Asklepios Fachkliniken

Gauting, Germany

Asklepios Fachkliniken

Gauting, Germany
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News Article | May 19, 2017
Site: www.eurekalert.org

Lung cancer patients are particularly susceptible to malignant pleural effusion, when fluid collects in the space between the lungs and the chest wall. Researchers at the Helmholtz Zentrum München, in partnership with the German Center for Lung Research (DZL), have discovered a novel mechanism that causes this to happen. Their study, published in 'Nature Communications', also shows that various active substances could potentially be used to treat this condition. Malignant pulmonary effusion (MPE) frequently occurs in patients with metastatic breast or lung cancer. It involves a build-up of excess fluid in the pleural cavity, the area between the lungs and the chest wall, with accompanying malignant cells. The lung is surrounded by fluid, which can cause shortness of breath and chest pain, for example, and may even prove fatal. "There is still no effective treatment for this," explains Professor Georgios Stathopoulos, research group leader at the Institute for Lung Biology (ILBD) and Comprehensive Pneumology Center (CPC) at the Helmholtz Zentrum München. "In the case of larger pulmonary effusions with volumes exceeding one liter, treatment usually involves aspiration in order to relieve pressure on the lung." Stathopoulos and his team are working to understand the causes of pleural effusion, which remain unclear, in an effort to advance the treatment of this condition in the future. In the current study, the scientists examined cancer cells they had obtained from pleural effusions with a malignant mutation in the KRAS gene. KRAS is known to play a key role in the growth of various malignant tumors. "We were able to show that these cells release a messenger substance into the bloodstream, which in turn attracts immune cells.* These cells then wander via the spleen to the pleural cavity, where they cause the effusion," Stathopoulos says, explaining the mechanism. In addition, the scientists found the KRAS-mutant cancer cells in the MPE material of lung cancer patients as well as in the cell lines derived from them. In order to verify whether their newly acquired knowledge could be applied in clinical practice, the researchers tested two active substances that interrupt the mechanism at two different points. In an experimental model they were able to demonstrate that both the KRAS inhibitor Deltarasin** and an antibody against the messenger substance released by the cancer cells prevented pleural effusion. "Nearly two thirds of all MPEs are the result of lung cancer. In view of the still large numbers of smokers, appropriate treatments are urgently needed," Stathopoulos stresses. "Our results lead us to assume that drugs that target the mechanism we have discovered could be a potential treatment option. Further studies are now needed to confirm that." Lung cancer expert Georgios Stathopoulos joined the Helmholtz Zentrum München in 2015. He also heads a working group at the Laboratory for Molecular Respiratory Carcinogenesis at the University of Patras in Greece. The study that has now been published was the outcome of collaboration between the two working groups. * The messenger substance in question is CCL2 (CC-Chemokinligand 2), which is often released when inflammation occurs. ** Deltarasin prevents the transport of the cancer-causing protein KRAS to the cell membrane. In 2015 a team headed by Professor Stathopoulos discovered that in lung cancer patients mast cells collect in the pleural cavity, where they cause a pleural effusion. In a preclinical model, initial experiments with Imatinib, a tyrosine kinase inhibitor, revealed a smaller pleural effusion and fewer mast cells. The co-authors of the study, Malamati Vreka and Mario Pepe, are PhD students at the CPC Research School and participants in the PhD training program at the Helmholtz Graduate School of Environmental Health, in short HELENA. The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www. The Comprehensive Pneumology Center (CPC) is a joint research project of the Helmholtz Zentrum München, the Ludwig-Maximilians-Universität Clinic Complex and the Asklepios Fachkliniken München-Gauting. The CPC's objective is to conduct research on chronic lung diseases in order to develop new diagnosis and therapy strategies. The CPC maintains a focus on experimental pneumology with the investigation of cellular, molecular and immunological mechanisms involved in lung diseases. The CPC is a site of the Deutsches Zentrum für Lungenforschung (DZL). http://www. The German Center for Lung Research (DZL) pools German expertise in the field of pulmonology research and clinical pulmonology. The association's head office is in Giessen. The aim of the DZL is to find answers to open questions in research into lung diseases by adopting an innovative, integrated approach and thus to make a sizeable contribution to improving the prevention, diagnosis and individualized treatment of lung disease and to ensure optimum patient care. http://www.


Merimsky O.,Tel Aviv Medical Center | Cheng C.-K.,Princess Margaret Hospital | Au J.S.-K.,Queen Elizabeth Hospital | Von Pawel J.,Asklepios Fachkliniken | Reck M.,Krankenhaus Grosshansdorf
Oncology Reports | Year: 2012

TaRceva LUng cancer Survival Treatment (TRUST) was an open-label, phase IV study of advanced non-small cell lung cancer (NSCLC). Patients failing or unsuitable for chemotherapy or radiotherapy received erlotinib 150 mg/day until progression. We examined a subpopulation of elderly patients (≥70 years) receiving first-line erlotinib (n=485) in TRUST. In this subpopulation, disease control rate (n=356 with best response data available) was 79% (vs. 69% for the overall TRUST population; P<0.0001); median progressionfree survival (PFS) was 4.57 months [95% confidence interval (CI), 3.68-5.22]; median overall survival (OS) was 7.29 months (95% CI, 6.27-8.67); and one-year survival, was 36.6%. PFS and OS were significantly longer in patients developing rash, compared to those without, and in those with good performance status (PS; 0/1), compared to poor PS (≥2). Eighty-seven subpopulation patients (18%) had an erlotinib-related AE; other than the protocol-defined frequent adverse events (AEs); 4% had a grade ≥3 erlotinib-related AE, 7% had an erlotinib-related serious AE. In the subpopulation, dose reductions were required in 27%, most (97%) were reductions to 100 mg/day; treatment was discontinued in 10%, and one death was associated with treatment-related toxicity (<1%). Erlotinib was effective and well-tolerated and may be considered for elderly patients with advanced NSCLC who are unsuitable for standard first-line chemotherapy or radiotherapy.


Ramalingam S.S.,Emory University | Janne P.A.,Dana-Farber Cancer Institute | Mok T.,Chinese University of Hong Kong | O'Byrne K.,Princess Alexandra Hospital | And 14 more authors.
The Lancet Oncology | Year: 2014

Background: Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study. Methods: In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554. Findings: Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2.6 months (95% CI 1.9-2.8) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0.941, 95% CI 0.802-1.104, one-sided log-rank p=0.229). For patients with wild-type KRAS, median progression-free survival was 2.6 months for dacomitinib (95% CI 1.9-2.9) and erlotinib (95% CI 1.9-3.0; stratified HR 1.022, 95% CI 0.834-1.253, one-sided p=0.587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [<1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib. Interpretation: Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations. Funding: Pfizer. © 2014 Elsevier Ltd.


O'Byrne K.J.,St James's Hospital | Gatzemeier U.,Hospital Grosshansdorf | Bondarenko I.,Dnepropetrovsk State Medical Academy | Barrios C.,Hospital Sao Lucas | And 14 more authors.
The Lancet Oncology | Year: 2011

Background: Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting. Methods: Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT00148798. Findings: KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17·5 months [95% CI 11·7-23·4] vs 8·5 months [7·1-10·8], hazard ratio [HR] 0·52 [0·32-0·84], p=0·0063; chemotherapy alone: 23·8 months [15·2-not reached] vs 10·0 months [8·7-11·0], HR 0·35 [0·21-0·59], p<0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11·4 months [8·6-13·6] vs 6·8 months [5·9-12·7], HR 0·80 [0·55-1·16], p=0·24; chemotherapy alone: 11·0 months [9·2-12·6] vs 9·3 months [7·6-11·9], HR 0·77 [0·54-1·10], p=0·16). Interpretation: The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed. Funding: Merck KGaA. © 2011 Elsevier Ltd.


Sebastian M.,Universitaetsmedizin | Reck M.,Hospital Grosshansdorf | Waller C.F.,Albert Ludwigs University of Freiburg | Kortsik C.,St Hildegardis Hospital | And 7 more authors.
Journal of Thoracic Oncology | Year: 2010

OBJECTIVE: To investigate the efficacy, safety, and pharmacokinetics of two dosing schedules of BI 2536, a novel polo-like kinase-1 inhibitor, in patients with relapsed stage IIIB/IV non-small cell lung cancer. METHODS: Ninety-five patients were randomized to intravenous BI 2536 on day 1 (200 mg) or days 1 to 3 (50 or 60 mg) of a 21-day treatment course. BI 2536 doses were escalated beyond course 2 if well tolerated. The primary objective was response, and the secondary objectives were progression-free survival (PFS) and overall survival (OS), quality of life, safety, and pharmacokinetics. Primary statistical aim was to demonstrate the difference in objective response rate to historical placebo for both treatment groups. RESULTS: Four patients (4.2%) had a partial response; two were confirmed by independent review. Median PFS was 8.3 weeks (58 days 95% confidence interval [CI]: 48-85) and 7 weeks (49 days 95% CI: 46-70) assessed by investigator and independent review, respectively. Median OS was 28.7 weeks (201 days 95% CI: 180-305). No statistically significant difference was observed between the two treatment schedules regarding clinical benefit, PFS, or OS. Grade 4 neutropenia occurred in 37% of patients; common nonhematologic adverse events were fatigue (31%) and nausea (27%). Two deaths (pulmonary hemorrhage and sepsis) were considered drug related. There was a trend in favor of the days 1 to 3 dosing schedule in quality of life. BI 2536 displayed moderate interpatient variability. CONCLUSIONS: BI 2536 monotherapy has modest efficacy and favorable safety in relapsed non-small cell lung cancer. The findings support the further development of polo-like kinase-1 inhibitors within this indication. © 2010 by the International Association for the Study of Lung Cancer.


PubMed | Institute Of Cancerologie Of Iouest, Princess Alexandra Hospital, Hospital Universitario 12 Of Octubre, Center of Oncology of Poland and 8 more.
Type: Clinical Trial, Phase III | Journal: The Lancet. Oncology | Year: 2014

Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study.In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554.Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 26 months (95% CI 19-28) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0941, 95% CI 0802-1104, one-sided log-rank p=0229). For patients with wild-type KRAS, median progression-free survival was 26 months for dacomitinib (95% CI 19-29) and erlotinib (95% CI 19-30; stratified HR 1022, 95% CI 0834-1253, one-sided p=0587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [<1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib.Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations.Pfizer.


Patients with advanced non-small-cell lung cancer survive four months longer with fewer side effects on an immunotherapy drug called atezolizumab compared to chemotherapy, according to a phase 3 clinical trial published in The Lancet. The trial enrolled 1225 advanced non-small-cell lung cancer patients who have no more treatment options, but this study used an early analysis of the first 850 patients from the trial. Half of the group were given atezolizumab and the other half were given docetaxel chemotherapy, which is the standard treatment for advanced non-small-cell lung cancer. Patients given atezolizumab - a drug that blocks the programmed death ligand 1 (PD-L1) protein - survived for an average of 13.8 months, compared with 9.6 months for those on chemotherapy. As well as the benefits in survival, atezolizumab also had fewer side effects than chemotherapy with 14.8% (90 of 609) of those given the drug having grade three or four side effects compared with 42.7% (247 of 578) of those given chemotherapy. However, 46 (of 609, 7.6%) of the patients given atezolizumab still gave up treatment due to side effects, as well as 108 (of 578 patients, 18.7%) of those on chemotherapy. "Lung cancer is the most common cancer affecting 1.8 million people each year worldwide. It is also the leading cause of cancer death worldwide and survival remains stubbornly low. Recently, important advances in the treatment of the disease have come from immunotherapies that target the PD-L1 and PD-1 pathway," said Dr Achim Rittmeyer, lead author, University Goettingen, Germany. "Atezolizumab reinvigorates patients' immune systems against cancer, and our trial has shown that this has significant results for their survival." [1] In the trial the researchers also studied the amount of PD-L1 protein on the patients' cancer and immune cells and how long patients survived for on each treatment. They found that the drug worked best for patients with the highest levels of the PD-L1 protein on their cells - more than doubling survival compared with those given chemotherapy (20.5 months compared with 8.9 months overall survival) - but still increased survival for those with little to no levels of the protein by three and a half months (12.6 compared with 8.9 months overall survival). "This is the first phase 3 trial of a PD-L1-directed immunotherapy in lung cancer. The fact that it improves survival in patients with all categories of PD-L1 expression is highly encouraging and adds to the already known benefits of immunotherapy in lung cancer." said Dr David Gandara, senior author, UC Davis Comprehensive Cancer Center, USA. [1] Other immunotherapies for non-small-cell lung cancer, such as nivolumab and pembrolizumab, are designed to block PD-L1's counterpart, the programmed cell death protein 1 (PD-1) which is located on the immune cell surface. Normally the PD-L1 and PD-1 proteins signal to one another to activate the immune system to attack tumours. It's thought that the extra PD-L1 protein on some cancer cells' surfaces helps them hide from the immune system, meaning it cannot find and kill cancer cells as usual. But by blocking the extra PD-L1 protein, atezolizumab may unveil the cells to the immune system so they can be attacked and destroyed. The study is the first phase 3 trial of a PD-L1 inhibitor drug and has shown longer survival than trials of PD-1 inhibitors. The authors note that the trial was 'open label', meaning that patients and doctors knew whether or not they were being given immunotherapy. In addition, after the study treatment finished some (17%) of those given chemotherapy on the trial were prescribed another immunotherapy drug (mostly nivolumab) by their own doctor. This could have increased survival in the chemotherapy group, meaning that the difference between two groups may be greater than shown in this study. Writing in a linked Comment, Professor Elisabeth Quoix, Hôpitaux Universitaires de Strasbourg, France, said: "After decades of disappointments with non-specific vaccines or more recently tumor associated antigen specific vaccines, immunotherapy with antibodies that target the PD-L1 and PD-1 pathway have emerged as a major therapeutic breakthrough. This treatment improves the prognosis of patients with non-small-cell lung cancer that cannot benefit from targeted therapies... The time in which chemotherapy will no more be the mainstay of treatment of metastatic non-small-cell lung cancer is perhaps not so far away. Nevertheless... Several points need to be clarified, such as the optimum therapeutic schedule and the optimum duration of treatment, to limit treatment costs. Additionally combinations of different immunotherapies might be of interest." The study was funded by F. Hoffman-La Roche Ltd and Genentech Ltd.. It was conducted by scientists from Lungenfachklinik Immenhausen, Aix Marseille Universite, Sungkyunkwan University School of Medicine, Seconda Università degli Studi di Napoli, Asklepios Fachkliniken München-Gauting, Karmanos Cancer Institute/Wayne State University, Aichi Cancer Center Hospital, Institute M. Sklodowska-Curie, Hospital Regional Universitario Carlos Haya, AOU San Gerardo, Minnesota Oncology, Southern California Permanente Medical Group, PUCRS School of Medicine, University of California, Centro Internacional de Estudios Clinicos, European Institute of Oncology, Istanbul University Cerrahpasa Medical Faculty Hospital, Seoul National University Bundang Hospital, Genentech Inc. and UC Davis Comprehensive Cancer Center. A declaration of interests is available in the Article. [ 1] Quote direct from author and cannot be found in the text of the Article. IF YOU WISH TO PROVIDE A LINK FOR YOUR READERS, PLEASE USE THE FOLLOWING, WHICH WILL GO LIVE AT THE TIME THE EMBARGO LIFTS: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32517-X/fulltext


von Pawel J.,Asklepios Fachkliniken | Gorbounova V.,Cancer Research Center | Reck M.,Member of German Center for Lung Research | Kowalski D.M.,Center of Oncology of Poland | And 5 more authors.
Lung Cancer | Year: 2014

Background: DISRUPT evaluated whether adding the vascular-disrupting agent ombrabulin to a taxane-platinum doublet in the first-line setting improved progression-free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC). Methods: Patients were randomised to ombrabulin 35mg/m2 or placebo followed by a taxane-platinum regimen every 3 weeks. Results: Overall, 176 patients were randomised. After 124 events, median PFS was not significantly improved with ombrabulin vs placebo (5.65 vs 5.45 months; HR 0.948; 60% CI 0.813-1.106; one-sided P= 0.39). The two groups showed similar overall survival (median 11.0 months in both groups), objective response rate (32% ombrabulin; 31% placebo) and safety profiles. Conclusion: This study did not meet its primary endpoint of improving PFS by adding ombrabulin to a taxane-platinum regimen for first-line treatment of metastatic NSCLC. © 2014 Elsevier Ireland Ltd.


Sequist L.V.,Harvard University | Von Pawel J.,Asklepios Fachkliniken | Garmey E.G.,ArQule | Akerley W.L.,Huntsman Cancer Institute | And 11 more authors.
Journal of Clinical Oncology | Year: 2011

Purpose: c-MET (MET) receptor activation is associated with poor prognosis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small-cell lung cancer (NSCLC). This global, randomized phase II trial examined erlotinib plus tivantinib (ARQ 197; ArQule, Woburn, MA), a novel MET inhibitor. Methods: Previously treated patients with EGFR TKI-naive advanced NSCLC were randomly assigned to receive oral erlotinib (150 mg daily) plus oral tivantinib (360 mg twice daily) or erlotinib plus placebo (EP). The primary end point was progression-free survival (PFS). At the time of progression, cross-over from EP to erlotinib plus tivantinib (ET) was permitted. Archival tumor tissue specimens were required. Results: One hundred sixty-seven patients were randomly assigned to ET (n = 84) and to EP (n = 83). Median PFS was 3.8 months for ET and 2.3 months for EP (hazard ratio [HR], 0.81; 95% CI, 0.57 to 1.16; P = .24). Exploratory analysis revealed that the small cohort with KRAS mutations achieved a PFS HR of 0.18 (95% CI, 0.05 to 0.70; interaction P = .006). Objective responses were seen in 10% of patients on ET, 7% of patients on EP, and in two patients who crossed over from EP to ET, including one with EGFR mutation and MET gene copy number greater than 5. There were no significant differences in adverse events between study arms. Conclusion: The combination of the MET inhibitor tivantinib and erlotinib is well-tolerated. Although the study did not meet its primary end point, evidence of activity was demonstrated, especially among patients with KRAS mutations. Additional study of tivantinib and erlotinib in patients with NSCLC is planned. © 2011 by American Society of Clinical Oncology.


Pirker R.,Medical University of Vienna | Pereira J.R.,Arnaldo Vieira Of Carvalho Cancer Institute | Von Pawel J.,Asklepios Fachkliniken | Krzakowski M.,Maria Curie Sklodowska University | And 10 more authors.
The Lancet Oncology | Year: 2012

Background: Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients. Methods: We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score <200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044). Interpretation: High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting. Funding: Merck KGaA. © 2012 Elsevier Ltd.

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