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P1.02-050 Acquired Resistance to EGFR Tyrosine Kinase Inhibitors (TKIs) in EGFR-Mutant Lung Adenocarcinoma among Hispanics (Rbiop-CLICaP)
January 2017
(6 exon 14 skipped and 8 amplified): 13 patients were male (93%), with a median age of 65.7 years (range: 4091), nine current smokers (64%) (40 pack-years, range: 20-60), and eight diagnosed in an advanced stage disease (III and IV) (57%). Correlation with c-MET protein expression by IHC is ongoing, and data will be presented at the meeting. Conclusion: As no concurrent MET mutated and amplified cases were found, our data support prospective identification of both, MET exon 14 skipping mutations and gene amplifications. These mutations define a new subset of NSCLC patients that should be analyzed independently of the status of MET gene copy number. Keywords: MET amplification, FISH, MET exon 14 skipping, MET alterations
P1.02-049 EGFR, KRAS and ALK Gene Alterations in Lung Cancer Patients in Croatia Topic: Driver Genes in NSCLC, Resistance, and Other Marko Jakopovic,1 Luka Brcic,2 Marija Misic,3 Gordana Bubanovic,1 Fran Seiwerth,4 Gordana Drpa,4 Branka Cucevic,4 Mihovil Roglic,4 Sanja Plestina,4 Suazana Kukulj,4 Silvana Smojver-Jezek,4 Sven Seiwerth,3 Miroslav Samarzija1 1Department for Respiratory Diseases “Jordanovac”, University Hospital Centre Zagreb, Zagreb/Croatia, 2Department of Pathology, University of Graz, Graz/Austria, 3Zagreb Medical School, Zagreb/ Croatia, 4University Hospital Centre Zagreb, Zagreb/ Croatia Background: Rates in targetable gene changes varies between different populations of lung cancer patients. Targetable gene changes include changes in EGFR and ALK gene, as well as KRAS gene. Primary aim of this study was to determine mutation status in purely Caucasian Croatian population. Methods: Rates in targetable gene changes varies between different populations of lung cancer patients. Targetable gene changes include changes in EGFR and ALK gene, as well as KRAS gene. Primary aim of this study was to determine mutation status in purely Caucasian Croatian population. Results: During 6 months period 324 newly diagnosed primary lung adenocarcinoma were tested. Out of 324 tested patients, 194 were males (60%) and 130 females (40%) mean age 64 years (range 35 to 88 years). Vast majority of patients were in stages 3 and 4 (more than
Abstracts
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80%). Among males, 87% of patients were ever smokers, and among females 61% of patients were ever smokers. Significantly higher rates of ever smokers were recorded among males. EGFR mutations were present in 15.7% of patients (51 patients). There was a difference in EGFR mutation rates between males and females (5.6 vs 30.8%, p<0.0001). KRAS mutations (codones 12/12 and 61) were present in 35.8% (116) patients, and ALK translocation detected by IHC in 3.7% (12) patients. Conclusion: Molecular testing in primary lung adenocarcinoma patients was done in purely Caucasian Croatian population. EGFR mutation and ALK translocation rates were similar to previously published data. However, KRAS mutation rates were higher than previously published. This can be associated with high smoking rates in Croatian population.
P1.02-050 Acquired Resistance to EGFR Tyrosine Kinase Inhibitors (TKIs) in EGFR-Mutant Lung Adenocarcinoma among Hispanics (Rbiop-CLICaP) Topic: Driver Genes in NSCLC, Resistance, and Other Andrés Cardona,1 Oscar Arrieta,2 Leonardo Rojas,3 Beatriz Wills,4 Noemi Reguart,5 Hernan Carranza,1 Carlos Vargas,1 Jorge Otero,1 Pilar Archila,6 Claudio Martin,7 Luis Corrales,8 Mauricio Cuello,9 Carlos Ortiz,1 Sandra Franco,1 Rafael Rosell10 1 Medical Oncology, Clinical and Traslational Oncology Group, Institute of Oncology, Clínica Del Country, Bogota/ Colombia, 2Laboratory of Experimental Oncology and Thoracic Oncology Unit, National Cancer Institute, Mexico City/Mexico, 3Centro Javeriano de Oncología, Hospital Universitario San Ignacio, Bogotá/Colombia, 4Internal Medicine Department, Johns Hopkins Hospital, Rochester/ United States of America, 5Medical Oncology, Hospital Clinic, Translational Genomics and Targeted Therapeutics in Solid Tumors, Institut D’Investigacions Biomèdiques August Pi I Sunyer (Idibaps), Barcelona/Spain, 6Pathology, Foundation for Clinical and Applied Cancer Research e Ficmac, Bogota/Colombia, 7Department of Clinical Oncology, Instituto Alexander Fleming, Buenos Aires/ Argentina, 8Clinical Oncology Department, Hospital San Juan de Dios (San José, Costa Rica), San Jose/Costa Rica, 9 Medical Oncology Department, Udelar (Montevideo, Uruguay), Montevideo/Uruguay, 10Hospital Germans Trias I Pujol, Catalan Institute of Oncology, Barcelona/Spain Background: Patients with epidermal growth factor receptor (EGFR)-mutant lung carcinoma eventually
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develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). In 50% of these cases, a secondary EGFR mutation, T790M, underlies the acquired resistance. Other alterations include amplification of MET, PI3K mutations, changes in MAPK1, Her2, AXL and even transformation to small cell lung carcinoma (SCLC). We assessed histological, clinical characteristics and survival outcomes in Hispanic patients with EGFR mutation after disease progression. Methods: 34 EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs were identified as part of a prospective registry (active between January 2011 and January 2015) in which post-progression tumor specimens were collected for molecular analysis using SNaPshot tumor genotyping assay to detect mutations in EGFR, KRAS, BRAF, PI3KCA, TP53, MET and Her2, and FISH for MET, ALK and EGFR. Samples also underwent immunohistochemistry analysis for Ecadherin, synaptophysin, CD56 and PDL1. Post-progression interventions, response and survival were assessed and compared to those with and without T790M. Results: Mean age was 59.4±13.9 years; 62% were female, 65% were never-smokers and 53% had a performance status 80%; main metastatic sites were lung (16/47%), bone (20/58%), brain (18/52%) and liver (13/38%). All patients received erlotinib as first- line treatment and documented mutations were: 60% DelE19 (Del746e750) and 40% L858R. Overall response rate (ORR) with first line TKI was 61.8% and progression free survival (PFS) was 16.8 months (range, 13.7e19.9 m). After progressing to TKI, all patients were re-biopsied, of whom 16 had the T790M mutation (47.1%); 5 had PI3K mutations (14.7), 5 had EGFR amplification (14.7%), 2 had a KRAS mutation (5.9%), 3 had MET amplification (8.8%), 2 had Her2 alterations (5.8%, deletions/insertions in e20), and one had SCLC transformation (2.9%). 79.4% received treatment after progression. ORR for post-TKI treatments was 47.1% (CR 2/PR 14) and median PFS was 8.3 months (CI95% 2.2e36.6). There were no differences in PFS according to gender (p¼0.10) or type of acquired alteration (p¼0.63). Median survival was 32.9 months (CI95% 30.4e35.3), and only the use of post-progression therapy affected OS in multivariate analysis (p¼0.05). Conclusion: Hispanic patients with acquired resistance to EGFR TKIs continued to be sensitive to other treatments after progression. Proportion of T790M+ patients appears to be similar to previously reported results in Caucasians. Keywords: Acquired resistance, EGFR-mutant lung adenocarcinoma, EGFR Tyrosine Kinase Inhibitors, Hispanics
Journal of Thoracic Oncology
Vol. 12 No. 1S
P1.02-051 Concomitant Driver Mutations in Advanced Stage Non-Small-Cell Lung Cancer of Adenocarcinoma Subtype with Activating EGFR-Mutation Topic: Driver Genes in NSCLC, Resistance, and Other Jens Benn Sørensen,1 Morten Grauslund,2 Linea Melchior,2 Jan Jakobsen,1 Eric Santoni-Rugiu2 1 Dept. Oncology, Finsen Centre/national University Hospital, Copenhagen/Denmark, 2Dept. Pathology, National University Hospital, Copenhagen/Denmark Background: Patients having non-small-cell lung cancer (NSCLC) with activating EGFR-mutations benefit from EGFR-Tyrosine Kinase Inhibitor (TKI) treatment. However, other driver mutations may occur simultaneously and other pathways may be amplified/overexpressed, potentially hampering efficacy of EGFR-TKI treatment. The frequency of such alterations at time of diagnosis was examined. Methods: All patients referred to Rigshospitalet, Copenhagen University Hospital for pulmonary adenocarcinoma (ADC) from July 2013 to August 2015 were routinely tested for EGFR-mutations by EGFR Cobas RTPCR technique (Roche Diagnostics) on DNA extracted from diagnostic tumor biopsies or cytological samples. If positive for EGFR-mutations these patients were, prior to any treatment, also tested by targeted Next Generation Sequencing (NGS; Ion Torrent Ampliseq Colon-Lung v.2 panel and PGM NGS-sequenator) for other simultaneous cancer-relevant mutations, by fluorescence in-situ hybridization (FISH) for MET-amplification, and by immunohistochemistry (IHC) for expression of MET receptor as well as ALK fusion-protein. Results: Totally 512 ADC patients were tested, among whom 22 out of 282 advanced stage patients (7.8%) had activating EGFR-mutations, distributed as follows: 1 G719Cmutation, 13 exon 19-deletions, 1 T790M-mutation, 1 S768I-mutation and 8 L858R-mutations with 2 of the patients harboring EGFR-double-mutations G719C + S768I and L858R + T790M (i.e., activating and resistance mutation), respectively. Complete concordance between EGFRmutation-status by EGFR Cobas and NGS was observed for all NGS tested patients. For one of the patients NGS analysis could not be carried out, due to lacking DNA-extract and remaining tumor tissue. NGS-analysis identified several concomitant driver mutations in the 21 analyzed patients, including one 1 with KRAS-mutation (G12V), 12 with TP53mutations (7 in TP53-exon 5), 1 with FGFR-mutation (S125_E126insS), 2 with CTNNB1-mutations (S33C and
(6 exon 14 skipped and 8 amplified): 13 patients were male (93%), with a median age of 65.7 years (range: 4091), nine current smokers (64%) (40 pack-years, range: 20-60), and eight diagnosed in an advanced stage disease (III and IV) (57%). Correlation with c-MET protein expression by IHC is ongoing, and data will be presented at the meeting. Conclusion: As no concurrent MET mutated and amplified cases were found, our data support prospective identification of both, MET exon 14 skipping mutations and gene amplifications. These mutations define a new subset of NSCLC patients that should be analyzed independently of the status of MET gene copy number. Keywords: MET amplification, FISH, MET exon 14 skipping, MET alterations
P1.02-049 EGFR, KRAS and ALK Gene Alterations in Lung Cancer Patients in Croatia Topic: Driver Genes in NSCLC, Resistance, and Other Marko Jakopovic,1 Luka Brcic,2 Marija Misic,3 Gordana Bubanovic,1 Fran Seiwerth,4 Gordana Drpa,4 Branka Cucevic,4 Mihovil Roglic,4 Sanja Plestina,4 Suazana Kukulj,4 Silvana Smojver-Jezek,4 Sven Seiwerth,3 Miroslav Samarzija1 1Department for Respiratory Diseases “Jordanovac”, University Hospital Centre Zagreb, Zagreb/Croatia, 2Department of Pathology, University of Graz, Graz/Austria, 3Zagreb Medical School, Zagreb/ Croatia, 4University Hospital Centre Zagreb, Zagreb/ Croatia Background: Rates in targetable gene changes varies between different populations of lung cancer patients. Targetable gene changes include changes in EGFR and ALK gene, as well as KRAS gene. Primary aim of this study was to determine mutation status in purely Caucasian Croatian population. Methods: Rates in targetable gene changes varies between different populations of lung cancer patients. Targetable gene changes include changes in EGFR and ALK gene, as well as KRAS gene. Primary aim of this study was to determine mutation status in purely Caucasian Croatian population. Results: During 6 months period 324 newly diagnosed primary lung adenocarcinoma were tested. Out of 324 tested patients, 194 were males (60%) and 130 females (40%) mean age 64 years (range 35 to 88 years). Vast majority of patients were in stages 3 and 4 (more than
Abstracts
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80%). Among males, 87% of patients were ever smokers, and among females 61% of patients were ever smokers. Significantly higher rates of ever smokers were recorded among males. EGFR mutations were present in 15.7% of patients (51 patients). There was a difference in EGFR mutation rates between males and females (5.6 vs 30.8%, p<0.0001). KRAS mutations (codones 12/12 and 61) were present in 35.8% (116) patients, and ALK translocation detected by IHC in 3.7% (12) patients. Conclusion: Molecular testing in primary lung adenocarcinoma patients was done in purely Caucasian Croatian population. EGFR mutation and ALK translocation rates were similar to previously published data. However, KRAS mutation rates were higher than previously published. This can be associated with high smoking rates in Croatian population.
P1.02-050 Acquired Resistance to EGFR Tyrosine Kinase Inhibitors (TKIs) in EGFR-Mutant Lung Adenocarcinoma among Hispanics (Rbiop-CLICaP) Topic: Driver Genes in NSCLC, Resistance, and Other Andrés Cardona,1 Oscar Arrieta,2 Leonardo Rojas,3 Beatriz Wills,4 Noemi Reguart,5 Hernan Carranza,1 Carlos Vargas,1 Jorge Otero,1 Pilar Archila,6 Claudio Martin,7 Luis Corrales,8 Mauricio Cuello,9 Carlos Ortiz,1 Sandra Franco,1 Rafael Rosell10 1 Medical Oncology, Clinical and Traslational Oncology Group, Institute of Oncology, Clínica Del Country, Bogota/ Colombia, 2Laboratory of Experimental Oncology and Thoracic Oncology Unit, National Cancer Institute, Mexico City/Mexico, 3Centro Javeriano de Oncología, Hospital Universitario San Ignacio, Bogotá/Colombia, 4Internal Medicine Department, Johns Hopkins Hospital, Rochester/ United States of America, 5Medical Oncology, Hospital Clinic, Translational Genomics and Targeted Therapeutics in Solid Tumors, Institut D’Investigacions Biomèdiques August Pi I Sunyer (Idibaps), Barcelona/Spain, 6Pathology, Foundation for Clinical and Applied Cancer Research e Ficmac, Bogota/Colombia, 7Department of Clinical Oncology, Instituto Alexander Fleming, Buenos Aires/ Argentina, 8Clinical Oncology Department, Hospital San Juan de Dios (San José, Costa Rica), San Jose/Costa Rica, 9 Medical Oncology Department, Udelar (Montevideo, Uruguay), Montevideo/Uruguay, 10Hospital Germans Trias I Pujol, Catalan Institute of Oncology, Barcelona/Spain Background: Patients with epidermal growth factor receptor (EGFR)-mutant lung carcinoma eventually
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develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). In 50% of these cases, a secondary EGFR mutation, T790M, underlies the acquired resistance. Other alterations include amplification of MET, PI3K mutations, changes in MAPK1, Her2, AXL and even transformation to small cell lung carcinoma (SCLC). We assessed histological, clinical characteristics and survival outcomes in Hispanic patients with EGFR mutation after disease progression. Methods: 34 EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs were identified as part of a prospective registry (active between January 2011 and January 2015) in which post-progression tumor specimens were collected for molecular analysis using SNaPshot tumor genotyping assay to detect mutations in EGFR, KRAS, BRAF, PI3KCA, TP53, MET and Her2, and FISH for MET, ALK and EGFR. Samples also underwent immunohistochemistry analysis for Ecadherin, synaptophysin, CD56 and PDL1. Post-progression interventions, response and survival were assessed and compared to those with and without T790M. Results: Mean age was 59.4±13.9 years; 62% were female, 65% were never-smokers and 53% had a performance status 80%; main metastatic sites were lung (16/47%), bone (20/58%), brain (18/52%) and liver (13/38%). All patients received erlotinib as first- line treatment and documented mutations were: 60% DelE19 (Del746e750) and 40% L858R. Overall response rate (ORR) with first line TKI was 61.8% and progression free survival (PFS) was 16.8 months (range, 13.7e19.9 m). After progressing to TKI, all patients were re-biopsied, of whom 16 had the T790M mutation (47.1%); 5 had PI3K mutations (14.7), 5 had EGFR amplification (14.7%), 2 had a KRAS mutation (5.9%), 3 had MET amplification (8.8%), 2 had Her2 alterations (5.8%, deletions/insertions in e20), and one had SCLC transformation (2.9%). 79.4% received treatment after progression. ORR for post-TKI treatments was 47.1% (CR 2/PR 14) and median PFS was 8.3 months (CI95% 2.2e36.6). There were no differences in PFS according to gender (p¼0.10) or type of acquired alteration (p¼0.63). Median survival was 32.9 months (CI95% 30.4e35.3), and only the use of post-progression therapy affected OS in multivariate analysis (p¼0.05). Conclusion: Hispanic patients with acquired resistance to EGFR TKIs continued to be sensitive to other treatments after progression. Proportion of T790M+ patients appears to be similar to previously reported results in Caucasians. Keywords: Acquired resistance, EGFR-mutant lung adenocarcinoma, EGFR Tyrosine Kinase Inhibitors, Hispanics
Journal of Thoracic Oncology
Vol. 12 No. 1S
P1.02-051 Concomitant Driver Mutations in Advanced Stage Non-Small-Cell Lung Cancer of Adenocarcinoma Subtype with Activating EGFR-Mutation Topic: Driver Genes in NSCLC, Resistance, and Other Jens Benn Sørensen,1 Morten Grauslund,2 Linea Melchior,2 Jan Jakobsen,1 Eric Santoni-Rugiu2 1 Dept. Oncology, Finsen Centre/national University Hospital, Copenhagen/Denmark, 2Dept. Pathology, National University Hospital, Copenhagen/Denmark Background: Patients having non-small-cell lung cancer (NSCLC) with activating EGFR-mutations benefit from EGFR-Tyrosine Kinase Inhibitor (TKI) treatment. However, other driver mutations may occur simultaneously and other pathways may be amplified/overexpressed, potentially hampering efficacy of EGFR-TKI treatment. The frequency of such alterations at time of diagnosis was examined. Methods: All patients referred to Rigshospitalet, Copenhagen University Hospital for pulmonary adenocarcinoma (ADC) from July 2013 to August 2015 were routinely tested for EGFR-mutations by EGFR Cobas RTPCR technique (Roche Diagnostics) on DNA extracted from diagnostic tumor biopsies or cytological samples. If positive for EGFR-mutations these patients were, prior to any treatment, also tested by targeted Next Generation Sequencing (NGS; Ion Torrent Ampliseq Colon-Lung v.2 panel and PGM NGS-sequenator) for other simultaneous cancer-relevant mutations, by fluorescence in-situ hybridization (FISH) for MET-amplification, and by immunohistochemistry (IHC) for expression of MET receptor as well as ALK fusion-protein. Results: Totally 512 ADC patients were tested, among whom 22 out of 282 advanced stage patients (7.8%) had activating EGFR-mutations, distributed as follows: 1 G719Cmutation, 13 exon 19-deletions, 1 T790M-mutation, 1 S768I-mutation and 8 L858R-mutations with 2 of the patients harboring EGFR-double-mutations G719C + S768I and L858R + T790M (i.e., activating and resistance mutation), respectively. Complete concordance between EGFRmutation-status by EGFR Cobas and NGS was observed for all NGS tested patients. For one of the patients NGS analysis could not be carried out, due to lacking DNA-extract and remaining tumor tissue. NGS-analysis identified several concomitant driver mutations in the 21 analyzed patients, including one 1 with KRAS-mutation (G12V), 12 with TP53mutations (7 in TP53-exon 5), 1 with FGFR-mutation (S125_E126insS), 2 with CTNNB1-mutations (S33C and