutic options. However, recent years have seen increasing interest in the role of the MET signaling pathway in this disease subtype, leading to the development and evaluation of MET-targeted therapeutics. Rilotumumab is a monoclonal antibody directed against hepatocyte growth factor, the only known ligand for the MET receptor. It is an unlicensed product which is currently undergoing evaluation in a randomized Phase III trial in ‘MET-positive’ gastric cancer. Here we discuss the background to the treatment of gastric cancer as well as the characteristics of rilotumumab and reported results with this agent in the trials performed to date.

Onartuzumab is a monovalent, humanized, monoclonal antibody that showed significant survival benefits in combination with erlotinib in MET-positive non-small-cell lung cancer (NSCLC) in pre-specified subgroup analyses of a randomized phase II study. We conducted a two-stage, open-label, multicenter, phase I study of onartuzumab in Japanese patients. Stage 1 investigated the safety, tolerability, pharmacokinetics (PK), and recommended dose of onartuzumab in patients with solid tumors, and Stage 2 determined the safety, tolerability, and PK of onartuzumab plus erlotinib in patients with MET-positive NSCLC. Nine patients received onartuzumab monotherapy (4, 15, or 30 mg/kg on Day 1 of each 21-day cycle) in Stage 1, and six patients received onartuzumab (15 mg/kg) plus erlotinib (150 mg/day) in Stage 2. There were no dose-limiting toxicities in either stage. Serious adverse events (AEs) occurred in one patient in Stage 1 (convulsion), and two patients in Stage 2 (once case each of diarrhea, vomiting, and pulmonary embolism), but there were no grade 4 AEs or AEs leading to death. Onartuzumab PKs were linear in the dose range of 4 to 30 mg/kg, and were not affected by co-administration with erlotinib. PK parameters of onartuzumab were similar to those reported in non-Japanese patients. A partial response was observed in a patient with MET immunohistochemistry 3+ NSCLC without MET gene amplification. Based on these results, the recommended dose of onartuzumab in Japanese patients with solid tumors is 15 mg/kg every 21 days. The combination of onartuzumab with erlotinib is feasible in Japanese patients with MET-positive lung cancer.

BACKGROUND The c-met protooncogene encodes the met protein, the receptor for scatter factor/hepatocyte growth factor, a growth factor that modulates the motility and stable interaction of the epithelial cells. This study assesses the expression of met receptor in breast carcinoma and its prognostic value with respect to survival. METHODS Immunofluorescence was used to evaluate 91 archival breast carcinoma specimens using a polyclonal antibody to the cytoplasmic domain of the receptor. Cases were scored by two pathologists on a percentage basis and then converted to binary scores (positive or negative) on the basis of a bimodal distribution. RESULTS Strong expression of met was found in 20 invasive ductal breast tumor specimens (22%). The 5-year survival of patients whose tumors showed decreased met expression was 89%, in contrast to a 52% 5-year survival rate in patients whose tumors expressed met (P = 0.008). This trend also was observed in patients without lymph node metastases at presentation, in whom met negative patients had a 95% 5-year survival compared with only 62% for met positive patients (P = 0.006) Multivariate analysis using the Cox proportional hazards model showed met expression to be an independent predictor of survival, with a predictive value nearly equivalent to that associated with lymph node status. CONCLUSIONS The authors conclude that expression of met in patients with invasive ductal carcinoma of the breast is a strong, independent predictor of decreased survival and may be a useful prognostic marker with which to identify a subset of patients with more aggressive disease. Cancer 1998;82:1513-20. © 1998 American Cancer Society.

The hepatocyte growth factor receptor (HGFR, c-Met or Met) is a receptor tyrosine kinase that is involved in embryogenesis, tissue regeneration and wound healing. Abnormal activation of this proto-oncogene product is implicated in the development, progression and metastasis of many cancers. Current therapies directed against Met, such as ligand- or, dimerization-blocking antibodies or kinase inhibitors, reduce tumor growth but hardly eradicate the tumor. In order to improve anti-Met therapy, we have designed a drug delivery system consisting of crosslinked albumin nanoparticles decorated with newly selected anti-Met nanobodies (anti-Met-NANAPs). The anti-Met NANAPs bound specifically to and were specifically taken up by Met-expressing cells and transported to lysosomes for degradation. Treatment of tumor cells with anti-Met NANAPs also resulted in downregulation of the total Met protein. This study shows that anti-Met NANAPs offer a potential system for lysosomal delivery of drugs into Met-positive tumor cells. © 2013 Elsevier Ltd.

Background: Activation of the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor receptor (MET) pathway promotes tumor growth, invasion and dissemination. Emibetuzumab is a humanized IgG4 monoclonal antibody that binds to and inhibits ligand-dependent and ligand-independent activation of MET. In the first-in-human dose escalation study NCT0128756, emibetuzumab demonstrated favorable tolerability when administered up to 2000mg Q2W IV in unselected patients. The study was expanded to evaluate emibetuzumab in expansion cohorts for patients with tumors positive for MET expression. Methods: Patients with locally advanced or metastatic castration-resistant prostate cancer (CRPC) with bone metastasis, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and hepatocellular carcinoma (HCC) received 2000 mg emibetuzumab Q2W IV on a 28-day cycle. RCC, NSCLC, and HCC patients were required to have measurable disease as defined by RECIST v1.1 and have MET positive tumors (≥50% of cells to be ≥2+ for MET expression) as determined by a MET IHC assay (Ventana). The objectives were to evaluate the safety and activity of emibetuzumab in patients with MET positive tumors. Additional objectives included pharmacokinetics (PK) and pharmacodynamics (PD). Results: A total of 62 patients received emibetuzumab across the 4 cohorts: CRPC n = 15, RCC n = 19, NSCLC n = 19,and HCC n = 9, with a median of prior systemic oncology therapies of 6, 3, 5, and 3, respectively. Common possibly related treatment-emergent adverse events included fatigue (29% all grades, 3% Gr3/4), nausea (13% all grades, no Gr3/4), edema of limbs (8% all grades, 2% Gr3/4), and anorexia (8%, no Gr3/4) and were similar among cohorts. No evidence of clinical activity was observed in CRPC patients. For RCC, NSCLC, and HCC patients with MET positive tumors, an overall disease control rate (DCR = partial response [PR] + stable disease [SD]) of 32% (15/47) was observed. In the individual cohorts, DCR was 26% (5/19) in RCC, 26% (5/19) in NSCLC, and 56% (5/9) in HCC. The median duration of disease stabilization in the 3 cohorts was: 4.2 months (range 1.6-24.6) in RCC, 3.9 months (range 2.5-6.4) in NSCLC, and 3.7 months (range 1.2-6.6) in HCC. One PR was observed in an HCC patient with MET amplification. After a single dose of 2000 mg emibetuzumab, PK parameters were similar among these cohorts and also comparable to patients treated at this dose during dose escalation. Conclusions: In cohorts enriched for tumor MET expression, limited single-agent activity of emibetuzumab was observed indicating that MET positivity by IHC (Ventana assay) at the cut-point employed here might not be a sufficient predictive biomarker to select patients receiving benefit from emibetuzumab monotherapy for the tumor types studied. Further evaluation of biomarkers/assays to identify patients who may benefit from treatment with emibetuzumab may be warranted. Citation Format: Michaela S. Banck, Rashmi Chugh, Ronald B. Natale, Alain Algazi, Bradley C. Carthon, Lee S. Rosen, Michael E. Menefee, Andrew Xiuxuan Zhu, Takami Sato, Brian Moser, P. Kellie Turner, Jay Tuttle, Xuejing Aimee Wang, Volker Wacheck, Frederick E. Millard. Phase 1 results of emibetuzumab (LY2875358), a bivalent MET antibody, in patients with advanced castration-resistant prostate cancer, and MET positive renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A55.

MET, a receptor tyrosine kinase for hepatocyte growth factor, is associated with tumor progression and acquired resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI). Therefore, MET gene alterations could be both prognostic and predictive. Fluorescence in situ hybridization (FISH) is one method for assessing gene alteration, but the frequency of positive cases varies due to a lack of standardized criteria. We evaluated MET gene copy number in lung adenocarcinoma and its association with clinicopathological characteristics. FISH was applied to evaluate high MET gene copy number and true amplification in 138 lung adenocarcinoma patients using two criteria: the Cappuzzo scoring system and PathVysion. MET positive cases according to the Cappuzzo scoring system evidenced both aneuploidy and true amplification, whereas PathVysion revealed only amplification. Proportion of MET FISH positive cases was 15% and 4% determined by the Cappuzzo system and PathVysion, respectively. PathVysion demonstrated higher frequencies of MET FISH positives among men and smokers and evidenced no MET FISH positives in patients with bronchioloalveolar carcinoma. Prognosis was significantly associated with MET FISH positive only as defined by the PathVysion system (gene amplification), not by the Cappuzzo system. However, progression-free survival time of patients with both EGFR mutations and MET FISH positive defined by the Cappuzzo scoring system was significantly shorter than with EGFR mutations alone. These results suggest that MET FISH is a potential prognostic factor and coexistence of MET FISH with EGFR mutations signifies worse prognosis.

4012 Background: Dysregulation of the MET/HGF pathway is associated with poor prognosis in GEC. Onartuzumab (O), a monovalent anti-MET antibody, inhibits the MET/HGF pathway. We investigated first-...

TPS226 Background: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor, the only known ligand of the MET receptor. In a phase 2 study, trends toward improved progression-free survival (PFS) and overall survival (OS) were seen with rilotumumab plus epirubicin, cisplatin and capecitabine (ECX) vs ECX alone in pts with G/GEJ cancer; the treatment effect of rilotumumab was enhanced in MET-positive pts (Iveson et al. Lancet Oncol 2014;15:1007). In a phase 1/1b study, rilotumumab plus CX had manageable toxicities and a favorable pharmacokinetic (PK) profile in Japanese pts with MET-positive G/GEJ cancer (Doi et al. J Clin Oncol 2014;32:5s,abstract 4051). Methods: In this phase 3 study, 450 pts from Asian countries are randomized 1:1 to CX (intravenous [IV] cisplatin 80 mg/m2 on day 1 and oral capecitabine 1000 mg/m2 twice daily on days 1−14) plus double-blind rilotumumab 15 mg/kg or placebo IV on day 1 every 3 weeks for up to 6 cycles. After cycle 6, pts will receive capecitabine plus rilotumumab or placebo. Randomization is stratified by disease extent (locally advanced vs metastatic), prior surgery for G/GEJ or esophageal cancer (yes vs no), and country (China vs other). Key eligibility criteria include previously untreated, pathologically confirmed unresectable locally advanced or metastatic G/GEJ adenocarcinoma, ≥20 years, ECOG score ≤1, MET-positive by centralized immunohistochemistry, HER2-negative, adequate organ function, and ≥6 months since neoadjuvant/adjuvant therapy. The primary endpoints are PFS and OS. A log-rank test stratified by the randomization factors will compare PFS and OS between arms. Key secondary endpoints include 12-month survival rate, time to progression, objective response and disease control rates, duration of/time to response, safety, and PK. Enrollment began in July 2014, and the trial continues to recruit participants. The study is overseen by an independent data monitoring committee. ClinicalTrials.gov: NCT02137343. Sponsor: Amgen Inc. Clinical trial information: NCT02137343.

Background: Sorafenib remains the only approved systemic first-line medical treatment for advanced hepatocellular carcinoma (HCC) patients (pts) with no validated option at the time of sorafenib failure. c-Met/hepatocyte growth factor (HGF) activation/overexpression is associated with poor prognosis. In a Phase I trial, the selective small-molecule c-Met inhibitor MSC2156119J displayed promising antitumor activity (Falchook et al. J Clin Oncol 2013). This disease-oriented Phase Ib/II, single-arm, multicenter study evaluates the safety and antitumor activity of MSC2156119J in Met-positive (Met+) advanced HCC pts with Child-Pugh Class A liver function, pretreated with sorafenib (EudraCT# 2013–002053–30). Trial design: Primary objectives are to determine the recommended Phase II dose of MSC2156119J (RP2D; Phase Ib) in HCC pts and to investigate antitumor activity by determining the progression-free survival (PFS) status at 12 wk per investigator read (Phase II). Secondary objectives include pharmacokinetics, antitumor activity (objective tumor response, time to progression, overall survival, PFS, and disease control), biochemical response, safety, and tolerability. European adults with confirmed, advanced HCC, Child-Pugh class A liver function, life expectancy >3 mo, ECOG status 0–1, available pretreatment tumor biopsy after sorafenib failure, pretreated with sorafenib for ≥4 wks and discontinued ≥14 days prior to day 1 of MSC2156119J treatment will be recruited. In the Phase II part, only Met+ pts with moderate or strong protein overexpression, as determined by immunohistochemistry, will be entered. Key exclusion criteria are prior treatment with systemic therapy other than sorafenib or with c-Met/HGF-targeting agents, impaired cardiac function, and chronic gastrointestinal disease. For the Phase Ib part, up to 18 pts are planned (3 + 3 design; 300 mg or 500 mg MSC2156119J p.o./day; 21-day cycle). For the Phase II part, 48 pts are planned to receive the RP2D of MSC2156119J (p.o./day; 21-day cycle), as determined in the Phase Ib part. Enrollment began on 06 May 2014. A Trial in Progress abstract was submitted to ASCO 2014. Disclosure: S. Faivre: Advisory board: Merck-Serono; B. Sarholz: Employee of Merck KGaA, Darmstadt, Germany A. Johne: Employee of Merck KGaA, Darmstadt, Germany; H. Zheng: Employee of EMD Serono, Boston, MA, USA Stock ownership: Merck/EMD Serono; E. Raymond: Advisory board: Merck-Serono

Aim: The reported prevalence of MET overexpression varies from 25-55% in non-small cell lung cancer (NSCLC) and clinical correlations are emerging slowly. In a well-defined NSCLC cohort of the Lungscape program, we explore the epidemiology, the natural history of IHC MET positivity and its association to OS, RFS and TTR. Methods: Resected stage I-III NSCLC identified based on the quality of clinical data and FFPE tissue availability were assessed for MET expression using immunohistochemistry (IHC) on TMAs (CONFIRM anti total c-MET assay, clone SP44, Ventana BenchMark platform). All cases were analysed at participating pathology laboratories using the same protocol, after passing an external quality assurance program. MET positive status is defined as ≥ 50% of tumor cells staining with 2+ or 3+ intensity. Results: A total of 2709 cases are included in the iBiobank and will be analysed. IHC MET expression is currently available for 1552 patients, with positive MET IHC staining in 380 cases [24.5%; IHC 3+ in 157 cases (41.3%) and 2+ in 223 cases (58.7%)]. The cohort of 1552 patients includes 48.2%, 44.7% and 4.4% cases of adenocarcinoma, squamous and large cell histologies, respectively. IHC MET status was independent of stage, age and smoking history. Significant differences in MET positivity were associated with gender (32% vs. 21% for female vs. male, p Conclusions: The preliminary results for this large multicentre European cohort describe a prevalence of MET overexpression that seems lower than previous observations in NSCLC, such as reported for the OAM4971g trial, suggesting potential biological differences between surgically resected and metastatic disease. Analysis for the full cohort is ongoing and results will be presented. Disclosure: L. Bubendorf: Disclosures: Stock ownership: Roche Advisory boards: Roche, Pfizer Research support: Roche; K. Schulze: Full time employee of Roche; A. Das-Gupta: I am a full time employee of Roche. All other authors have declared no conflicts of interest.

TPS8121 Background: Resistance to EGFR tyrosine kinase inhibitors (eg, gefitinib) in EGFRm+ NSCLC patients (pts) is mainly caused by a secondary mutation in the EGFR (ie, T790M) or by activation of...

8017 Background: Despite high response rates to EGFR tyrosine kinase inhibitors (TKIs), most patients (pts) with EGFR-mut NSCLC ultimately relapse. Dysregulation of the MET pathway is implicated as...

TPS4151 Background: Patients (pts) with HCC have a poor prognosis. Effective treatments are limited, particularly in Asia, which carries about 80% of the HCC burden. In a Phase I trial (Falchook et...

4051 Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor, the MET receptor ligand. This study assessed the safety, PK, and tumor response of R + CX in J...

e19047 Background: MET amplification is recognized as one of common molecular mechanisms of acquired resistance (AR) to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in advanced non-small-cell lung cancer (NSCLC). The aim of the present study is to investigate the frequency of MET overexpression, the correlated clinicopathologic features and the possible treatments in NSCLC with AR. Methods: Advanced NSCLC patients with AR to EGFR TKIs were detected for MET overexpression by immunohistochemistry (IHC). ≥50% tumor cells with moderate to high intensity staining were defined as MET positive. MET positive patients were recommended to participate a clinical trial if eligible or receive other molecularly targeted therapies. The statuses of EGFR, ALK, KRAS and ROS1 were also tested. Results: From January 2013 to January 2014, 58 advanced NSCLC patients with AR to gefitinib or erlotinib were enrolled prospectively. The frequencies of MET overexpression was 32.8% (19/58), MET overexpressi...

The tyrosine kinase receptor encoded by the MET oncogene has the unusual property of mediating the invasive growth of epithelial cells upon binding with the hepatocyte growth factor (HGF). The MET/HGF receptor is known to be overexpressed in thyroid carcinomas originated from follicular cells, but has not been reported in C cell tumors. To investigate the role of HGF and of its receptor (encoded by MET oncogene) in medullary carcinoma of the thyroid (MCT), we studied the expression of HGF and MET in 20 cases by means of different techniques. By RT-PCR, HGF mRNA was found in 10/20 cases, while MET mRNA presence was demonstrated in 8/20, of which 7 also expressed HGF. Northern blot analysis and in situ hybridization were performed in selected cases and confirmed RT-PCR data in some cases, although the lower sensitivity of these procedures did not allow the identification of all RT-PCR positive cases. By immunohistochemistry (using specific monoclonal antibodies) HGF was demonstrated in 8/9 RT-PCR positive cases and a monoclonal to MET immunostained 5/6 RT-PCR positive cases. All receptor positive cases also expressed the ligand in the same tumor cell population. These findings demonstrate MET and HGF co-expression in a subset of MCT, in which autocrine/paracrine circuits may be active. No correlation was found between HGF/MET expression and clinico-pathological parameters, except for the more common multifocality of HGF/MET positive MCT. Whether the potential activation of MET in MCT is responsible for local invasion and malignant evolution is to be further investigated, especially in multifocal and aggressive tumors.

Objective: In an attempt to find more efficacious alternatives for the diagnosis of gestational diabetes mellitus, we evaluated whether (1) there is a glucose loading test value above which all glucose tolerance test results are positive, (2) omission of the third-hour plasma glucose measurement of the glucose tolerance test alters the sensitivity of the test, and (3) the presence of a fasting plasma glucose concentration ≥105 mg/dL suffices as a diagnostic standard after an abnormal glucose loading test result. Study Design: The charts of 512 patients who underwent 3-hour glucose tolerance tests at our institution between January 1995 and December 1996 were reviewed. Only subjects for whom the glucose loading test yielded plasma glucose levels ≥140 mg/dL were selected. The positive predictive value of a glucose loading test result ≥185 mg/dL was calculated. Results of glucose tolerance tests of subjects with elevated fasting plasma glucose concentrations were then evaluated to determine the positive predictive value for gestational diabetes mellitus of an elevated fasting plasma glucose concentration. Results: Among the subjects who underwent glucose tolerance tests, 22% (114/512) met positive test criteria for gestational diabetes mellitus. The positive predictive value for a glucose loading test result ≥185 mg/dL was 57% (25/44), whereas a glucose loading test result >199 mg/dL showed a positive predictive value of 69% (4/13). Omission of the third-hour glucose tolerance test value yielded a sensitivity of 87% (99/114). Among the 24 women with fasting plasma glucose concentrations ≥105 mg/dL, 96% had positive glucose tolerance test results. An elevated fasting plasma glucose concentration was highly associated with gestational diabetes mellitus necessitating insulin therapy (65%). Conclusion: An elevated glucose loading test result was associated with but not highly predictive of gestational diabetes mellitus. Omission of the 3-hour glucose tolerance test measurement resulted in failure to diagnose 13% of gestational diabetes mellitus cases. A fasting plasma glucose concentration ≥105 mg/dL was highly predictive of an abnormal glucose tolerance test result among patients with an elevated glucose loading test value. (Am J Obstet Gynecol 1999;181:1158-61.)

TPS4155 Background: Dysregulation of the HGF/MET pathway in patients with gastroesophageal cancer (GEC) is associated with diminished survival and poor prognostic features, such as nodal and organ metastasis, disease stage and tumor invasiveness. Preclinical data suggest that inhibition of the HGF/MET axis may increase the anti-tumor properties of platinum agents by overcoming HGF-mediated resistance mechanisms. Overexpression and inappropriate activation of the MET pathway has been shown to promote peritoneal metastasis in murine models of GEC. Overexpression of HGF or MET has also been linked to metastatic spread to the liver and peritoneum in patients with GEC. Clinical studies suggest that antibody-based inhibitors of the HGF/MET pathway are active in GEC. Onartuzumab, a monovalent monoclonal antibody, specifically binds to the MET receptor preventing HGF binding thereby inhibiting signal transduction. The most commonly reported adverse events associated with onartuzumab are grade 1–3 peripheral edema, hypoalbuminemia and fatigue. Methods: MetGastric is a randomized placebo-controlled, international phase III study in patients with previously untreated metastatic GEC. Only patients with tumors classified as both HER2-negative and MET-positive (by IHC) are eligible. Patients will be randomized (1:1) to receive mFOLFOX6 plus onartuzumab or mFOLFOX6 plus placebo. A maximum of 12 cycles of mFOLFOX6 are permitted. Onartuzumab or placebo will be continued until disease progression. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, overall response rate, safety and correlative biomarker studies. Primary and secondary analyses will include all randomized patients, analyzed according to treatment arm assignment and MET IHC score. Safety will be assessed in all patients who receive at least one dose of study treatment. This study is open for accrual. Clinical trial information: NCT01662869.

TPS4153 Background: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor that inhibits signaling through the MET receptor. In a randomized phase II study in patients with advanced G/GEJ adenocarcinoma, addition of rilotumumab every 3 weeks (Q3W) to ECX showed trends toward improved overall survival (OS) and progression-free survival (PFS) compared with ECX alone. In patients with high tumor MET expression and high rilotumumab exposure, the treatment effect of rilotumumab combined with ECX was significantly enhanced. Methods: In this phase III study, patients (planned N=450) are randomized 1:1 to ECX (intravenous [IV] epirubicin 50 mg/m2 on day 1, IV cisplatin 60 mg/m2 on day 1, and oral capecitabine 625 mg/m2 twice daily on days 1−21) plus double-blind rilotumumab 15 mg/kg or placebo IV Q3W. Randomization is stratified by disease extent (locally advanced vs metastatic) and Eastern Cooperative Oncology Group (ECOG) score (0 vs 1). Key eligibility criteria include previously untreated, pathologically confirmed unresectable locally advanced or metastatic G/GEJ adenocarcinoma; ECOG score 0 or 1; ≥18 years old; MET-positive by centralized immunohistochemistry; HER2-negative; adequate organ function; and ≥6 months since neoadjuvant/adjuvant therapy. The primary endpoint is OS. Key secondary endpoints include PFS, 12-month survival rate, objective response, OS in MET expression tertiles, safety, and pharmacokinetics. An exploratory objective is to assess associations between outcomes and tumor and circulating biomarkers. Enrollment began in November 2012, and the trial continues to accrue. An independent data monitoring committee will conduct planned interim reviews for safety and efficacy. Status: recruiting participants. Sponsored by Amgen Inc. Clinical trial information: NCT01697072.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Under normal conditions MET receptor activation, internalization, and degradation is a highly controlled process regulated by the binding of its ligand, HGF. In many cancers however, MET becomes highly dysregulated, and MET overexpression, with or without gene amplification, is associated with a poorer prognosis. Aberrant activation of MET can also occur through mutation, or increased autocrine or paracrine HGF production. MET activation leads to increased oncogenic activities including cell migration, proliferation, invasion, survival, tumor neovascularization and decreased apoptosis. Several inhibitors of MET, including type I and type II kinase inhibitors, are currently being investigated in clinical trials. LY2801653 is a type II MET kinase inhibitor being investigated in patients with advanced cancer (trial I3O-MC-JSBA, [NCT01285037][1]). In addition to MET, LY2801653 also inhibits ROS1 kinase, and the serine/threonine kinases MKNK1/2, with cell-based IC50 of 23nM and 7nM respectively. ROS1 is an orphan receptor that can be constitutively activated as a fusion protein either by genomic microdeletion or translocation. ROS1 fusion proteins are found in glioblastoma, NSCLC and cholangiocarcinoma. MKNK1/2 are kinases downstream of ERK and p38 and are capable of regulating translation through the direct phosphorylation of eIF4E. Increased MKNK1/2-dependent phosphorylation of the translation factor eIF4E is observed in head and neck squamous cell carcinoma and is correlated with a poor prognosis. This study evaluated the relative inhibitory effects of LY2801653, Crizotinib, XL184, XL880, and PF4217903 in a variety of cell lines against MET, ROS1, MKNK1/2, ERK, and other downstream molecules. In HCC78, a ROS1-fusion protein bearing cell line, and in NIH3T3 cells stably transfected with the FIG-ROS(s) fusion, LY2801653, XL184 and XL880 were more potent inhibitors of ROS1 compared with Crizotinib. Moreover, LY2801653 and Crizotinib were both efficacious in NIH3T3 FIG-ROS(s) xenografts, although LY2801653 was more potent in reducing p-ROS1 in these tumors than Crizotinib. In NCI-H2122 and Hs746T cells (mutated MET), A2780 cells (MET-negative), KP-4 cells (MET autocrine), H441 cells (HGF-independent; MET positive), HCT116 (mutated KRAS), and the cholangiocarcinoma cell lines EGI-1 and TFK-1, LY2801653 demonstrated more potent inhibitory activity against MKNK1/2 versus treatment with XL184 and XL880, while Crizotinib had no observed inhibitory activity against MKNK1/2. LY2801653 also showed inhibitory activity against MKNK1/2 in MET-amplified MKN45 cells. These findings suggests there may be clinical merits to testing LY2801653 in tumor types associated with increased MKNK1/2 activity or ROS1 fusion proteins alone, or in conjunction with aberrant MET activity, such as colorectal carcinoma, head and neck squamous cell carcinoma, and cholangiocarcinoma. Citation Format: Sau-Chi B. Yan, Megan N. Thobe, Bruce W. Konicek, Victoria L. Peek, Suzane L. Um, Richard A. Walgren, Huaxing Pei, Timothy P. Burkholder, Jeremy R. Graff. LY2801653: An orally bioavailable MET kinase inhibitor with inhibitory activity against the oncoproteins ROS1 and MKNK1/2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3042. doi:10.1158/1538-7445.AM2013-3042 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01285037&atom=%2Fcanres%2F73%2F8_Supplement%2F3042.atom

Overexpression of MET has been reported in various malignancies and is associated with cell proliferation, inhibition of apoptosis and metastasis. MET amplification has been reported to contribute to acquired resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in non-small-cell lung cancer (NSCLC), being observed among 5–10% of those patients. Therefore, MET gene alterations could be both prognostic and predictive, and evaluation of that is indispensable in practice. However, the frequency of positive cases varies due to a lack of standardized criteria of fluorescence in situ hybridization (FISH). The purpose of this study is to find which criteria could be useful in terms of the association with clinical characteristics. We evaluated the MET gene copy number of FISH using two different criteria in lung adenocarcinoma: the Cappuzzo scoring system and PathVysion and its association with clinicopathological characteristics. MET positive cases according to the Cappuzzo scoring system evidenced both aneuploidy and true amplification, whereas PathVysion revealed only amplification. One hundred and thirty-eight lung adenocarcinoma tissue samples were evaluated, and the proportion of MET FISH positive cases was 15 and 4% determined by the Cappuzzo system and PathVysion, respectively. PathVysion demonstrated higher frequencies of MET FISH positives among men and smokers and evidenced no MET FISH positives in patients with bronchioloalveolar carcinoma. Prognosis was significantly associated with MET FISH positive only as defined by the PathVysion system (gene amplification), not by the Cappuzzo system. However, the progression-free survival time of patients with both EGFR mutations and MET FISH positive defined by the Cappuzzo scoring system was significantly shorter than with EGFR mutations alone. These results suggest that MET FISH is a potential prognostic factor and co-existence of MET FISH with EGFR mutations signifies worse prognosis.

Background R (AMG 102) is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor, the MET receptor ligand. Safety and efficacy of a placebo-controlled, double-blind, randomized phase 2 study of R + ECX in G/EGJ cancer from a 12.5-month (mo) follow up were previously reported (Iveson et al, Eur J Cancer. 2011; 47(suppl 1):S443. abstract 6.504). Updated data from a 21.7-mo follow up are presented. Methods Eligibility included unresectable, locally advanced or metastatic G/EGJ adenocarcinoma; ECOG PS ≤1; and no prior systemic therapy for this disease. Patients (pts) were randomized 1:1:1 to ECX (50 mg/m2 IV day 1, 60 mg/m2 IV day 1, 625 mg/m2 BID orally days 1–21, respectively) + R 15 mg/kg (Arm A); R 7.5 mg/kg (Arm B); or placebo (Arm C) IV day 1 every 3 weeks. Overall survival (OS) and progression-free survival (PFS) were evaluated. MET protein was measured in archival tumor samples by IHC. R serum concentrations for all pts were measured. Individual R steady-state Cminss were estimated with a population PK model. Results 121 pts (Arms A/B/C: 40/42/39) were randomized Oct 2009 to June 2010. See table for data (Jan 16, 2012 cutoff). Conclusions Within the context of a small, randomized phase 2 study, R + ECX improved outcomes in G/EGJ cancer pts. The treatment effect was strongest in pts with high MET tumors and high R exposure. Consistent with previously reported data, these results show continued separation of Arm A + B vs C beyond 16 mo. A planned phase 3 study will test the safety and efficacy of R + ECX in MET-positive G/EGJ cancer. Table: 687P Median OS (80% CI), mo OS HR (95% CI) Median PFS (80% CI), mo PFS HR (95% CI) All pts Arm A + B n = 82 10.6 (9.5–12.0) 5.7 (5.1–6.9) Arm C n = 39 8.9 (5.7–10.6) 4.2 (3.7–4.6) Arm A + B vs C 0.70 (0.45–1.09) 0.60 (0.39–0.91) METH * Arm A + B n = 27 11.5 (9.2–12.1) 6.9 (5.5–7.5) Arm C n = 11 5.7 (4.5–10.4) 4.6 (3.7–5.2) Arm A + B vs C 0.34 (0.15–0.78) 0.44 (0.20–0.96) METH * , RH † Arm A + B n = 13 17.6 (13.3–21.0) 10.7 (6.9–15.3) Arm C n = 11 5.7 (4.5–10.4) 4.6 (3.7–5.2) Arm A + B vs C 0.18 (0.06–0.52) 0.19 (0.06–0.57) * Pts with >50% tumor cells MET positive, † Pts with R median Cminss ≥ 94 µg/mL. Disclosure T. Iveson: Dr. Iveson received research funding and travel payment from Amgen Inc. Y. Jiang: Dr. Jiang is an employee of and owns stock in Amgen Inc. M. Zhu: Dr. Zhu is an employee of and owns stock in Amgen Inc. K.S. Oliner: Dr. Oliner is an employee of and owns stock in Amgen Inc. S. Dubey: Dr. Dubey is an employee of and owns stock in Amgen Inc. E. Loh: Dr. Loh is an employee of and owns stock in Amgen Inc. All other authors have declared no conflicts of interest.

Background Dysregulation of the HGF/Met pathway has been associated with tumorigenesis in many malignancies, including NSCLC. Onartuzumab (MetMAb) is a recombinant, humanized, monovalent monoclonal antibody directed against Met. By binding to the extracellular domain of Met, onartuzumab selectively blocks ligand binding and subsequent activation by HGF. Current data support a strategy of combining onartuzumab with numerous chemotherapies and targeted agents (bevacizumab, erlotinib). In a phase Ia/Ib study, onartuzumab (monotherapy and in combination with bevacizumab) was shown to be well tolerated in pts with advanced solid tumors (Moss et al. Ann Oncol 2010;21(Suppl. 8):Abstr. 504P). A phase II study of onartuzumab in combination with erlotinib in pts with previously treated NSCLC reported a significant benefit in PFS (HR 0.53; p = 0.04) and OS (HR 0.37; p = 0.002) in pts with Met-positive (Met IHC diagnostic positive) tumors (Spigel et al. J Clin Oncol 2011;29 (Suppl.):Abstr. 7505). Pts with Met-negative tumors who received onartuzumab + erlotinib reported worse outcomes compared with erlotinib alone (PFS HR 1.82; p = 0.05; OS HR 1.78; p = 0.16). The most commonly reported adverse events associated with onartuzumab are peripheral edema and fatigue. Methods In this phase II study, pts with squamous NSCLC are randomized (1:1) to receive 4 cycles of paclitaxel, cisplatin (or carboplatin) and either placebo or onartuzumab. Pts without disease progression may continue to receive placebo or onartuzumab as maintenance therapy until disease progression, unacceptable toxicity, or death. The primary study endpoint is PFS in all pts. PFS by Met IHC diagnostic status (Met positive vs Met negative) will also be analyzed. Secondary endpoints include OS, ORR, safety, and PK. A minimum of 110 pts will be randomized to achieve 55 pts with Met-positive squamous NSCLC. A maximum of 55 pts with Met-negative squamous NSCLC will be enrolled. This study is open for accrual; further details can be found on ClinicalTrials.gov (NCT01519804). Disclosure F.R. Hirsch: Advisory relationship: Genentech-Roche, Boehringer-Ingelheim, Pfizer, Merck-Serono, Bristol-Myers Squibb. Research funding (through University of Colorado): Imclone-Lilly, Celgene, Morphotek. Board of Directors: IASLC. D. Gandara: Dr. Gandara reports a consultant/advisory relationship with Genentech, Inc. He also receives research funding from Genentech, Inc. R. Govindan: Dr. Govindan reports a consultant/advisory relationship with Bristol-Myers Squibb, Boehringer-Ingelheim, Astra Zeneca, Pfizer, Genentech, Inc. and GlaxoSmithKline. V.E. Paton: Dr Paton is a full-time employee of Genentech, Inc. and minor stockholder of Hoffmann-La Roche, Inc. W. Yu: Dr Yu is a full-time employee of Genentech, Inc. and minor stockholder of Hoffmann-La Roche, Inc.

MET, which is located in 7q31, is a receptor tyrosine kinase for hepatocyte growth factor. Overexpression of MET has been reported in various malignancies and is associated with cell proliferation, inhibition of apoptosis, and metastasis. MET amplification has been reported to contribute to acquired resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in non-small cell lung cancer(NSCLC), being observed among 5-10% of those patients. Therefore, MET gene alterations could be both prognostic and predictive. To evaluate MET gene copy number, fluorescence in situ hybridization (FISH), real-time PCR, and comparative genomic hybridization (CGH) have been used. The results of real-time PCR do not directly reflect cancer cells. CGH is not suitable for the evaluation of a large number of specimens due to cost. Therefore, FISH is the most practical method for evaluation of MET gene copy number. However, the frequency of positive cases varies due to a lack of standardized criteria. We evaluated MET gene copy number in lung adenocarcinoma and its association with clinicopathological characteristics. FISH was applied to evaluate high MET gene copy number and true amplification in 138 lung adenocarcinoma patients using two criteria: the Cappuzzo scoring system and PathVysion. MET positive cases according to the Cappuzzo scoring system evidenced both aneuploidy and true amplification, whereas PathVysion revealed only amplification. Proportion of MET FISH positive cases was 15% and 4% determined by the Cappuzzo system and PathVysion, respectively. PathVysion demonstrated higher frequencies of MET FISH positives among men and smokers and evidenced no MET FISH positives in patients with bronchioloalveolar carcinoma, which is recognized as pure lepidic growth without invasion of stroma, blood vessels, or pleura. Prognosis was significantly associated with MET FISH positive only as defined by the PathVysion system (gene amplification), not by the Cappuzzo system. However, progression-free survival time of patients with both EGFR mutations and MET FISH positive defined by the Cappuzzo scoring system was significantly shorter than with EGFR mutations alone. These results suggest that MET FISH is a potential prognostic factor and co-existence of EGFR mutation and MET FISH positive status evidences poorer prognosis compared to EGFR mutation alone, which is consistent with the results of in vitro experiments. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1737. doi:1538-7445.AM2012-1737