P3.03-024 Real-Life Experience and Clinical Characterization of BRAF V600E Mutation in Austrian NSCLC Patients

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P3.03-023 Nintedanib Selectively Inhibits the Activation and Tumor-Promoting Effects of Fibroblasts from Lung Adenocarcinoma Patients M. Gabasa,1 R. Ikemori,1 F. Hilberg,2 J. Alcaraz,1 N. Reguart3 1Dept of Biomedicine, School of Medicine, University of Barcelona, Barcelona/ ES, 2Boehringer Ingelheim Austria, Vienna/AT, 3Medical Oncology, Hospital Clinic, Translational Genomics and Targeted Therapeutics in Solid Tumors, Institut D’Investigacions Biomèdiques August Pi I Sunyer (Idibaps), Barcelona/ES Background: There is growing awareness that tumor-associated fibroblasts (TAFs) play critical roles in both tumor progression and response to therapies in solid tumors including non-small cell lung cancer (NSCLC). Nintedanib (NTD) is a multi-kinase inhibitor of VEGF, FGF and PDGF receptors that has been recently approved to treat advanced lung adenocarcinoma (ADC) patients in combination with docetaxel. The main goal of this study was to assess how TAFs contribute to the selective therapeutic effects of NTD in lung ADC. Method: Because TAFs are largely activated in vivo, patient derived lung TAFs from ADC and squamous cell carcinoma (SCC) patients as well as paired control fibroblasts from non-malignant pulmonary tissue were activated with TGF- b1 in the presence of increasing concentrations of NTD. Conditioned medium was also collected and used to stimulate the growth and invasion of several cancer cell lines. A panel of activation markers indicative of fibrosis was analyzed in TAFs, including alpha-smooth muscle actin, collagen-I/III and P4HA2. Result: Nintedanib dose-dependently inhibited the TGF-b1-induced expression of all activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved lung parenchyma, whereas such inhibition was very modest in SCC-TAFs, suggesting that TAF activation is regulated by different mechanisms in ADC and SCC. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by the conditioned medium from activated TAFs in ADC but not SCC. These results reveal that the pro-tumorigenic effects of ADC-TAFs in vitro are markedly reduced in the presence of NTD. Conclusion: These results reveal that nintedanib is an effective inhibitor of fibrosis and its associated tumor-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that preclinical models based on carcinoma-TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumors. Keywords: nintedanib, fibroblasts

P3.03-024 Real-Life Experience and Clinical Characterization of BRAF V600E Mutation in Austrian NSCLC Patients S. Schwab,1 U. Setinek,2 D. Krenbek,2 S. Watzka,3 S. Gasser,4 F. Huemer,1 I. Kapfhammer,1 H. Fabikan,1 E. Hauptmann-Repitz,1 O. Burghuber,1 M. Hochmair1 1Department of Respiratory and Critical Care Medicine, and Ludwig Boltzmann Institute of COPD and Respiratory Epidemiology, Otto Wagner Hospital, Vienna/AT, 2Institute of Pathology, Otto Wagner Hospital, Vienna/AT, 3Institute of Thoracic Surgery, Otto Wagner Hospital, Vienna, Austria, Vienna/AT, 4Institute of Radiology, Otto Wagner Hospital, Vienna, Austria, Vienna/AT Background: Targeted therapy is becoming increasingly important and has improved the overall survival for patients with NSCLC. BRAFV600E mutations (Val600Glu) are observed in 1-2% of lung cancer and play a major role in targeted therapy by providing an opportunity for affected patients as possible allocable target. In Austria an effective therapy is available with Dabrafenib and Trametinib. The aim of this retrospective

Journal of Thoracic Oncology

Vol. 12 No. 11S2

analysis was to support ongoing research on the frequency of this promising genetic alteration by determining the prevalence of BRAFV600E mutations among Austrian NSCLC patients. We also examined clinical characteristics of these patients. Method: Patient characteristics including age, sex, race, smoking history and localization of biopsy were collected. Tumor tissue from bronchoscopy, CT- and ultrasound guided biopsies as well as surgical specimen with histological type of adenocarcinoma and NSCLC NOS (Not Otherwise Specified) excluding large cell carcinoma and neuroendocrine carcinoma was reflex tested independent of the tumor stage and clinical characteristics (like sex, smoking history, demography) for BRAF mutations. The BRAF mutation detection was performed since February 2017 with the BRAF/NRAS Mutation Test Kit from Roche on a COBAS® z 4800 Analyzer. Result: BRAF alterations were found in 11 of 118 tested patients (9.3%), of which 7 patients (5.9%) showed a BRAFV600E positive mutation. Out of these patients with BRAFV600E positive mutation, 4 were women and 3 men. 3 patients were Never-Smoker, 2 were former smokers and 2 smokers. Biopsies in 5 patients were taken from the primary tumor, in 1 patient from the lymph nodes and in 1 patient the analysis was performed by drainage of pleura effusions. Median age was 69 years. All patients were Caucasian. Conclusion: The prevalence of BRAFV600E mutation in this real-world data, assessed in a cohort of 118 people, was higher than BRAFV600E mutation rates previously reported by other published data, and thus underline the importance of reflex testing for this druggable target independent of clinical characteristics. Keywords: NSCLC BRAF, BRAF

P3.03-025 Tumor Biomarkers for the Routine Care of Advanced Non-Small-Cell Lung Cancer: A Decade of Experience in Implementing Predictive Genomic Events D. Rangachari,1 P. Vanderlaan,2 X. Le,1 A. Majid,3 M. Parikh,3 S. Gangadharan,3 M. Kent,3 M. Huberman,1 S. Kobayashi,1 D. Costa1 1 Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA/US, 2Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA/US, 3 Surgery, Beth Israel Deaconess Medical Center, Boston, MA/US Background: Although a growing list of mandatory genomic/immunebased biomarkers are now routinely integrated into the management of advanced non-small-cell lung cancer (NSCLC), few reports have detailed the evolution of NSCLC predictive biomarker assessment in routine clinical practice. Method: We retrospectively probed 1,000+ NSCLC-patient pairs analyzed for predictive biomarkers from 2004 to 2017 at our institution and evaluated patterns of testing as well as correlation with clinical-pathologic characteristics. Result: The majority of 1,009 patient-tumor pairs had advanced adenocarcinoma with most specimens obtained from lung, mediastinal/hilar nodes, and pleura and with a similar distribution between surgical, small biopsy, and cytology specimens. All were tested for EGFR mutations, 895 for ALK rearrangement, 841 for KRAS mutation, 537 for ROS1rearrangement, and 179 using comprehensive genomic profiling. Implementation of near-universal genomic biomarker testing for EGFR, ALK, ROS1 and PD-L1 occurred within the first year following evidence of activity/ approval of a paired therapy. The failure rate after use of the best specimen for the most common tests was 5.5%. A quarter of tumors had a driver oncogene (EGFR/ALK/ROS1/BRAF-V600E) with an approved oral therapy, with the highest prevalence in patients with 15 pack-years tobacco use. Conclusion: Tumor biomarker testing in routine clinical NSCLC specimens at our institution evolves rapidly following approval of new therapies linked to diagnostic assays. Our practice’s decade-plus experience indicates that it will be feasible for the thoracic oncology community to continue to expand the use of predictive genomic and immune biomarkers using currently available clinical specimens. Keywords: NSCLC, EGFR, ALK