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Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC
Abstract
7505 Background: Met is associated with a poor outcome in many cancers, including NSCLC. Met activation is a mechanism of resistance to EGFR inhibition, supporting dual inhibition of Met/EGFR. MetMAb is a monovalent monoclonal antibody that specifically binds the Met receptor. Methods: OAM4558g is a global randomized, double-blind phase II study comparing MetMAb plus erlotinib (ME) to placebo plus erlotinib (PE) in 2nd/3rd line NSCLC. Tissue collection was mandatory to assess c-Met IHC expression levels (Met Dx). Co-primary endpoints were PFS in the Met Dx+ and ITT populations. Safety and OS were additional endpoints. Following the initial unblinding, Met Dx- patients (pts) were removed from ME. Results: 128 NSCLC pts were equally randomized to receive ME or PE. 95% of tissue was evaluable for c-Met IHC, 88% for EGFR and KRAS mutations (mut), and 75% for MET FISH. Baseline characteristics were well balanced. 54% of pts had Met Dx+ NSCLC, which was associated with a worse outcome (OS HR 2.52, PE cohort). A...
... [45] The development of septic shock is an indication for ICU supportive care usually involving invasive monitoring, fluid resuscitation, renal replacement therapy, and vasopressor, inotropic, and mechanical ventilatory support. [46,47] Adjunctive use of recombinant G-CSF holds no clinical utility for improving sepsis from melioidosis and other aetiologies. Both animal and human trials -including prospective, multicentre, randomised, double-blind, and placebo-controlled studies -confirm this. ...
... [50] Other immunomodulatory adjuncts such as corticosteroids do not improve survival. [46] In light of the paucity of effective evidence-based prevention strategies and adjunct therapies for underserved populations, we turn to a novel potential for tertiary prevention. ...
... [45] Onartuzumab, an anti-MET receptor monoclonal antibody has shown increased PFS and overall survival when given with Erlotinib as compared to placebo. [46] A phase I study of cabozantinib (XL184), a drug which targets both VEGF and MET receptors, has shown promise after preliminary analysis. [9] Others Multiple targets with great potential are currently being investigated. ...
... 73,74 In 2011, Spigel et al presented the results of a randomized Phase II study comparing onartuzumab + erlotinib versus erlotinib alone in 128 pretreated patients with NSCLC. 75 The two coprimary endpoints of the study were progression-free survival in the entire population and progression-free survival in patients with high MET expression, defined as $50% of tumor cells staining moderately or strongly for MET by immunohistochemistry. Although the study did not meet the primary endpoint in the whole population, the risk of progression was significantly lower in patients with high MET expression (progression-free survival 3.0 versus 1.5 months; hazards ratio 0.47; P = 0.002). ...
... It is important to highlight that none of the aforementioned trials included molecular selection of patients. 75,80,81,[88][89][90][91]97,115 Preplanned subgroup analyses suggest that overexpression of MET assessed by immunohistochemistry could be useful for predicting the efficacy of anti-MET monoclonal antibodies. 75,127 Indeed, onartuzumab increased progression-free survival in patients with high MET expression, but had a detrimental effect in those with low or negative MET expression. ...
... 75,80,81,[88][89][90][91]97,115 Preplanned subgroup analyses suggest that overexpression of MET assessed by immunohistochemistry could be useful for predicting the efficacy of anti-MET monoclonal antibodies. 75,127 Indeed, onartuzumab increased progression-free survival in patients with high MET expression, but had a detrimental effect in those with low or negative MET expression. 75 Notably, in advanced gastric cancer, addition of rilotumumab to chemotherapy produced a higher response rate and longer survival than chemotherapy alone in patients with high MET expression. ...
The transmembrane tyrosine kinase mesenchymal-epidermal transition (MET) receptor and its ligand, hepatocyte growth factor, also known as scatter factor, have recently been identified as novel promising targets in several human malignancies, including non-small cell lung cancer (NSCLC). Amplification, mutation, or overexpression of the MET gene can result in aberrant activation of the MET axis, leading to migration, invasion, proliferation, metastasis, and neoangiogenesis of cancer cells, suggesting that interfering with the MET/hepatocyte growth factor pathway could represent a potential antitumor strategy. While the role of MET mutations in NSCLC is not as yet fully understood, retrospective studies have shown that an increased MET gene copy number is a negative prognostic factor. In NSCLC, amplification of the MET gene is a relatively rare event, occurring in approximately 4% of patients not previously exposed to systemic therapies and in up to 20% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors. In preclinical models, the presence of MET amplification is a predictor of high sensitivity to anti-MET compounds, and several agents have entered in clinical trials for patients having advanced disease, with promising results. The aim of the present review is to summarize available data on the role of MET in NSCLC and to describe therapeutic strategies under investigation. © 2013 Landi et al, publisher and licensee Dove Medical Press Ltd.
... In a phase II double blind randomized trial (OAM4558g), onartuzumab (15 mg/kg iv every 3 weeks) was studied in combination with erlotinib 150 mg oral daily (OE) versus placebo plus erlotinib (PE) in the second or third line treatment of NSCLC patients who had no previous exposure to an EGFR-TKI (52,53). Tissue was required for all patients enrolled, of which 95% were evaluable for MET IHC and 75% for MET FISH testing. ...
... MET+ by IHC had the highest sensitivity in detecting clinical improvement with onartuzumab, and establish that diagnostics need to evolve concurrently to identify the appropriate population for targeted therapies. For example, when MET-FISH positivity is defined as ≥5 copies per cell, there was trend to an improved OS (HR 0.47, P=0.19) but not at lower copy numbers (53); and when reverse transcriptase-PCR was used, the OS benefit in MET+ patients was not present at all (HR 0.69, P=0.48) (54). ...
... patients (including those with squamous histology) and also in combination with erlotinib in patients who had previously received an EGFR TKI (42,46). Onartuzumab has a unique MET inhibition mechanism as a monovalent one armed 5D5 monoclonal antibody and has shown significant improvement in PFS and OS in MET IHC positive tumors when combined with erlotinib (52,53). Other particularly promising MET inhibitors include crizotinib and amuvatinib, of which the latter is being tested in small cell lung cancer where the role of MET is less clear (72) [NCT01357395]. ...
MET and its ligand hepatocyte growth factor/scatter factor (HGF) influence cell motility and lead to tumor growth, invasion, and angiogenesis. Alterations in MET have been observed in non-small cell lung cancer (NSCLC) tumors, with increased expression associated with more aggressive cancer, as well as acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). MET inhibitors act via two basic mechanisms. Small molecule inhibitors antagonize ATP in the intracellular tyrosine kinase domain of MET, with studies on the following agents reviewed here: tivantinib (ARQ-197), cabozantinib (XL-184), crizotinib (PF-02341066), amuvatinib (MP470), MGCD265, foretinib (EXEL-2880), MK2461, SGX523, PHA665752, JNJ-38877605, SU11274, and K252A. The monoclonal monovalent antibody fragment onartuzumab (MetMAb) is also discussed here, which binds to and prevents the extracellular activation of the receptor by ligand. MET inhibition may both overcome the negative prognostic effect of MET tumor expression as well as antagonize MET-dependent acquired resistance to EGFR inhibitors. Here we discuss MET inhibitors in combination with other therapies in lung cancer.
... There is also evidence that HGF may serve as a reliable biomarker for onartuzumab target engagement [181]. In a phase II study of second-/third-line treatment in NSCLC with onartuzumab as monotherapy or in combination with erlotinib, patients with c-MET immunohistochemistrypositive (IHC+) tumors significantly benefited from onartuzumab plus erlotinib treatment compared to placebo plus erlotinib (c-MET IHC+, OS of 4.6 months versus and 12.6 months; p = 0.002; c-MET IHC-, OS of 9.2 months versus of 5.5 months; p = 0.021; [182]). Other subgroups did not benefit with onartuzumab. ...
... Other subgroups did not benefit with onartuzumab. This strongly suggested that a population of higher c-MET-expressing patients derived disproportionate benefit from the combined therapy [182,183]. ...
The kinase receptor c-MET (MET proto-oncogene, receptor tyrosine kinase; also known as the hepatocyte growth factor receptor) and its ligand hepatocyte growth factor/scatter factor (HGF/SF) are two promising, potentially therapeutically exploitable targets in head and neck squamous cell carcinoma (HNSCC). c-MET is commonly overexpressed in head and neck cancer cells compared to normal epithelial cells and HGF/SF is often detected at high expression levels in tumor-adjacent mesenchymal cells, inducing paracrine activation of c-MET to support tumor growth and proliferation. Blocking this paracrine activity has been shown to reduce the proliferative capacity of HNSCC cells. Importantly, c-MET signaling outputs intersect with those of multiple other signaling pathways that drive or otherwise contribute to HNSCC cell survival and spread, including EGFR, HER2, SRC, STAT3, PI3K, RAS, GRB2, and others. In this review, we emphasize the roles of c-MET and HGF in HNSCC as well as the potential for therapeutic targeting of this signaling axis.
... Use of IHC for determination of c-MET protein overexpression has been extensively reviewed [71,72], but the variability among published studies in current literature suggests that standardisation of protocols is warranted [12]. Identifying MET-positive/high patients using IHC has been studied as part of various trials, such as the phase II trials of ornatuzumab or placebo with erlotinib in advanced NSCLC [73], rilotumumab or placebo combined with chemotherapy in advanced gastric or gastric oesophageal cancer [74], and tivantinib or placebo in advanced HCC [15,16]. The three trials defined different IHC cut-off criteria: at least 50% tumour cells with 2+ or 3+ staining was referred to as "MET diagnostic positive" in the ornatuzumab study and "MET-high" in the tivantinib study, whereas the rilotumumab study defined "MET-positive" as at least 25% membrane staining of tumour cells at any intensity. ...
... In the onartuzumab trial [73], additional subgroup analyses were performed to determine the effect of MET copy number changes and EGFR mutational status. c-MET IHC was found to correlate with MET FISH, but benefit to c-MET-targeted therapy was seen in patients positive by IHC but negative by FISH. ...
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death. In patients with advanced or unresectable HCC, there are few treatment options. Conventional chemotherapy has limited benefits. Sorafenib, a multi-kinase inhibitor, improves survival, but options for patients intolerant of or progressing on sorafenib are limited. There has been much interest in recent years in molecular therapeutic targets and drug development for HCC. One of the more promising molecular targets in HCC is the cellular-mesenchymal-epithelial transition (c-MET) factor receptor. Encouraging phase II data on two c-MET inhibitors, tivantinib and cabozantinib, has led to phase III trials. This review describes the c-MET/hepatocyte growth factor (HGF) signalling pathway and its relevance to HCC, and discusses the preclinical and clinical trial data for inhibitors of this pathway in HCC.
... Approximately 50% of such patients have tumors that harbor the T790M mutation, and another ≈20% have tumors with MET amplifications. (39,40) Specific inhibitors of the T790M mutation (AZD9291 and CO1696) are under study, as are potential MET inhibitors (onartuzumab and tivantinib). (40) However, none of those have proven to be clinically effective in this scenario. ...
... (39,40) Specific inhibitors of the T790M mutation (AZD9291 and CO1696) are under study, as are potential MET inhibitors (onartuzumab and tivantinib). (40) However, none of those have proven to be clinically effective in this scenario. (41) The second-generation EGFR-TKI afatinib is an irreversible ErbB family blocker that is effective in patients with the more common mutations and seems to be effective even in patients with the less common mutations, including the T790M mutation in exon 20, which is one of the main mechanisms of resistance to firstgeneration EGFR-TKIs. ...
Lung cancer is the leading cause of cancer-related deaths worldwide. Promising new therapies have recently emerged from the development of molecular targeted drugs; particularly promising are those blocking the signal transduction machinery of cancer cells. One of the most widely studied cell signaling pathways is that of EGFR, which leads to uncontrolled cell proliferation, increased cell angiogenesis, and greater cell invasiveness. Activating mutations in the EGFR gene (deletions in exon 19 and mutation L858R in exon 21), first described in 2004, have been detected in approximately 10% of all non-squamous non-small cell lung cancer (NSCLC) patients in Western countries and are the most important predictors of a response to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Studies of the EGFR-TKIs gefitinib, erlotinib, and afatinib, in comparison with platinumbased regimens, as first-line treatments in chemotherapy-naïve patients have shown that the EGFR-TKIs produce gains in progression-free survival and overall response rates, although only in patients whose tumors harbor activating mutations in the EGFR gene. Clinical trials have also shown EGFR-TKIs to be effective as secondand third-line therapies in advanced NSCLC. Here, we review the main aspects of EGFR pathway activation in NSCLC, underscore the importance of correctly identifying activating mutations in the EGFR gene, and discuss the main outcomes of EGFR-TKI treatment in NSCLC. © 2015, Sociedade Brasileira de Pneumologia e Tisiologia. All rights reserved.
... In the MET IHC 2+ or 3+ group (n = 65), MetMAb resulted in a statistically and clinically significant improvement in both PFS (median 3.0 months versus 1.5 months, HR 0.47, P = 0.01) and OS (median 12.6 months versus 4.6 months, HR 0.37, P = 0.002). 96 In the MET IHC low/negative group, OS was worse in the MetMAb plus erlotinib group (HR 3.02, P = 0.021). Erlotinibrelated toxicities were comparable between treatment arms. ...
... Dovepress Dovepress survival benefit becoming statistically insignificant (P = 0.29) in the analysis likely due to a small sample size. 96 A complete and durable (lasting 2 years) response of MetMAb was observed in a 48 year-old female with chemorefractory metastatic gastric cancer to the liver who was treated in a phase I clinical trial with MetMAb. 97 These results lend support for further investigation of MetMAb as a potential personalized MET targeting cancer therapy. ...
MET, the receptor for hepatocyte growth factor, has been identified as a novel promising target in various human malignancies, including lung cancer. Research studies have demonstrated that MET signaling plays important physiologic roles in embryogenesis and early development, whereas its deregulation from an otherwise quiescent signaling state in mature adult tissues can lead to upregulated cell proliferation, survival, scattering, motility and migration, angiogenesis, invasion, and metastasis in tumorigenesis and tumor progression. The MET pathway can be activated through ligand (hepatocyte growth factor, HGF) or MET receptor overexpression, genomic amplification, MET mutations, and alternative splicing. A number of novel therapeutic agents that target the MET/hepatocyte growth factor pathway have been tested in early-phase clinical studies with promising results. Phase III studies of MET targeting agents have recently been initiated. This paper will review the MET signaling pathway and biology in lung cancer, and the recent clinical development and advances of MET/hepatocyte growth factor targeting agents. Emphasis will be placed on discussing various unanswered issues and key strategies needed to optimize further clinical development of MET targeting personalized lung cancer therapy. © 2012 Feng and Ma, publisher and licensee Dove Medical Press Ltd.
... In oncology, the presence of the circulating tumor cfDNA (ctDNA) and the analysis of its genetic alterations allows the detection of cancer disease, the monitoring of treatment response, and the detection of minimal residual disease, enabling personalized treatment strategies [17,18]. Currently, the most common use of ctDNA analysis is therapy selection and stratification of patients based on the likelihood of response to targeted therapies [19][20][21][22] by searching for specific mutation markers for resistance or sensitivity, such as tyrosine kinase inhibitors, programmed death inhibitors-1 [23], programmed death ligand-1 [24], and cytotoxic T lymphocyte-associated protein 4 [25]. Through ctDNA analysis is, therefore, possible to differentiate and predict immune checkpoint blockade response pa erns [26,27], characterize the tumor heterogeneity [28], and early detect resistance for targeted therapy and chemotherapy [29][30][31][32]. ...
Circulating cell-free DNA (cfDNA) refers to small fragments of DNA molecules released after programmed cell death and necrosis in several body fluids such as blood, saliva, urine, and cerebrospinal fluid. The discovery of cfDNA has revolutionized the field of non-invasive diagnostics in the oncologic field, in prenatal testing, and in organ transplantation. Despite the potential of cfDNA and the solid results published in recent literature, several challenges remain, represented by low abundance, need for highly sensitive assays and analytical issues. In this review, the main technical advances in cfDNA analysis are presented and discussed, with a comprehensive examination of the current available methodologies applied in each field. Considering the potential advantages of cfDNA, this biomarker is increasing its consensus among clinicians, as it consents to monitor patients’ conditions in an easy and non-invasive way, offering a more personalized care. Nevertheless, cfDNA analysis is still considered a research marker to be further validated, and very few centers are implementing its analysis in the real-life assistance. As technical improvements are enhancing the performances of cfDNA analysis, its application will transversally improve patients’ quality of life.
... In oncology, the presence of the circulating tumor cfDNA (ctDNA) and the analysis of its genetic alterations allows the detection of cancer disease, the monitoring of treatment response, and the detection of minimal residual disease, enabling personalized treatment strategies [17,18]. Currently, the most common use of ctDNA analysis is therapy selection and stratification of patients based on the likelihood of response to targeted therapies [19][20][21][22] by searching for specific mutation markers for resistance or sensitivity, such as tyrosine kinase inhibitors, programmed death inhibitors-1 [23], programmed death ligand-1 [24], and cytotoxic T lymphocyte-associated protein 4 [25]. Through ctDNA analysis, it is, therefore, possible to differentiate and predict immune checkpoint blockade response patterns [26,27], characterize the tumor heterogeneity [28], and detect resistance for targeted therapy and chemotherapy early [29][30][31][32]. ...
Circulating cell-free DNA (cfDNA) refers to small fragments of DNA molecules released after programmed cell death and necrosis in several body fluids such as blood, saliva, urine, and cerebrospinal fluid. The discovery of cfDNA has revolutionized the field of non-invasive diagnostics in the oncologic field, in prenatal testing, and in organ transplantation. Despite the potential of cfDNA and the solid results published in the recent literature, several challenges remain, represented by a low abundance, a need for highly sensitive assays, and analytical issues. In this review, the main technical advances in cfDNA analysis are presented and discussed, with a comprehensive examination of the current available methodologies applied in each field. Considering the potential advantages of cfDNA, this biomarker is increasing its consensus among clinicians, as it allows us to monitor patients’ conditions in an easy and non-invasive way, offering a more personalized care. Nevertheless, cfDNA analysis is still considered a diagnostic marker to be further validated, and very few centers are implementing its analysis in routine diagnostics. As technical improvements are enhancing the performances of cfDNA analysis, its application will transversally improve patients’ quality of life.
... MET is a proto-oncogene that encodes for the MET tyrosine receptor kinase and its only known ligand is hepatocyte growth factor. Although 30−40% of squamous NSCLC is expected to be classified as MET-positive, 15,16 of patients in NCT01519804 were MET-positive. High levels of receptor expression, as well as high MET gene copy number, are independent prognostic factors for poor outcome in patients with NSCLC. ...
Oncology drug development increasingly relies on single‐arm clinical trials. External controls (EC) derived from electronic health record (EHR) databases may provide additional context. Patients from a US based oncology EHR database were aligned with patients from randomized controlled trials (RCTs) and trial specific eligibility criteria were applied to the EHR dataset. Overall survival (OS) in the EC derived control arm was compared to OS in the RCT experimental arm. The primary outcome was OS, defined as time from randomization or treatment initiation (EHR) to death. Cox regression models were used to obtain effect estimates using EHR data. EC‐derived hazard ratio (HR) estimates aligned closely with those from the corresponding RCT with one exception. Comparing log HRs between all RCT and EC results gave a Pearson correlation coefficient of 0.86. Properly selected control arms from contemporaneous EHR data could be used to put single‐arm trials of OS in advanced non‐small cell lung cancer (aNSCLC) into context. This article is protected by copyright. All rights reserved.
... Depuis, un grand nombre de TKI présentant une meilleure tolérance ont été mis au point. , comparé à l'Erlotinib seul ces résultats n'ont pas été confirmés en phase III (Spigel et al., 2011(Spigel et al., , 2017. De la même manière, une deuxième étude de phase III chez des patients atteints de cancer gastrique, a montré que l'ajout d'Onartuzumab à une chimiothérapie standard n'apportait aucun bénéfice (Shah et al., 2015). ...
Les RTKs sont impliqués dans le dialogue au sein des tissus par la régulation de nombreuses réponses cellulaires dont la survie, la prolifération ou la mobilité. Dans les cancers, ces récepteurs sont fréquemment dérégulés notamment par des mutations activatrices. Ainsi, la suractivation des RTKs induit la transformation cellulaire et la tumorigenèse en favorisant par exemple la survie cellulaire. Depuis le début des années 2000, le développement de molécules inhibitrices de l’activité tyrosine kinase (TKI) et d’anticorps bloquant l’interaction ligand/récepteur ont montré que les RTKs représentent des cibles thérapeutiques majeures dans le traitement des cancers.MET est un RTK exprimé par les cellules épithéliales, dont le ligand est l’Hepatocyte Growth Factor/Scatter Factor (HGF/SF). En plus de son rôle pro-survie, MET peut également favoriser l’apoptose en absence de ligand et sous l’effet d’un stress. MET est alors clivé par les caspases et libère dans le cytosol un fragment de 40 kDa nommé p40MET. Ce fragment active la voie intrinsèque de l’apoptose en causant la perméabilisation des mitochondries. Cependant, les mécanismes moléculaires responsables de cette perméabilisation et l’impact physiologique de la fonction pro-apoptotique de MET étaient encore inconnus.Mon travail de thèse a permis de démontrer que le fragment p40MET se localise dans la région des MAMs, constituant l’interface entre le réticulum endoplasmique et les mitochondries, où il favorise un transfert de calcium entre les deux organites. Ce transfert déclenche une surcharge de calcium dans les mitochondries, responsable de leur perméabilisation. De plus, nous avons développé une lignée de souris transgéniques dans lesquelles MET est muté sur l’un des sites caspases. Ces souris sont incapables de produire le fragment p40MET pro-apoptotique. Ce modèle nous a permis de démontrer l'importance du clivage de MET dans l’amplification de l’apoptose in vivo. Ainsi, nos travaux apportent les premières preuves de la fonction de MET en tant que récepteur à dépendance au sein d’un organisme et décrivent un nouveau mécanisme de signalisation pro-apoptotique par la dérégulation des flux calciques.Ces dernières années, la découverte de mutations touchant les RTKs dans les cancers a augmenté de façon exponentielle. Toutefois, pour une grande majorité de mutations, leurs conséquences fonctionnelles sont totalement inconnues. Ainsi, en parallèle de mon principal sujet de thèse nous avons évalué la pertinence biologique et clinique des mutations de RTK identifiées par séquençage haut débit à partir d’échantillons de patients. Le séquençage de tissus sains, de tumeurs colorectales et de métastases hépatiques de 30 patients a permis d'identifier de nombreuses mutations somatiques. Parmi elles, certaines affectent le domaine kinase des récepteurs et sont présentes à la fois dans les tumeurs et les métastases. L’analyse fonctionnelle que j’ai menée sur 7 de ces mutations révèle qu’elles ne provoquent ni la suractivation de la kinase ni la transformation des fibroblastes NIH3T3. Au contraire, deux mutations de RTKs provoquent une inhibition drastique de leur activité kinase. Ces résultats démontrent que ces variants de RTK ne sont pas des cibles appropriées pour l’utilisation de TKI à des fins thérapeutiques et démontre l’intérêt de coupler la recherche de variants à des études fonctionnelles [...]
... 96 Studies suggest an improvement in progression-free survival with the addition of anti-MET antibodies to an EGFR inhibitor in patients whose tumors display MET overexpression. 97 ...
... 96 Studies suggest an improvement in progression-free survival with the addition of anti-MET antibodies to an EGFR inhibitor in patients whose tumors display MET overexpression. 97 ...
... For these MET signalling pathway inhibitors, finding predictive biomarkers early in clinical development is critical (Brunetto et al, 2010). Earlier phase II trials of tivantinib and MetMAb in NSCLC patients showed that MET overexpression rather than MET amplification could be useful in enriching patients (Spigel et al, 2011;Rodig et al, 2012). Indeed, patients who were negative for MET expression performed worse on MetMAb when compared with chemotherapy alone, highlighting the potential for both positive enrichment and negative exclusion. ...
Background:
Gastric cancer (GC) is a leading cause of cancer deaths worldwide. Since the approval of trastuzumab, targeted therapies are emerging as promising treatment options for the disease. This study aimed to explore the molecular segmentation of several known therapeutics targets, human epidermal growth factor receptor 2 (HER2), MET and fibroblast growth factor receptor 2 (FGFR2), within GC using clinically approved or investigational kits and scoring criteria. Knowledge of how these markers are segmented in the same cohort of GC patients could improve future clinical trial designs.
Methods:
Using immunohistochemistry (IHC) and FISH methods, overexpression and amplification of HER2, FGFR2 and MET were profiled in a cohort of Chinese GC samples. The correlations between anti-tumour sensitivity and the molecular segments of HER2, MET and FGFR2 alterations were further tested in a panel of GC cell lines and the patient-derived GC xenograft (PDGCX) model using the targeted inhibitors.
Results:
Of 172 GC patients, positivity for HER2, MET and FGFR2 alternations was found in 23 (13.4%), 21 (12.2%) and 9 (5.2%) patients, respectively. Positivity for MET was found in 3 of 23 HER2-positive GC patients. Co-positivity for FGFR2 and MET was found in 1 GC patient, and amplification of the two genes was found in different tumour cells. Our study in a panel of GC cell lines showed that in most cell lines, amplification or high expression of a particular molecular marker was mutually exclusive and in vitro sensitivity to the targeted agents lapatinib, PD173074 and crizotinib was only observed in cell lines with the corresponding high expression of the drugs' target protein. SGC031, an MET-positive PDGCX mouse model, responded to crizotinib but not to lapatinib or PD173074.
Conclusions:
Human epidermal growth factor receptor 2, MET and FGFR2 oncogenic driver alterations (gene amplification and overexpression) occur in three largely distinct molecular segments in GC. A significant proportion of HER2-negative patients may potentially benefit from MET- or FGFR2-targeted therapies.
... Lastly, c-MET targeted monoclonal antibodies are being studied in this setting, including onartuzumab (MetMab) (68). Phase II data suggests prolonged PFS (3.0 vs. 1.5 months; HR 0.47; P=0.01) and OS (12.6 vs. 4.6 months; HR 0.37; P=0.002) in patients with c-MET positive NSCLC receiving MetMab plus erlotinib versus erlotinib alone (71). As such, a phase III trial is ongoing to validate these findings. ...
Until recently, the majority of genomic cancer research has been in discovery and validation; however, as our knowledge of tumor molecular profiling improves, the idea of genomic application in the clinic becomes increasingly tangible, paralleled with the drug development of newer targeted therapies. A number of profiling methodologies exist to identify biomarkers found within the patient (germ-line DNA) and tumor (somatic DNA). Subsequently, commercially available clinical assays to test for both germ-line and somatic alterations that are prognostic and/or predictive of disease outcome, toxicity or treatment response have significantly increased. This review aims to summarize clinically relevant cancer biomarkers that serve as targets for therapy and their potential relationship to lung cancer. In order to realize the full potential of genomic cancer medicine, it is imperative that clinicians understand these intricate molecular pathways, the therapeutic implication of mutations within these pathways, and the availability of clinical assays to identify such biomarkers.
... Our findings and other studies suggest that MET inhibitors are most effective against high MET-expressing tumors (43,44). Those studies focused on the primary tumor environment, yet MET may also be a critical therapeutic target in metastatic disease and chemotherapy-treated patients. ...
Purpose:
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that is associated with poor clinical outcome. There is a vital need for effective targeted therapeutics for TNBC patients, yet treatment strategies are challenged by the significant intertumoral heterogeneity within the TNBC subtype and its surrounding microenvironment. Receptor tyrosine kinases (RTKs) are highly expressed in several TNBC subtypes and are promising therapeutic targets. In this study, we targeted the MET receptor which is highly expressed across several TNBC subtypes.
Experimental design:
Using the small molecule inhibitor cabozantinib (XL184), we examined the efficacy of MET inhibition in preclinical models that recapitulate human TNBC and its microenvironment. To analyze the dynamic interactions between TNBC cells and fibroblasts over time, we utilized a 3D model referred to as MAME (Mammary Architecture and Microenvironment Engineering) with quantitative image analysis. To investigate cabozantinib inhibition in vivo, we used a novel xenograft model that expresses human HGF and supports paracrine MET signaling.
Results:
XL184 treatment of MAME cultures of MDA-MB-231 and HCC70 cells (+/- HGF-expressing fibroblasts) was cytotoxic and significantly reduced multicellular invasive outgrowths even in cultures with HGF-expressing fibroblasts. Treatment with XL184 had no significant effects on METneg breast cancer cell growth. In vivo assays demonstrated that cabozantinib treatment significantly inhibited TNBC growth and metastasis.
Conclusions:
Using preclinical TNBC models that recapitulate the breast tumor microenvironment, we demonstrate that cabozantinib inhibition is an effective therapeutic strategy in several TNBC subtypes.
... It was well tolerated in a phase I trial [74]. A randomized phase II trial suggested that the combination of onartuzumab plus erlotinib may have more benefit than erlotinib alone in patients with MET-over expressing tumors [75,76]. Unfortunately, a phase III trial of the drug combination in advanced NSCLC was stopped in 2014 because there was no apparent benefit to patients receiving the drug combination compared to erlotinib alone (NCT01456325). ...
The therapeutic utility of antibodies and their derivatives is achieved by various means. The FDA has approved several targeted antibodies that disrupt signaling of various growth factor receptors for the treatment of a number of cancers. Rituximab, and other anti-CD20 monoclonal antibodies are active in B cell malignancies. As more experience has been gained with anti-CD20 monoclonal antibodies, the multifactorial nature of their anti-tumor mechanisms has emerged. Other targeted antibodies function to dampen inhibitory checkpoints. These checkpoint inhibitors have recently achieved dramatic results in several cancers, including melanoma. These and related antibodies continue to be investigated in the clinical and pre-clinical settings. Novel antibody structures that target two or more antigens have also made their way into clinical use. Tumor targeted antibodies can also be conjugated to chemo- or radiotherapeutic agents, or catalytic toxins, as a means to deliver toxic payloads to cancer cells. Here we provide a review of these mechanisms and a discussion of their relevance to current and future clinical applications.
Copyright © 2015 Elsevier Ltd. All rights reserved.
... One hundred and twenty-eight NSCLC patients were enrolled with a baseline immunohistochemical evaluation of Met: 54% of the patients were considered as Met positive (high protein expression at IHC). Met positive patients treated in the experimental arm had a significantly higher PFS (3.0 vs. 1.5 months; HR 0.47; P=0.01) and OS (12.6 vs. 4.6 months; HR 0.37; P=0.002) (132). ...
Targeted agents have completely changed cancer treatment strategy, leading it from a "one size fits all" approach to a customized therapy. In this scenario Met, a heterodimere receptor tyrosine kinase deeply involved into embryogenesis and organogenesis, has been introduced many years ago as a potential target for biological agents, becoming "druggable" only in this last period of time. Met can be altered through receptor overexpression, genomic amplification, mutations or alternative splicing, autocrine or paracrine secretion of hepatic growth factor (HGF): these dysregulations stimulate tumorigenesis (in terms of cell-cell detachment, proliferation, invasion, angiogenesis and survival) and metastatization. Met is overexpressed in lung cancer and Met gene amplification can drive the dependency of cell survival and proliferation upon the Met signaling. Both Met overexpression and amplification seem to correlate with poor prognosis. Met amplification is also described to be linked to EGFR acquired resistance. Several Met inhibitors have been tested both in preclinical and human trials, demonstrating activity in lung cancer treatment. This paper aims to summarize data on Met biological function, on its interaction with cell signaling and other pathways and to present data on those Met inhibitors currently under evaluation.
... MET amplification is found to be associated with acquired resistance in up to 20% of cases and inhibition of MET with the use of monoclonal antibodies (31)(32)(33) or small molecule TK inhibitor (34) alone or in combination with other targeted agents are currently under investigations. Anti-MET strategies have been extensively discussed elsewhere (35)(36)(37). ...
In the last few years, the treatment of Non-Small-Cell Lung Cancer (NSCLC) has dramatically changed. Presence of activating mutations in the Epidermal Growth Factor Receptor (EGFR) identified a particular group of NSCLC patients with different clinical characteristics and outcome. For EGFR mutant patients first-generation EGFR tyrosine-kinase inhibitors (TKIs), such as gefitinib and erlotinib, represent the best therapeutic option in first, second and maintenance setting. Unfortunately, all patients develop acquired resistance and despite an initial benefit, virtually all patients progress due to the development of resistance. Several molecular mechanisms are responsible for acquired resistance and the two prominent are the up-regulation of the downstream signal by mesenchymal-epidermal transition (MET) amplification and the emergence of T790M EGFR gatekeeper mutation. Preclinical and early clinical trials suggested a potential efficacy of a new class of panHER inhibitor, also called irreversible or covalent inhibitor, in overcome acquired resistance related to T790M. Afatinib, dacomitinib and neratinib, are currently in development in different setting and results from these trials are awaited in order to establish the role of these new compounds in the treatment of NSCLC.
... In the MET positive group (n=65), MetMAb plus erlotinib resulted in a statistically and clinically significant improvement in both PFS (median 3 vs. 1.5 months, HR 0.47, P=0.01) and OS (12.6 vs. 4.6 months, HR 0.37, P=0.002) (21). Currently, the phase III MetLUNG trial study is ongoing, which is a randomized, phase III, multicenter, double-blind, placebo-controlled study where patients with MET positive (Dx+ with IHC 2+/3+) tumors who failed at least 1 but no more than 2 prior lines of platinum-based chemotherapy for advanced NSCLC are eligible. ...
Molecular targeted therapy has made significant progress in human cancers in the past decade and has become an integral part of modern human cancer treatment. Targeted drugs are now moving closer to be used in tailored therapy with personalized molecular predictive biomarkers assay development to couple with the therapeutics. Much progress has been made in non-small cell lung cancer (NSCLC) using the tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib to target the epidermal growth factor receptor (EGFR) clinically in patients with advanced disease (1). However, the long term efficacy of the TKIs is still inevitably limited, as patients with NSCLC who initially have primary tumor response, always develop acquired resistance against EGFR-TKI monotherapy typically after 6-12 months of treatment (2). Recent research studies to elucidate mechanisms of acquired EGFR TKI resistance identified alternative molecular targets of receptor tyrosine kinases (RTKs) to be responsible, such as AXL (3), as well as MET receptor (4) and its natural ligand hepatocyte growth factor (HGF) (5), as implicated in mediating the tumor escape process.
... There are several ways to inhibit the MET signaling pathway, including anti-MET antibodies, inactivation of MET ligand, namely the hepatocyte growth factor (HGF) or inhibition of MET kinase activity. Currently, the anti-MET monoclonal antibody MetMab and the MET-TKI tivantinib have been tested in randomized phase II studies of chemotherapy pretreated advanced NSCLCs, which were hypothesis-generating for identifying biomarkers of sensitivity to MET inhibition such as MET expression by immunohistochemistry and MET gene copy number as assessed by fluorescence in situ hybridizaton (72,73). However none of the ongoing studies with these agents has been thought for the EGFR-mutated NSCLC population undergoing resistance to a reversible EGFR-TKI. ...
Patients with advanced non-small-cell lung cancer (NSCLC) and somatic activating mutations of the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene represent a biologically distinct disease entity that shows exquisite sensitivity to the reversible EGFR-TK inhibitors (-TKIs) gefitinib or erlotinib. Phase III randomized studies have clearly demonstrated that a reversible EGFR-TKI is significantly superior in terms of response rate, progression-free survival and quality of life to platinum-based chemotherapy in advanced NSCLC patients who carry an activating EGFR mutation, thus resulting into a new standard of care for this biologically selected group of patients. Unfortunately, approximately one third of EGFR-mutated patients show primary resistance to gefitinib or erlotinib, whereas virtually all patients who initially benefit from treatment will eventually develop acquired resistance. Importantly, revealing the molecular mechanisms that underlie resistance to reversible EGFR-TKIs is key to the development of EGFR-targeting strategies with the potential to prevent, delay or overcome such resistance. Early results of clinical trials with irreversible EGFR-TKIs or dual combination strategies aiming to block EGFR-mediated signaling at different levels have shown encouraging results in EGFR-mutated patients pretreated or not with a reversible EGFR-TKI. Therefore, in the near future it is reasonable to hypothesize that EGFR-mutated NSCLCs could be treated with multiple lines of EGFR-targeting therapies beyond disease progression, limiting chemotherapy to selected cases of resistant disease. This evolving treatment scenario highlights once again how important is the identification of a single oncogenic "addiction" that functions as unique determinant of progression and survival of NSCLC.
... Demonstrating this, a recent phase II study showed that previously-treated NSCLC patients using a combination therapy of OAM4558g (MET-MAb) plus erlotinib versus just erlotinib alone reported that the MET-MAb plus erlotinib therapy significantly improved PFS and OS, resulting in a near 3-fold reduction in the risk of death. This benefit was observed in patients with MET activation, as evaluated by IHC [19]. However in the Phase III trials, when those patients selected for high MET expression were treated OAM4558g added to erlotinib, it was shown to be not superior to erlotinib alone [20]. ...
Lung adenocarcinoma patients with EGFR gene mutations have shown a dramatic response to gefitinib. However, drug resistance eventually emerges which limits the mean duration of response. With that in view, we examined the correlations between MET gene status as assessed by fluorescence in situ hybridization (FISH) with overall survival (OS) and progression-free survival (PFS) in adenocarcinoma patients with EGFR gene mutations who had received gefitinib therapy.
We evaluated 35 lung cancer samples with EGFR mutation from adenocarcinoma patients who had received gefitinib. Gene copy numbers (GCNs) and amplification of MET gene before gefitinib therapy was examined by FISH. MET protein expression was also evaluated by immunohistochemistry (IHC).
FISH assessment showed that of the 35 adenocarcinoma samples, 10 patients (29%) exhibited high polysomy (5 copies≦mean MET per cell) and 1 patient (3%) exhibited amplification (2≦MET gene (red)/CEP7q (green) per cell). IHC evaluation of MET protein expression could not confirm MET high polysomy status. The Eleven patients with MET FISH positivity had significantly shorter progression-free survival (PFS) and overall survival (OS) than the 24 patients who were MET FISH-negative (PFS: p = 0.001 and OS: p = 0.03). Median PFS and OS with MET FISH-positivity were 7.6 months and 16.8 months, respectively, whereas PFS and OS with MET FISH-negativity were 15.9 months and 33.0 months, respectively. Univariate analysis revealed that MET FISH-positivity was the most significant independent factor associated with a high risk of progression and death (hazard ratio, 3.83 (p = 0.0008) and 2.25 (p = 0.03), respectively).
Using FISH analysis to detect high polysomy and amplification of MET gene may be useful in predicting shortened PFS and OS after Gefitinib treatment in lung adenocarcinoma. The correlation between MET gene status and clinical outcomes for EGFR-TKI should be further evaluated using large scale samples.
... Sollten sich die in Phase II mit Met-Mab beobachteten Therapieerfolge in der laufenden Phase-III-Studie bestätigen, dürfte demnächst als eine weitere immunhistochemische Testindikation die MET-IHC zur Patientenselektion beim NSCLC anstehen [17]. ...
Die Immunhistochemie (IHC) ist heute aus dem diagnostischen Armentarium eines Pathologen nicht mehr wegzudenken. Im Bereich der Onkologie stellt sie den Eckpfeiler einer verlässlichen histogenetischen Tumorklassifikation (Typing) dar [5]. Aufgrund der rasanten Entwicklung neuartiger molekular definierter, sog. zielgerichteter Therapien, kommt sowohl der molekularen Subklassifikation von Tumoren wie auch dem Nachweis therapiebarer Zielstrukturen eine zunehmend zentralere Rolle zu [19].Diese Entwicklung lässt sich – pars pro toto – besonders deutlich am Beispiel des Bronchialkarzinoms aufzeigen, wo inzwischen eine Therapieentscheidung nicht mehr ohne exakte Subtypisierung und molekulare Charakterisierung der Tumoren zu treffen ist [2, 8, 21]. Gleichzeitig erfordert das oft nur spärliche Probenmaterial (Biopsie, Zytologie) einen verantwortungsvollen Umgang mit dem Einsatz von Stufenschnitten und immunhistochemischen Einzelfärbungen. Multiplexverfahren [1, 13], der Einsatz mutationsspezifi ...
... ALK expression was scored as negative (ALK IHC−) or positive (ALK IHC+); the latter was defined as strong granular cytoplasmatic staining pattern [18]. MET expression was scored according to the MetMAb trial criteria [7,19]: samples with no (IHC score 0) or weak (IHC score 1+) membranous and/or cytoplasmatic staining in ≥50% of tumor cells were considered MET IHC negative (MET IHC−). Tumors with moderate (IHC score 2+) or strong (IHC score 3+) membranous and/or cytoplasmatic staining in ≥50% of tumor cells were considered MET IHC positive (MET IHC+). ...
... Preclinical studies show promising results for cabozantinib (XL184) in cancers with a deregulated MET and VEGFR pathway [61][62][63]. A Phase II trial in which the MET-targeted antibody MetMAb was combined with erlotinib in the treatment of advanced NSCLC showed increases in progression-free survival and overall survival compared with patients treated with erlotinib [64]. Phase III trials are being conducted. ...
Until recently, therapeutic options for lung cancer were limited, and the division into non-small-cell lung cancer and small-cell lung cancer and staging of the disease was adequate for treatment decisions in most lung cancer patients. With the discovery of new treatment options, new challenges emerged. This review focuses on recent diagnostic and predictive biomarkers in lung cancer. In addition, new techniques will enable us to perform more molecular analyses in a shorter timespan. These developments require a modern interaction between treating physicians and pathologists for optimal tissue management, allowing more molecular markers to be tested.
Cell-free DNA (cfDNA) in the circulating blood plasma of patients with cancer contains tumour-derived DNA sequences that can serve as biomarkers for guiding therapy, for the monitoring of drug resistance, and for the early detection of cancers. However, the analysis of cfDNA for clinical diagnostic applications remains challenging because of the low concentrations of cfDNA, and because cfDNA is fragmented into short lengths and is susceptible to chemical damage. Barcodes of unique molecular identifiers have been implemented to overcome the intrinsic errors of next-generation sequencing, which is the prevailing method for highly multiplexed cfDNA analysis. However, a number of methodological and pre-analytical factors limit the clinical sensitivity of the cfDNA-based detection of cancers from liquid biopsies. In this Review, we describe the state-of-the-art technologies for cfDNA analysis, with emphasis on multiplexing strategies, and discuss outstanding biological and technical challenges that, if addressed, would substantially improve cancer diagnostics and patient care. This Review discusses the challenges and opportunities, biological and technical, of technologies for the analysis of cell-free DNA for the diagnosis of cancer.
In normal cells, proliferation and survival are highly regulated processes that involve the integration of extracellular and intracellular signals through a network of protein and lipid intermediates to produce a specific output. Transformation to a cancerous state occurs when singular or multinodal genomic alterations, such as gene mutation, amplification, deletion, chromosomal translocation, gene or protein overexpression, or epigenetic silencing, alter the specificity, amplitude and/or duration of signaling which in turn results in uncontrolled growth and/or enhanced survival or motility. This chapter reviews the major signal transduction cascades that are frequently altered in human cancers. Within each cascade, specific oncogenes and tumor suppressor genes that are critical to tumorigenesis are highlighted. Additionally, FDA-approved drugs, standard of care biomarkers and promising therapeutics being tested in clinical trials are presented for actionable gene-level or mutation-level molecular targets as a function of tumor lineage. The increasing application of large scale next-generation sequencing efforts to cancer care will increasingly inform treatment selection for cancer patients and will likely serve as a source of new drug targets. Tumor genomic profiling may also help combat challenges to the successful implementation of individualized treatment regimens, including tumor lineage-based differences in drug response, the emergence of drug resistance, and the impact of intrapatient tumor heterogeneity.
Crizotinib, a targeted molecular therapy drug which inhibits tyrosine kinase, is approved for treatment of non-small cell lung carcinoma which has some ocular side effects like photopsia and delayed dark adaptation.This report documents a unique case of persistent conjunctival chemosis likely due to side effects of crizotinib therapy. A 64-year-old gentleman on crizotinib for metastatic adenocarcinoma of the lung presented with conjunctival chemosis in right eye which appeared 1 month after uneventful clear corneal phacoemulsification surgery. The patient was on crizotinib 250 mg twice a day started 2 months before cataract surgery. Clinical examination revealed marked inferior bulbar conjunctival edema of the right eye. Anterior segment optical coherence tomography, slit-lamp photographs, and magnetic resonance imaging orbit and systemic investigation were done to rule out other causes of conjunctival edema. Magnetic resonance imaging shows conjunctival and preseptal edema around both eye and thinning of the optic nerve in the right eye. Anterior segment optical coherence tomography revealed elevated hyper-reflective thickened conjunctival layer with dilated empty thin wall dark spaces of varying caliber. Chemosis was persisted for the next 3 months and not responded to oral acetazolamide, topical steroid and decongestive eyedrops. After 3 months, crizotinib was discontinued by oncologist due to drug intolerance and surprisingly within 1 week, the conjunctival edema was disappeared totally. To the best of the authors' knowledge, this is the first reported case of persistent unilateral non-inflammatory conjunctival chemosis caused by crizotinib. The physicians should be vigilant about these complications.
This article considers the use of pretest probability in non-small cell lung cancer (NSCLC) and how its use in EGFR testing has helped establish clinical guidelines on selecting patients for EGFR testing. With an ever-increasing number of molecular abnormalities being identified and often limited tissue available for testing, the use of pretest probability will need to be increasingly considered in the future for selecting investigations and treatments in patients. In addition we review new mutations that have the potential to affect clinical practice.
Aberrant activation of the HGF/c-Met signalling pathways is shown to be related with cell proliferation, progression, metastasis and worse prognosis in several tumor types, including gastrointestinal cancers, suggesting its value as a stimulating-target for cancer-therapy. Several approaches have been developed for targeting HGF and/or c-Met, and one of them, crizotinib (dual c-Met/ALK inhibitor), is recently been approved by FDA for lung-cancers with ALK-rearrangement. The main aim of current review is to give an overview on the role of c-Met/HGF pathway in gastrointestinal cancer, in preclinical and clinical trials. Although several important matters is still remained to be elucidated on the molecular pathways underlying the antitumor effects of this therapy in gastrointestinal-cancers. Further investigations are warranted to recognize the main determinants of the activity of c-Met inhibitors, for parallel targeting signalling pathway associated/activated via MET/HGF pathway or in response to the cell resistance to anti-c-Met agents. Additionally, identification of patients that might benefit from therapy could help to increase the selectivity and efficacy of the therapy
Ionizing radiation has been shown to activate and interact with multiple growth factor receptor pathways that can influence tumor response to therapy. Among these receptor interactions, the epidermal growth factor receptor (EGFR) has been the most extensively studied with mature clinical applications during the last decade. The combination of radiation and EGFR-targeting agents using either monoclonal antibody (mAb) or small-molecule tyrosine kinase inhibitor (TKI) offers a promising approach to improve tumor control compared to radiation alone. Several underlying mechanisms have been identified that contribute to improved anti-tumor capacity after combined treatment. These include effects on cell cycle distribution, apoptosis, tumor cell repopulation, DNA damage/repair, and impact on tumor vasculature. However, as with virtually all cancer drugs, patients who initially respond to EGFR-targeted agents may eventually develop resistance and manifest cancer progression. Several potential mechanisms of resistance have been identified including mutations in EGFR and downstream signaling molecules, and activation of alternative member-bound tyrosine kinase receptors that bypass the inhibition of EGFR signaling. Several strategies to overcome the resistance are currently being explored in preclinical and clinical models, including agents that target the EGFR T790 M resistance mutation or target multiple EGFR family members, as well as agents that target other receptor tyrosine kinase and downstream signaling sites. In this chapter, we focus primarily on the interaction of radiation with anti-EGFR therapies to summarize this promising approach and highlight newly developing opportunities.
Molecular targeted therapy has the potential to dramatically improve survival in patients with cancer. However, complete and durable responses to targeted therapy are rare in individuals with advanced-stage solid cancers. Even the most effective targeted therapies generally do not induce a complete tumor response, resulting in residual disease and tumor progression that limits patient survival. We discuss the emerging need to more fully understand the molecular basis of residual disease as a prelude to designing therapeutic strategies to minimize or eliminate residual disease so that we can move from temporary to chronic control of disease, or a cure, for patients with advanced-stage solid cancers. Ultimately, we propose a shift from the current reactive paradigm of analyzing and treating acquired drug resistance to a pre-emptive paradigm of defining the mechanisms that result in residual disease, to target and limit this disease reservoir.
Therapeutic monoclonal antibodies exert their antitumor effect through a variety of mechanisms, including apoptotic induction, extracellular mechanisms and the involvement of the innate and possibly the adaptative immune systems. Due to this complexity there are still few data regarding mechanisms of resistance to monoclonal antibody therapy. In this review, we discuss the available data for three of the best described antibodies, rituximab, trastuzumab and cetuximab. A variety of approaches and strategies has been suggested or are currently being tested to circumvent resistance to these antibodies.
Hepatocyte growth factor/c-MET (HGF/c-MET) signaling pathway can be abnormal activated by many mechanisms such as c-MET mutation, amplification and the overexpression of HGF, and it plays an important role in the development of non-small cell lung cancer (NSCLC), as well as in the tolerance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in NSCLC. Therefore, c-MET is a new molecular target for the therapy of NSCLC since EGFR and ALK. At present, although the c-MET inhibitors have shown a potential prospect in some clinical trials, its assessment of safety and effectiveness in clinical applications, and the choice of testing methods and standards still need a further discussion. In this paper, we summarized the mechanism of c-MET in NSCLC, as well as its treatment prospect and selection of testing methods.
This chapter will review the latest emerging novel targeted agents and gene therapy in nonsmall cell lung cancer treatment. In the targeted therapies section, each class of drug will have a review of the scientific rationale and an update on the clinical development. Among the agents reviewed are hsp90 inhibitors, MET/HCF inhibitors, MEK inhibitors for KRAS mutated patients, PI3K/AKT/mTOR inhibitors, PARP inhibitors, NOTCH/Hedgehog pathway inhibitors, and mitotic inhibitors. The gene therapy section will focus on the science and background behind p53 gene replacement, review the clinical trial studies completed to date, and discuss the clinical trial results of FUS1 replacement with DOTAP.
The paradigm of lung cancer treatment has rapidly changed in the last 10 years thanks to the introduction of molecularly tailored drugs, especially for lung adenocarcinoma. After the successes obtained with target agents in the treatment of EGFR mutation and ALK rearrangement positive patients, a number of new molecular markers have been identified, such as HER2 aberrations, MET and FGFR1 amplification, BRAF and DDR2 mutations, and others. A molecular driver may be identified in up to 60 % of adenocarcinoma, whereas biological knowledge of squamous cell carcinoma is at an earlier stage and a targetable alteration may be found in only 30 % of cases. Most of the molecular changes display low frequency (<5 %) but may represent appealing actionable targets for therapy. Drugs already approved for use in other tumors and novel agents are currently being explored in molecularly selected subcategories of lung cancer, such as neratinib in HER2 mutated patients or dabrafenib in subjects bearing BRAF mutation. Initial results of clinical studies and reports are promising and allow to envision a brighter future for research and treatment of lung cancer.
Chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene were recently identified in patients with nonsmall cell lung cancer (NSCLC). Although found in a small subset of patients, ALK rearrangements define an important model of oncogene-driven NSCLC. ALK rearrangements are associated with specific clinical and pathologic features, such as younger age, adenocarcinoma histology, and lack of smoking history. Screening for ALK rearrangements can be performed using ALK FISH, immunohistochemistry or RT-PCR, though only ALK FISH is clinically validated. Patients with ALK rearrangements are uniquely sensitive to the ALK tyrosine kinase inhibitor crizotinib, which results in high response rates (60%) and a median progression-free survival of over 8 months. The success of crizotinib validates treatment paradigms using molecularly targeted therapies and underscores the value of incorporating tumor genotyping into routine clinical practice.
Head and Neck Squamous Cell Carcinoma (HNSCC) remains a formidable challenge to physicians, scientists, and patients. New targets that can be exploited to improve the outcome of patients afflicted with this dreadful disease are desperately needed: one such potential target is c-MET. The c-MET receptor tyrosine kinase, also known as hepatocyte growth factor receptor (HGFR), is robustly overexpressed and sometimes mutated or amplified in head and neck cancer cells, while overexpression of its ligand, hepatocyte growth factor/scatter factor (HGF/SF), often occurs in tumor-adjacent mesenchymal cells, providing paracrine signals that support tumor growth. Activation of c-MET stimulates numerous downstream signaling pathways that contribute to tumor growth, including GRB2/RAS, PI3K, STAT3, SRC, β-catenin, and Notch. Overexpression or anomalous activation of c-MET is often associated with resistance to targeted therapies inhibiting receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR), that communicate to similar growth factor cascades. In this review, we emphasize the role of c-MET/HGF in HNSCC as well as the potential for therapeutic targeting of this receptor.
Epidermal growth factor receptor (EGFR)-targeted agents have been extensively evaluated for management of recurrent/metastatic nonsmall cell lung cancers. Clinical trials utilizing EGFR tyrosine kinase inhibitors and antibodies have been completed in the frontline setting, as well as in the settings of maintenance and salvage therapy. In this chapter, the results of the main studies on this topic will be reviewed. Novel strategies related to targeting the EGFR axis will also be discussed.
Recently developed pathway-targeted drug therapies have had an enormous impact on the clinical management of several types of advanced cancer. For example, inhibitors of kinases, including EGFR, HER2, BCR-ABL, BRAF, and ALK, as well as nonkinase targets such as the hedgehog pathway component Smoothened, have demonstrated impressive clinical activity in treated patients – even in the metastatic setting in many cases. Importantly, the efficacy of such agents is largely limited to subsets of patients whose tumors are defined by specific genotypes associated with pathway activation and a state of “oncogene addiction.” This relatively new paradigm, in which patients most likely to benefit from a particular therapeutic can be prospectively identified to guide treatment decisions, has been described as “personalized cancer medicine,” and it has highlighted the critical role of predictive biomarkers for the optimal development of new cancer drug therapies. The discovery of such biomarkers can be challenging, although recent advances in genomic technologies and improvements in preclinical models, including large cancer cell line panels, have substantially aided these efforts. The discovery of a variety of mechanisms of acquired drug resistance, which inevitably limit the efficacy of new pathway-targeted drug treatments, has also provided insights into predictive biomarkers. However, significant challenges remain, for example, with the increasing need to identify predictive biomarkers in the context of drug combination treatments, and for treatments that target the tumor vasculature, demanding more sophisticated preclinical models and methods of data analysis to discover such biomarkers.
In the past decade, the characterization of non-small-cell lung cancer (NSCLC) into subtypes based on genotype and histology has resulted in dramatic improvements in disease outcome in select patient subgroups. In particular, molecularly targeted agents that inhibit EGFR or ALK are approved for the treatment of NSCLC harbouring genetic alterations in the genes encoding these proteins. Although acquired resistance usually limits the duration of response to these therapies, a number of new agents have proven effective at tackling specific resistance mechanisms to first-generation inhibitors. Large initiatives are starting to address the role of biomarker-driven targeted therapy in squamous lung cancers, and in the adjuvant setting. Immunotherapy undeniably holds great promise and our understanding of subsets of NSCLC based on patterns of immune response is continuing to evolve. In addition, efforts are underway to identify rare genomic subsets through genomic screening, functional studies, and molecular characterization of exceptional responders. This Review provides an overview of the key developments in the treatment of NSCLC, and discusses potential strategies to further optimize therapy by targeting disease subtypes.
SUMMARY Lung cancers harboring mutations in the EGFR respond to EGF receptor-tyrosine kinase inhibitor, which at present represent the most appropriate treatment for EGFR mutation-positive advanced non-small-cell lung cancer. Unfortunately drug resistance invariably emerges with different known mechanisms, including the EGFR T790M mutation, MET gene amplification, EGFR amplification, mutations in the PIK3CA gene, mutations in the HER2 gene, IGF1R amplification, transformation of non-small-cell lung cancer into small-cell lung cancer and moreover epithelial-to-mesenchymal transition. Various strategies to manage secondary resistance have been explored and in this review we will analyze scientific data in support of these different strategies to assess the most adequate to use in relation to the progression disease.
Dans le domaine de la cancérologie thoracique, les communications du congrès de l’European Respiratory Society 2012 se sont essentiellement intéressées à deux thèmes en plein essor. D’une part, la recherche de nouveaux marqueurs pronostiques et prédictifs de réponse aux traitements a été largement étudiée. D’autre part, le congrès a été l’occasion d’une mise au point sur la prise en charge des patients atteints de cancer bronchique non à petites cellules avec de nouvelles molécules ou des stratégies thérapeutiques innovantes.
A major cause of death worldwide is cancer, and pathological angiogenesis is critical in cancer progression. Tumor cells acquire oxygen and nutrients mainly via angiogenesis, and therefore angiogenesis inhibition might be a promising approach for anticancer therapy. Therapeutic antibodies as a cancer treatment approach are focused in the following main points: modes of action, adverse effects, mechanisms of resistance, and new developments. Targeting the VEGF (vascular endothelial growth factor) signaling pathway with monoclonal antibodies is one possible approach in angiogenesis inhibition. For instance, bevacizumab is a highly specific recombinant humanized monoclonal IgG (immunoglobin G) antibody targeting VEGF-A. Antibodies targeting other angiogenesis proteins together with VEGF-A is a promising antitumor therapy strategy, which is in the focus of current research. A combination therapy approach with anti-angiogenic antibodies, such as ARQ197 plus erlotinib/sorafenib or MetMab plus erlotinib, might be even more promising because angiogenesis is a complex process with various components involved.
Squamous cancer of the lung (SQCC), although no longer the premier variant of non-small cell lung cancer, continues to impose a heavy world-wide burden. Advanced SQCC has enjoyed little of the recent progress benefiting patients with adenocarcinoma of the lung, but that has now begun to change. This article reviews the underlying molecular pathology of SQCC, as well as potential new targets and the corresponding novel targeted agents; included are some of which may soon be approvable in this notoriously hard-to-treat indication.
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