MET Dysregulation Research Articles

Biophysical and structural characterization of the impacts of MET phosphorylation on tepotinib binding

The receptor tyrosine kinase MET is activated by hepatocyte growth factor binding, followed by phosphorylation of the intracellular kinase domain (KD) mainly within the activation loop (A-loop) on Y1234 and Y1235. Dysregulation of MET can lead to both tumor growth and metastatic progression of cancer cells. Tepotinib is a highly selective, potent type Ib MET inhibitor and approved for treatment of non-small cell lung cancer harboring METex14 skipping alterations. Tepotinib binds to the ATP site of unphosphorylated MET with critical π-stacking contacts to Y1230 of the A-loop, resulting in a high residence time. In our study, we combined protein crystallography, biophysical methods (surface plasmon resonance, differential scanning fluorimetry), and mass spectrometry to clarify the impacts of A-loop conformation on tepotinib binding using different recombinant MET KD protein variants. We solved the first crystal structures of MET mutants Y1235D, Y1234E/1235E, and F1200I in complex with tepotinib. Our biophysical and structural data indicated a linkage between reduced residence times for tepotinib and modulation of A-loop conformation either by mutation (Y1235D), by affecting the overall Y1234/Y1235 phosphorylation status (L1195V and F1200I) or by disturbing critical π-stacking interactions with tepotinib (Y1230C). We corroborated these data with target engagement studies by fluorescence cross-correlation spectroscopy using KD constructs in cell lysates or full-length receptors from solubilized cellular membranes as WT or activated mutants (Y1235D and Y1234E/1235E). Collectively, our results provide further insight into the MET A-loop structural determinants that affect the binding of the selective inhibitor tepotinib.

Improved Survival Outcomes in Patients With MET-Dysregulated Advanced NSCLC Treated With MET Inhibitors: Results of a Multinational Retrospective Chart Review

BackgroundWe evaluated the disease and patient characteristics, treatment, and MET testing patterns, predictive biomarkers and survival outcomes in patients with MET-dysregulated metastatic non–small-cell lung cancer (NSCLC) in a real-world setting. Patients and MethodsThis was a multinational, retrospective, noninterventional chart review study. Data from medical records of patients with advanced/metastatic EGFR wild-type, MET-dysregulated NSCLC (December 2017-September 2018) were abstracted into electronic data collection forms. ResultsOverall, 211 patient charts were included in this analysis; 157 patients had MET exon 14 skipping mutations (METex14; with or without concomitant MET amplification) and 54 had MET amplification only. All patients were tested for METex14, whereas MET amplification was evaluated in 168 patients. No overlap was reported between MET dysregulation and ALK, ROS1 or RET rearrangements, or HER2 exon 20 insertions. Overall, 56 of 211 patients (26.5%) received MET inhibitor (METi) therapy in any treatment-line setting (31.2% in the METex14 cohort; 13% in the MET-amplified only cohort). In the METex14 cohort, median OS in patients receiving METi was 25.4 months versus 10.7 months in patients who did not (HR [95% CI]: 0.532 [0.340-0.832]; P = .0055). In the MET-amplified only cohort, median OS was 20.6 months in patients treated with METi compared with 7.6 months in those without METi (HR [95% CI]: 0.388 [0.152-0.991]; P = .0479). ConclusionsMET alterations in NSCLC typically occur in the absence of other oncogenic driver mutations and are associated with poor survival outcomes. Notably, METi therapies are associated with improved survival outcomes in patients with MET-dysregulated NSCLC.

Longitudinal Plasma Proteomics-Derived Biomarkers Predict Response to MET Inhibitors for MET-Dysregulated NSCLC.

MET inhibitors have shown promising efficacy for MET-dysregulated non-small cell lung cancer (NSCLC). However, quite a few patients cannot benefit from it due to the lack of powerful biomarkers. This study aims to explore the potential role of plasma proteomics-derived biomarkers for patients treated with MET inhibitors using mass spectrometry. We analyzed the plasma proteomics from patients with MET dysregulation (including MET amplification and MET overexpression) treated with MET inhibitors. Thirty-three MET-dysregulated NSCLC patients with longitudinal 89 plasma samples were included. We classified patients into the PD group and non-PD group based on clinical response. The baseline proteomic profiles of patients in the PD group were distinct from those in the non-PD group. Through protein screening, we found that a four-protein signature (MYH9, GNB1, ALOX12B, HSD17B4) could predict the efficacy of patients treated with MET inhibitors, with an area under the curve (AUC) of 0.93, better than conventional fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) tests. In addition, combining the four-protein signature with FISH or IHC test could also reach higher predictive performance. Further, the combined signature could predict progression-free survival for MET-dysregulated NSCLC (p < 0.001). We also validated the performance of the four-protein signature in another cohort of plasma using an enzyme-linked immunosorbent assay. In conclusion, the four plasma protein signature (MYH9, GNB1, ALOX12B, and HSD17B4 proteins) might play a substitutable or complementary role to conventional MET FISH or IHC tests. This exploration will help select patients who may benefit from MET inhibitors.

Abstract CT558: Capmatinib vs docetaxel as second- or third-line therapy in patients with locally advanced or metastatic METex14-mutated NSCLC: The GeoMETry-III trial

Abstract Background: MET dysregulation is a poor prognostic factor in advanced non-small cell lung cancer (NSCLC). MET exon 14 skipping (METex14) mutations occur in ~3% of patients with NSCLC. There is limited evidence of the efficacy of standard therapies, such as chemotherapy or immunotherapy, in patients with METex14-mutated advanced NSCLC. Capmatinib, a MET inhibitor (METi), is approved for the treatment of adult patients with metastatic METex14-mutated NSCLC, based on the results of the phase 2 GEOMETRY mono-1 study. Results (data cutoff: September 18, 2020) of this study in patients with METex14-mutated NSCLC treated with capmatinib showed an overall response rate (ORR) of 66.7% in first line (N=60), 51.6% in second line (N=31) and 40.6% in second- or third-line (2/3L; N=69). GeoMETry-III (NCT04427072) is a multicenter, open-label, randomized, controlled, global, phase 3 trial that is further evaluating the efficacy and safety of capmatinib vs docetaxel in the 2/3L setting in patients with METex14-mutated NSCLC. Methods: This study began enrollment in September 2020 and is currently recruiting adult patients with EGFR wild-type, ALK-negative, stage IIIB/IIIC/IV METex14-mutated NSCLC, who have progressed on 1 or 2 prior lines of systemic therapy for advanced/metastatic disease and are candidates for single-agent docetaxel. Other eligibility criteria include ≥1 measurable lesion per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), an Eastern Cooperative Oncology Group performance status of ≤1 and no prior treatment with any METi or hepatocyte growth factor-targeting therapies. Patients with neurologically unstable, symptomatic central nervous system (CNS) metastases or those requiring increasing doses of steroids ≤2 weeks prior to study entry to manage CNS symptoms are excluded. Around 90 patients will be randomized 2:1 to receive either oral capmatinib 400 mg twice daily or intravenous docetaxel 75 mg/m2 every 21 days. Randomization is stratified by number of prior lines (1 or 2) of systemic therapy. Patients meeting protocol-specified eligibility criteria can cross over from the docetaxel to the capmatinib arm after blinded independent review committee (BIRC)-confirmed progressive disease as per RECIST 1.1.The primary endpoint is progression-free survival (PFS) by BIRC per RECIST 1.1. The key secondary endpoint is ORR by BIRC per RECIST 1.1. Other secondary endpoints include investigator-assessed ORR and PFS; duration of response, time to response and disease control rate (DCR) by BIRC and investigator; overall survival; safety; pharmacokinetics; patient-reported outcomes; overall intracranial response rate, intracranial DCR, duration of- and time to- intracranial response by BIRC per the Response Assessment in Neuro-Oncology Brain Metastases criteria in patients with baseline CNS lesions. Citation Format: Pierre Jean Souquet, Sang-We Kim, Johan F. Vansteenkiste, Anna Robeva, Aline Jary, Sabine Glaser, Alejandro Yovine, Juergen Wolf. Capmatinib vs docetaxel as second- or third-line therapy in patients with locally advanced or metastatic METex14-mutated NSCLC: The GeoMETry-III trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT558.

Phase I results of S49076 plus gefitinib in patients with EGFR TKI-resistant non-small cell lung cancer harbouring MET/AXL dysregulation

BackgroundMET and AXL dysregulation is reported as a bypass mechanism driving tumour progression in non-small cell lung cancer (NSCLC) with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This non-comparative phase I study investigated the combination of gefitinib with S49076, a MET/AXL inhibitor, in advanced EGFR TKI-resistant NSCLC patients with MET and/or AXL dysregulation. MethodsPatients received S49076 at escalating doses of 500 or 600 mg with a fixed dose of 250 mg gefitinib orally once daily in continuous 28day cycles. MET and AXL dysregulation and EGFR/T790M mutation status were centrally assessed in tumour biopsies at screening. Tumour response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST). EGFR TKI resistance mechanisms were analysed by next-generation sequencing. The clonal evolution of tumours was monitored with the analysis of circulating tumour DNA. ResultsOf 92 pre-screened patients, 22 met the molecular inclusion criteria and 14 were included. The recommended dose was 600 mg daily S49076. Best overall responses were 2 partial responses (1 patient with MET dysregulation only, 1 MET and AXL co-dysregulation) and 8 patients with stable disease. Other potential concomitant mechanisms of resistance to EGFR TKI were identified in more than half of the included patients. ConclusionsS49076 plus gefitinib demonstrated a good tolerability with limited anti-tumour activity. Due to the low number of eligible patients, no tendency in term of activity appeared in any specific molecular subset and the data did not allow for identification of AXL overexpression as an oncogenic driver.

The Clinical Impact of Capmatinib in the Treatment of Advanced Non-Small Cell Lung Cancer with MET Exon 14 Skipping Mutation or Gene Amplification.

PurposeCapmatinib, an oral MET kinase inhibitor, has demonstrated its efficacy against non–small cell lung cancer (NSCLC) with MET dysregulation. We investigated its clinical impact in advanced NSCLC with MET exon 14 skipping mutation (METex14) or gene amplification.Materials and MethodsPatients who participated in the screening of a phase II study of capmatinib for advanced NSCLC were enrolled in this study. MET gene copy number (GCN), protein expression, and METex14 were analyzed and the patients’ clinical outcome were retrospectively reviewed.ResultsA total of 72 patients were included in this analysis (group A: GCN ≥ 10 or METex14, n=14; group B: others, n=58). Among them, 13 patients were treated with capmatinib (group A, n=8; group B, n=5), and the overall response rate was 50% for group A, and 0% for group B. In all patients, the median overall survival (OS) was 20.2 months (95% confidence interval [CI], 6.9 to not applicable [NA]) for group A, and 11.3 months (95% CI, 8.2 to 20.3) for group B (p=0.457). However, within group A, median OS was 21.5 months (95% CI, 20.8 to NA) for capmatinib-treated, and 7.5 months (95% CI, 3.2 to NA) for capmatinib-untreated patients (p=0.025). Among all capmatinib-untreated patients (n=59), group A showed a trend towards worse OS to group B (median OS, 7.5 months vs. 11.3 months; p=0.123).ConclusionOur data suggest that capmatinib is a new compelling treatment for NSCLC with MET GCN ≥ 10 or METex14 based on the improved survival within these patients.

Genotyping of Cerebrospinal Fluid Associated With Osimertinib Response and Resistance for Leptomeningeal Metastases in EGFR-Mutated NSCLC.

Patients with NSCLC with leptomeningeal metastases (LM) presented dismal prognosis. Cerebrospinal fluid (CSF) is suggested as a medium of liquid biopsy of LM. However, the clinical implications of CSF genotyping on treatment outcomes remained elusive. Patients with EGFR-mutated advanced NSCLC with LM were included: cohort 1, patients with LM who were treated with osimertinib with CSF and plasma genotyping performed before the first dosing of osimertinib (baseline, n= 45); cohort 2, CSF genotyping on progression on osimertinib and development of LM (the progression event on osimertinib is the diagnosis of LM, n= 35). Circulating tumor DNA in CSF underwent next-generation sequencing. Sensitivity of CSF genotyping for EGFR-sensitizing mutations was 93.3% (42 of 45) and 97.1% (34 of 35) in cohorts 1 and 2, respectively. In cohort 1, patients with EGFR exon 19 deletion had higher median intracranial progression free survival (iPFS) than those with EGFR exon 21 L858R mutation (11.9 versus 2.8 mo; p= 0.02). Median iPFS was significantly longer in patients with T790M-positive CSF genotyping (15.6 mo) than T790M-negative CSF (7.0 mo, p= 0.04). Concurrent CDK4 (2.8 versus 11.6 mo, p= 0.002) and CDKN2A (2.5 versus 9.6 mo, p= 0.04) mutation with EGFR-sensitizing mutations indicated lower median iPFS. Patients with T790M-negative CSF, EGFR exon 21 L858R mutation, concurrent FGF3 alteration, and over first-line osimertinib had shortened iPFS. In cohort 2, possible EGFR-related and EGFR-independent resistance mechanisms were found including C797S mutation, MET dysregulation, and TP53 plus RB1 co-occurrence. Patients with loss of T790M in CSF had a shorter median iPFS (7.4 mo) compared with those with reserved T790M (13.6 mo, p= 0.01). Genotyping of CSF indicated heterogeneous response to osimertinib and revealed the genetic characteristic of LM on osimertinib failure in patients with EGFR-mutated NSCLC diagnosed with LM.

481P - Bioavailability of tepotinib: Impact of omeprazole and food

BackgroundAcid-inhibitory drugs (e.g. proton pump inhibitors - PPIs) increase intragastric pH, which may decrease solubility, bioavailability, and efficacy of oral cancer drugs. Furthermore, polypharmacy in cancer patients is common and different requirements for treatment with or without food can impact compliance. Tepotinib is an oral, highly selective MET inhibitor being investigated in patients with solid tumors with MET dysregulation (METex14 mutations or MET amplification). In the pivotal clinical trial, tepotinib has been administered with breakfast; this represents the intended posology. Tepotinib has pH-dependent low solubility, suggesting that food intake and/or co-administration with a PPI may impact bioavailability. We investigated the effects of the PPI omeprazole and food on tepotinib. MethodsIn a 3-period, cross-over study, healthy volunteers (n=12) received 500mg/day tepotinib as a single dose 30 mins after a continental breakfast (treatment A) and co-administered on Day 5 after receiving omeprazole (40mg QD for 5 days) under fasted conditions (treatment B) and after a continental breakfast (treatment C). The impact of omeprazole on the AUC0-t, AUC0-∞, and Cmax of tepotinib under fed conditions was evaluated comparing treatments A and C; corresponding ratios of the geometric least-squares means (GLSM) (90% CI) were reported. In a separate study, food effect was investigated in healthy volunteers (n=12) by administering single doses of 500mg tepotinib under fasted state and after a high-fat, high-calorie breakfast. ResultsIn the first study, there was a negligible effect of omeprazole co-administration on the bioavailability of tepotinib under fed conditions. The GLSM ratios (90% CI) for treatment C/A were 1.09 (1.01, 1.17) for AUC0-t; 1.10 (1.02, 1.19) for AUC0-∞; and 1.04 (0.93, 1.17) for Cmax. In the second study, the ratio (90% CI) of “high-fat” /”fasted” for tepotinib AUC0-∞ was 1.87 (1.64, 2.13) and for Cmax was 2.37 (2.16, 2.59). ConclusionsThe intended posology of tepotinib, i.e. with food, is in agreement with the moderate food effect (approximately 2-fold increase in exposure of tepotinib). When tepotinib is administered at 500mg/day together with food, co-administration of PPI is not expected to have clinically relevant drug interactions. Clinical trial identificationNCT03531762 and NCT03629223. Editorial acknowledgementMedical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Sandra Cuscó, PhD of Bioscript Group (Macclesfield, UK). Legal entity responsible for the studyMerck Healthcare KGaA. FundingMerck Healthcare KGaA. DisclosureR. Strotmann: Full / Part-time employment: Merck Healthcare KGaA. A. Becker: Full / Part-time employment: Merck Healthcare KGaA. A. Krebs-Brown: Full / Part-time employment: Merck Healthcare KGaA. N. Mammasse: Full / Part-time employment: Merck Healthcare KGaA. Ö. Yalkinoglu: Full / Part-time employment: Merck Healthcare KGaA. All other authors have declared no conflicts of interest.

MA09.09 Long-Term Outcomes to Tepotinib Plus Gefitinib in Patients with EGFR-Mutant NSCLC and MET Dysregulation: 18-Month Follow-Up

MA09.09 Long-Term Outcomes to Tepotinib Plus Gefitinib in Patients with EGFR-Mutant NSCLC and MET Dysregulation: 18-Month Follow-Up

Abstract 2521: Molecular profiling of T790M-negative NSCLC patients progressing on EGFR-TKI enrolled in the CL1-49076-003 trial with a MET/AXL/FGFR inhibitor in combination with gefitinib

Abstract Background Non-small cell lung cancer (NSCLC) tumors with mutations in the EGF receptor (EGFR) relapse to therapy with EGFR tyrosine kinase inhibitors (EGFR TKIs) due to a variety of mechanisms, such as emergence resistance mutations, dysregulation of AXL, MET, HER2 or FGFR1 receptors or histological transformation. The CL1-49076-003 trial of the MET/AXL/FGFR inhibitor S49076 in combination with gefitinib enrolled T790M-negative patients in progression to first-line EGF TKIs and showing dysregulation of MET and/or AXL. Molecular screening was performed in 47 patients, 23 of them met the molecular eligibility criteria and 14 were enrolled in the trial. Baseline biopsies of the 14 patients were submitted to molecular profiling. Methods Ten patients had enough material available for Next Generation Sequencing (NGS), that was performed using the GeneRead QIAact Lung UMI Panel (Qiagen, Hilden, FRG). The panel included mutation detection in 16 genes, copy number variations in 5 and the MET exon 14 splicing variant. Amplifications detected by NGS were confirmed by FISH. Of the 4 patients with insufficient material for NGS, 3 were submitted to FISH for HER2 and MET and quantitative PCR for BRAF and PIK3CA hotspot mutations. Finally, of the remaining patient only FISH for MET could be performed. Results Copy number gains were the most prevalent alterations in patients progressing to EGFR TKIs. Four of 14 evaluable patients (29%) showed MET amplification, 4/13 (31%) HER2 amplification and 3/10 (30%) EGFR copy number gains. FGFR1 amplifications were absent in the patient cohort. The baseline sensitizing mutation was confirmed in all cases. Two patients showed additional mutations that could be related to resistance, namely a p.G724S mutation in EGFR and a p.N784fs*2 mutation in MET. Remarkably, these two patients did not present gene amplifications. No other mutations were detected in the rest of genes analyzed, including BRAF, PIK3CA, KRAS, NRAS or ERBB2. Among the 4 patients with more than 6 months of progression free survival, 2 had MET amplifications. The patient with the p.G724S experienced rapid progression of target lesions. Conclusion Next Generation Sequencing can be used to determine mechanisms of resistance to EGFR TKIs at progression, and can give useful clinical information in order to select therapies for second line treatment Citation Format: Monica Garzon Ibanez, Nuria Jordana Ariza, María González Cao, Ruth Román Lladó, Alejandro Martínez Bueno, Lidia Alonso Landeira, María de los Llanos Gil, Miguel Ángel Molina Vila, Niki Karachaliou, Veronika Smutna, Valerie Cattan, Rafael Rosell, Santiago Viteri. Molecular profiling of T790M-negative NSCLC patients progressing on EGFR-TKI enrolled in the CL1-49076-003 trial with a MET/AXL/FGFR inhibitor in combination with gefitinib [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 2521.

A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification

PurposeDysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation. MethodsThis was a phase I dose-escalation (3 + 3 design [50–740 mg/m2]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose-limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort. ResultsIn total, 72 patients were enrolled: dose escalation, N = 33; dose expansion, N = 39; 570 mg/m2 was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m2, five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p-MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number. ConclusionThe MTD of once-weekly SAR125844 was 570 mg/m2; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC.Clinical trial registration number: NCT01391533

Phase I study of INC280 plus erlotinib in patients with MET expressing adenocarcinoma of the lung.

2587 Background: MET dysregulation is one mechanism of EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor) resistance in patients (pts) with EGFR mutated lung cancer. INC280 is a ...

Targeting MET in Cancer: Obstacles and Potentials

MET is a tyrosine kinase receptor involved in cell proliferation, survival, and migration. MET pathway is activated in cancer by gene amplification and overexpression, ligand overexpression and autocrine/paracrine activation, and activating MET mutations. MET dysregulation is also found to be responsible for resistance to treatment and targeted therapy including EGFR TKIs for NSCLC. Preclinical studies and early phase clinical trials of inhibitors of HGF-MET pathway showed encouraging results but several late phase clinical trials failed. In trials evaluating drugs designed to inhibit HGF-MET binding, patient selection may explain the lack of efficacy in those carrying MET amplification or activating mutations. Novel drugs capable of inducing MET degradation in addition to targeting HGF-MET binding have great potential in blocking MET oncogenic pathway and demonstrating clinical efficacy.

Targeting met mediated epithelial-mesenchymal transition in the treatment of breast cancer.

Mesenchymal epithelial transition factor receptor (Met) is a receptor tyrosine kinase that plays a critical role in promoting cancer cell malignant progression. Met is activated by its ligand hepatocyte growth factor (HGF). HGF-dependent Met activation plays an important role in stimulating epithelial-mesenchymal transition (EMT) in tumor cells, resulting in increased tumor cell proliferation, survival, motility, angiogenesis, invasion, and metastasis. The HGF/Met axis has thus attracted great interest as a potential target in the development of novel cancer therapies. In an effort to suppress tumor cell malignant progression, efforts have been made to develop agents capable of inhibiting inhibit Met-induced EMT, including specific Met tyrosine kinase inhibitors, HGF antagonists that interfere with HGF binding to Met, and antibodies that prevent Met activation and/or dimerization. Tocotrienols, a subgroup within the vitamin E family of compounds, display potent anticancer activity that results, at least in part, from inhibition of HGF-dependent Met activation and signaling. The present review will provide a brief summary of the increasing importance of the HGF/Met axis as an attractive target for cancer chemotherapy and the role of tocotrienols in suppressing Met activation, signaling and HGF-induced EMT in breast cancer cells. Evidence provided suggests that γ-tocotrienol therapy may afford significant benefit in the treatment of breast cancers characterized by Met dysregulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s40169-014-0030-5) contains supplementary material, which is available to authorized users.

Emerging molecular targets in oncology: clinical potential of MET/hepatocyte growth-factor inhibitors.

The MET/hepatocyte growth-factor (HGF) signaling pathway plays a key role in the processes of embryogenesis, wound healing, and organ regeneration. Aberrant activation of MET/HGF occurs through multiple mechanisms including gene amplification, mutation, protein overexpression, and abnormal gene splicing interrupting autocrine and paracrine regulatory feedback mechanisms. In many cancers including non-small-cell lung cancer, colorectal, gastric, renal, and hepatocellular cancer, dysregulation of MET may lead to a more aggressive cancer phenotype and may be a negative prognostic indicator. Successful therapeutic targeting of the MET/HGF pathway has been achieved using monoclonal antibodies against the MET receptor and its ligand HGF in addition to MET-specific and multitargeted small-molecule tyrosine-kinase inhibitors with several drugs in late-phase clinical trials including onartuzumab, rilotumumab, tivantinib, and cabozantinib. MET frequently interacts with other key oncogenic tyrosine kinases including epidermal growth-factor receptor (EGFR) and HER-3 and these interactions may be responsible for resistance to anti-EGFR therapies. Similarly, resistance to MET inhibition may be mediated through EGFR activation, or alternatively by increasing levels of MET amplification or acquisition of novel “gatekeeper” mutations. In order to optimize development of effective inhibitors of the MET/HGF pathway clinical trials must be enriched for patients with demonstrable MET-pathway dysregulation for which robustly standardized and validated assays are required.

The potential roles of hepatocyte growth factor (HGF)-MET pathway inhibitors in cancer treatment.

MET is located on chromosome 7q31 and is a proto-oncogene that encodes for hepatocyte growth factor (HGF) receptor, a member of the receptor tyrosine kinase (RTK) family. HGF, also known as scatter factor (SF), is the only known ligand for MET. MET is a master regulator of cell growth and division (mitogenesis), mobility (motogenesis), and differentiation (morphogenesis); it plays an important role in normal development and tissue regeneration. The HGF-MET axis is frequently dysregulated in cancer by MET gene amplification, translocation, and mutation, or by MET or HGF protein overexpression. MET dysregulation is associated with an increased propensity for metastatic disease and poor overall prognosis across multiple tumor types. Targeting the dysregulated HGF-MET pathway is an area of active research; a number of monoclonal antibodies to HGF and MET, as well as small molecule inhibitors of MET, are under development. This review summarizes the key biological features of the HGF-MET axis, its dysregulation in cancer, and the therapeutic agents targeting the HGF-MET axis, which are in development.

MET dysregulation is a hallmark of aggressive disease in multiple myeloma patients

Abnormal activation of MET/HGF (Hepatocyte Growth Factor) pathway has been described in several tumours and increased HGF plasmatic levels have been detected in patients with aggressive multiple myeloma (MM). MET and HGF mRNA expression was investigated in 105 samples of purified plasma cells derived from newly diagnosed MM patients treated with bortezomib-based induction therapy. Gene expression was compared with response to therapy and clinical outcome. MET gene copy number was also evaluated. MET mRNA expression was higher in CD138(+) than in CD138(-) cells (median 76·90 vs. 11·24; P = 0·0009). Low MET mRNA expression characterized patients with better response (complete response or very good partial response) compared to other patients (median 56·10 vs. 134·83; P = 0·0006). After a median follow-up of 50 months, patients with high MET mRNA expression displayed a worse progression-free survival (PFS; P = 0·0029) and overall survival (OS; P = 0·0023) compared to those with low MET mRNA levels. Patients with both high MET mRNA expression and high β2-microglobulin level (>5·5 mg/l) had further worse median PFS (P < 0·0001) and OS (P < 0·0001). Patients carrying 4 MET gene copies (8 out of 82, 9·8%) also had a short PFS. High MET mRNA expression identifies patients with dismal PFS and OS and the combination with high β2-microglobulin further characterizes patients with worse outcome.

Activity of cabozantinib (XL184) in metastatic NSCLC: Results from a phase II randomized discontinuation trial (RDT).

7514 Background: Dysregulation of MET and VEGFR2 signaling has been observed in NSCLC and MET upregulation has been implicated in resistance to EGFR inhibitors. Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. A RDT evaluated activity and safety in 9 tumor types. Here we report on the metastatic NSCLC cohort which included patients who received prior EGFR and VEGF pathway targeted therapy. Methods: All eligible patients (pts) were required to have measurable disease at baseline. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Results: Enrollment to this cohort is complete (n = 60); all pts are unblinded. Baseline characteristics: median age 67 years; adenocarcinoma 72% and squamous cell 28%; 6 pts with known EGFR mutation (of 28 tested), all having received prior erlotinib; bone metastases 20%; median prior lines of therapy 3 (range 0 - 6); prior exposure to anti-EGFR therapy 50%, prior exposure to anti-VEGF pathway therapy 32%. Median follow-up was 2 months (range 0.4 - 22.3 months). At Wk 12, ORR per RECIST was 10% and overall disease control rate (PR+SD) was 40%. Objective tumor regression was observed in 30/47 pts (64%) with post-baseline tumor assessments, some of whom had known driver mutations in KRAS (3 pts) or EGFR (4 pts). 24 pts (40%) completed Lead-in stage with 15 randomized to continue cabo (N = 8) or to placebo (N = 7). No differences with respect to PFS were observed between treatment arms in the randomized phase of the study. Median PFS from study day 1 for all pts was 4.2 months. Most common Grade 3/4 AEs were fatigue (13%), Palmar-plantar erythrodyesthesia (8%), diarrhea (7%) and asthenia (7%); one related Grade 5 AE of hemorrhage was reported during Lead-in stage. Conclusions: Cabo treatment demonstrates activity in heavily pretreated metastatic NSCLC pts with 4.2 months median PFS, 10% RECIST response, and 64% rate of objective tumor regression. The safety profile of cabo was comparable to that seen with other VEGFR TKIs. Future studies are warranted in NSCLC.

Activity of cabozantinib (XL184) in metastatic breast cancer (MBC): Results from a phase II randomized discontinuation trial (RDT).

535 Background: Dysregulation of MET and VEGF signaling has been implicated in breast cancer development and progression, including tumor invasion and dissemination. Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. A RDT evaluated activity and safety in 9 tumor types, including MBC. Methods: Eligible patients (pts) were required to have progressive measurable disease per RECIST. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Primary endpoint in the randomized discontinuation phase was progression-free survival (PFS). Results: Enrollment to this cohort is complete (n = 45); all pts are unblinded. Baseline characteristics: median age 56; invasive ductal 86%, invasive lobular 7%; ER+ 93%, HER2+ 18%, triple- 5%; visceral disease 91%; bone metastases 73%; median prior lines of therapy 3 (range 1-8), including 71% with prior anthracyclines. Median follow-up was 2.9 mos (range 0.1 -16). 21 pts (47%) completed Lead-in stage with only 9 randomized to continue cabo (n = 5) or placebo (n = 4). Median PFS from Study Day 1 was 4.1 mos. At wk 12, objective response rate was 14% and disease control rate 48%. Tumor regression was observed in 25/39 pts (64%) with ≥1 post-baseline tumor assessment. 4/10 pts evaluable by bone scan had partial resolution of bone lesions. Of 12 pts receiving narcotics for bone pain, 5 pts reported improved pain and 2 pts had decreased narcotics use, per investigator. 4/14 evaluable pts (29%) with bone metastases experienced ≥50% decline in serum NTx. Most common Grade 3/4 AEs were palmar-plantar erythrodyesthesia (13%) and fatigue (11%). One related Grade 5 AE of respiratory compromise was reported during the Lead-in stage. Conclusions: Cabo demonstrated a 14% rate of objective tumor regression in heavily pretreated MBC pts. Observed effects on bone scan and pain are consistent with those seen in other malignancies. The safety profile of cabo was comparable to that seen with other VEGFR TKIs.

Identification of a novel germline MET mutation in dogs

The MET proto-oncogene encodes a transmembrane tyrosine kinase receptor that mediates multiple functions such as migration, cycling and survival by binding to hepatocyte growth factor (HGF). Dysregulation of MET through inappropriate expression or mutation has been shown to play an important role in human cancers. Furthermore, inherited mutations in MET are known to contribute to the development of gastric and renal cancer in humans. Lastly, mouse models of MET mutations lead to the development of a wide variety of cancers including lymphomas, sarcomas and some forms of carcinoma. In the process of cloning canine MET, a novel germline point mutation was found in the juxtamembrane domain (G966S) in two of the templates used for cloning, both of which were derived from Rottweiler dogs, a breed believed to be at high risk for the development of several cancers. Screening of germline DNA from a variety of breeds revealed that this mutation was present in approximately 70% of Rottweiler dogs and <5% of all other breeds examined, suggesting a breed-specific heritable mutation. Stable transfection of the G966S mutant form of MET into NIH3T3 cells resulted in enhanced baseline scattering and migration of the cells, which was further increased in the presence of HGF. This study supports the notion that particular dog breeds may carry germline mutations that contribute to high rates of cancer in a manner similar to heritable, cancer-associated mutations in humans.