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P3.01-073 TPX-0005 with an EGFR Tyrosine Kinase Inhibitor (TKI) Overcomes Innate Resistance in EGFR Mutant NSCLC
S2230 are not mature. All 81 patients received study treatment. No grade 4/5 adverse events (AEs were observed with dacomitinib, while 3 grade 4 AEs and 1 grade 5 AE (disease progression) occurred with gefitinib. The most common grade 3 AEs were dermatitis acneiform (27.5%) and paronychia (22.5%) with dacomitinib and alanine aminotransferase increased (12.2%) and abnormal hepatic function (7.3%) with gefitinib. No new safety signals were identified. Conclusion: Dacomitinib significantly improved PFS and duration of response over gefitinib in first-line treatment of Japanese patients with advanced EGFR+ NSCLC, with a manageable safety profile. Keywords: Dacomitinib, Non-smallcell lung cancer, EGFR mutation
P3.01-073 TPX-0005 with an EGFR Tyrosine Kinase Inhibitor (TKI) Overcomes Innate Resistance in EGFR Mutant NSCLC R. Rosell,1 N. Karachaliou,2 J.J. Cui,3 I. Chaib,4 J. Berenguer,5 J. Bratch,5 X. Li,6 J. Yang,7 A. Drozdowskyj,8 C. Codony Servat,5 J. Codony Servat,5 A. Giménez-Capitán,5 S. Viteri,9 M. Molina-Vila,5 G. López-Vivanco,10 A. Vergnenegre,11 J.M. Sánchez-Torres,12 M. Provencio,13 F. De Marinis,14 A. Passaro,15 E. Carcereny,16 N. Reguart,17 R. García Campelo,18 S. Ignatius Ou,19 A. Cardona,20 P. Cao7 1Director, Cancer Biology & Precision Medicine Program, Catalan Institute of Oncology, Germans Trias I Pujol Health Sciences Institute and Hospital, Badalona, Barcelona/ES, 2Grupo Quirónsalud, Instituto Oncológico Dr Rosell (Ior), Hospital Universitario Sagrat Cor, Barcelona/ ES, 3Oncology, TP Therapeutics, Inc., San Diego/US, 4Laboratory of Molecular Biology, Institut de Recerca Germans Trias I Pujol (Igtp), Badalona/ES, 5Laboratory of Molecular Biology, Pangaea Oncology, Barcelona/ES, 6Medical Oncology, Shanghai Pulmonary Hospital, Shanghai/CN, 7Laboratory of Cellular and Molecular Biology, Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing, Nanjing/ CN, 8Pivotal, Madrid/ES, 9Hospital Uni. Quirón-Dexeus, Barcelona/ES, 10 Oncology, Hospital de Cruces, Baracaldo/ES, 11CHU de Limoges, Limoges/FR, 12Oncología Médica, Hospital Universitario de La Princesa, Madrid/ES, 13Medical Oncology, Hospital Universitario Puerta de Hierro, Madrid/ES, 14Thoracic Oncology Division, European Institute of Oncology, Milan/IT, 15Division of Thoracic Oncology, European Institute of Oncology, Milano/IT, 16Catalan Institute of Oncology Badalona—Germans Trias I Pujol Hospital Badalona, Badalona/ES, 17 Medical Oncology, Hospital Clinic, Barcelona/ES, 18Hospital Universitario A Coruna - A Corunac, A Coruna/ES, 19Medical Oncology, University of California, Irvine School of Medicine, Orange County/CA/US, 20 Clinical and Translational Oncology Group, Foundation for Clinical and Applied Cancer Research - FICMAC, Bogotá/CO Background: Overexpression of several receptor tyrosine kinases (RTKs) substitutes EGFR signaling in EGFR-mutant NSCLC. The MET ligand hepatocyte growth factor (HGF) provides an alternative signaling mechanism for EGFR by inducing inter-receptor cross talk with EphA2, CUB domain-containing protein-1 (CDCP1) or AXL. SHP2, a non-receptor protein tyrosine phosphatase is central in signal transduction downstream of RTK signaling and in Src activation. We previously demonstrated that STAT3 and Src-YAP1 signaling limits EGFR TKI efficacy in EGFR-mutant NSCLC. We are now exploring the possibility of multiple RTK activation through a Src-YAP1-mediated transcriptional program. We are evaluating whether combined EGFR inhibition with TPX-0005, a novel orally available multikinase inhibitor and potent Src/FAK and JAK2 inhibitor, can be more efficient than EGFR inhibition alone in EGFR-mutant NSCLC cells. Method: We studied the mRNA expression levels of stromal HGF and tumor RTKs, AXL, CDCP1, MET, and EphA2, as well as SHP2, and clinical outcome in baseline samples of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKI. We combined in vitro approaches to explore whether gefitinib or osimertinib combined with TPX-0005 can abolish STAT3 and Src-YAP1 and downregulate the expression of RTKs. Result: High
Journal of Thoracic Oncology
Vol. 12 No. 11S2
levels of AXL, CDCP1 and SHP2 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 14.5 and 23.4 months for patients with high and low AXL mRNA, respectively (p¼0.0359). Median PFS was 9.1 and 20.2 months for patients with high and low CDCP1 mRNA, respectively (p¼0.0179). Tumoral EPHA2 and MET or stromal HGF levels did not affect PFS. Median PFS was 11.4 and 24.1 months for patients with high and low SHP2 mRNA, respectively (p¼0.0094). The combination of gefitinib/osimertinib with TPX-0005 resulted in highly synergistic suppression of cell viability and reduced colony formation in two EGFR-mutant cell lines. The combination abolished the EGFR inhibition-induced STAT3 and YAP1 phosphorylation, as confirmed by western blotting and immunofluorescence. The results of TaqMan quantitative-PCR assay revealed that gefitinib/osimertinib plus TPX-0005 reduced the mRNA levels of AXL, CDCP1 and MET, an effect that could not be obtained with EGFR inhibition alone. In vivo experiments are ongoing. Conclusion: AXL and CDCP1 are adverse predictive markers of PFS in EGFR-mutant NSCLC patients. STAT3 and Src-YAP1 signaling limits the efficacy EGFR TKI. Combined EGFR inhibition with TPX-0005 (currently in phase I clinical testing) is a particularly attractive strategy. Keywords: EGFR-mutant NSCLC, EGFR TKI, TPX-0005
P3.01-074 Genomic Analysis of Tumor and Plasma in T790M Mutant Positive EGFR Lung Cancer Patients before and after Osimertinib Treatment J.C. Yang,1 C. Yu,2 J. Shih,2 C. Ho,2 W. Liao,2 J. Lee,3 T. Tsai,2 K. Su,4 M. Shih,5 Y.L. Chang,5 Y. Bai,3 D. Huang,3 K. Thress,6 C. Lin3 1 Graduate Institute of Oncology, National Taiwan University, Taipei/TW, 2 Department of Internal Medicine, National Taiwan University Hospital, Taipei/TW, 3Department of Oncology, National Taiwan University Hospital, Taipei/TW, 4Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei/TW, 5 Department of Pathology, National Taiwan University, Taipei/TW, 6 Astrazeneca, Imed Oncology, Waltham, MA/US Background: Osimertinib is a third-generation, central nervous system active epidermal growth factor receptor (EGFR) e tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-sensitising and EGFR T790M resistance mutations. Osimertinib is approved for EGFR mutation positive non-small cell lung cancer (NSCLC) patients who develop EGFR T790M resistant mutation and resistant to prior EGFR TKI. Osimertinib resistance pattern and clinical outcome after osimertinib treatment are undergoing intensive investigation. Method: Seventy-one EGFR-TKI resistant patients received osimertinib in the AURA study in one medical center. We excluded patients treated as first-line or who do not have detectable T790M mutation. We collect available data of pre-osimertinib treatment plasma and tissue and postosimertinib plasma, tissue samples and tested for EGFR, HER2, K-ras, Braf, mutations, ALK fusion and cMET or HER2 gene amplification. Clinical and pathological characteristics before and after osimertinib treatment were collected. Result: Of the 53 T790M-positive patients, 6 did not progress. Three and 18 patients discontinued osimertinib due to side effect or progression, respectively; 26 received osimertinib beyond progression (1.1 to 20.5 months); 7 patients received osimertinib combination after progression. Fourteen patients are still alive. Median progression-free survival (PFS), overall survival(OS) and post-progression survival (PPS) were 11.1 months, 16.9 months and 5.0 months, respectively (only progression patients). In 47 progressive patients, post progression EGFR plasma tests were available in 40 patients. T790M was detected by BEAMing in 12 patients (4 patients combined with C797S) and not detected in 28 patients (70%). OS and PPS was longest for patients with no detectable EGFR activating mutation and T790M in the plasma before and/or after osimertinib
P3.01-073 TPX-0005 with an EGFR Tyrosine Kinase Inhibitor (TKI) Overcomes Innate Resistance in EGFR Mutant NSCLC R. Rosell,1 N. Karachaliou,2 J.J. Cui,3 I. Chaib,4 J. Berenguer,5 J. Bratch,5 X. Li,6 J. Yang,7 A. Drozdowskyj,8 C. Codony Servat,5 J. Codony Servat,5 A. Giménez-Capitán,5 S. Viteri,9 M. Molina-Vila,5 G. López-Vivanco,10 A. Vergnenegre,11 J.M. Sánchez-Torres,12 M. Provencio,13 F. De Marinis,14 A. Passaro,15 E. Carcereny,16 N. Reguart,17 R. García Campelo,18 S. Ignatius Ou,19 A. Cardona,20 P. Cao7 1Director, Cancer Biology & Precision Medicine Program, Catalan Institute of Oncology, Germans Trias I Pujol Health Sciences Institute and Hospital, Badalona, Barcelona/ES, 2Grupo Quirónsalud, Instituto Oncológico Dr Rosell (Ior), Hospital Universitario Sagrat Cor, Barcelona/ ES, 3Oncology, TP Therapeutics, Inc., San Diego/US, 4Laboratory of Molecular Biology, Institut de Recerca Germans Trias I Pujol (Igtp), Badalona/ES, 5Laboratory of Molecular Biology, Pangaea Oncology, Barcelona/ES, 6Medical Oncology, Shanghai Pulmonary Hospital, Shanghai/CN, 7Laboratory of Cellular and Molecular Biology, Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing, Nanjing/ CN, 8Pivotal, Madrid/ES, 9Hospital Uni. Quirón-Dexeus, Barcelona/ES, 10 Oncology, Hospital de Cruces, Baracaldo/ES, 11CHU de Limoges, Limoges/FR, 12Oncología Médica, Hospital Universitario de La Princesa, Madrid/ES, 13Medical Oncology, Hospital Universitario Puerta de Hierro, Madrid/ES, 14Thoracic Oncology Division, European Institute of Oncology, Milan/IT, 15Division of Thoracic Oncology, European Institute of Oncology, Milano/IT, 16Catalan Institute of Oncology Badalona—Germans Trias I Pujol Hospital Badalona, Badalona/ES, 17 Medical Oncology, Hospital Clinic, Barcelona/ES, 18Hospital Universitario A Coruna - A Corunac, A Coruna/ES, 19Medical Oncology, University of California, Irvine School of Medicine, Orange County/CA/US, 20 Clinical and Translational Oncology Group, Foundation for Clinical and Applied Cancer Research - FICMAC, Bogotá/CO Background: Overexpression of several receptor tyrosine kinases (RTKs) substitutes EGFR signaling in EGFR-mutant NSCLC. The MET ligand hepatocyte growth factor (HGF) provides an alternative signaling mechanism for EGFR by inducing inter-receptor cross talk with EphA2, CUB domain-containing protein-1 (CDCP1) or AXL. SHP2, a non-receptor protein tyrosine phosphatase is central in signal transduction downstream of RTK signaling and in Src activation. We previously demonstrated that STAT3 and Src-YAP1 signaling limits EGFR TKI efficacy in EGFR-mutant NSCLC. We are now exploring the possibility of multiple RTK activation through a Src-YAP1-mediated transcriptional program. We are evaluating whether combined EGFR inhibition with TPX-0005, a novel orally available multikinase inhibitor and potent Src/FAK and JAK2 inhibitor, can be more efficient than EGFR inhibition alone in EGFR-mutant NSCLC cells. Method: We studied the mRNA expression levels of stromal HGF and tumor RTKs, AXL, CDCP1, MET, and EphA2, as well as SHP2, and clinical outcome in baseline samples of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKI. We combined in vitro approaches to explore whether gefitinib or osimertinib combined with TPX-0005 can abolish STAT3 and Src-YAP1 and downregulate the expression of RTKs. Result: High
Journal of Thoracic Oncology
Vol. 12 No. 11S2
levels of AXL, CDCP1 and SHP2 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 14.5 and 23.4 months for patients with high and low AXL mRNA, respectively (p¼0.0359). Median PFS was 9.1 and 20.2 months for patients with high and low CDCP1 mRNA, respectively (p¼0.0179). Tumoral EPHA2 and MET or stromal HGF levels did not affect PFS. Median PFS was 11.4 and 24.1 months for patients with high and low SHP2 mRNA, respectively (p¼0.0094). The combination of gefitinib/osimertinib with TPX-0005 resulted in highly synergistic suppression of cell viability and reduced colony formation in two EGFR-mutant cell lines. The combination abolished the EGFR inhibition-induced STAT3 and YAP1 phosphorylation, as confirmed by western blotting and immunofluorescence. The results of TaqMan quantitative-PCR assay revealed that gefitinib/osimertinib plus TPX-0005 reduced the mRNA levels of AXL, CDCP1 and MET, an effect that could not be obtained with EGFR inhibition alone. In vivo experiments are ongoing. Conclusion: AXL and CDCP1 are adverse predictive markers of PFS in EGFR-mutant NSCLC patients. STAT3 and Src-YAP1 signaling limits the efficacy EGFR TKI. Combined EGFR inhibition with TPX-0005 (currently in phase I clinical testing) is a particularly attractive strategy. Keywords: EGFR-mutant NSCLC, EGFR TKI, TPX-0005
P3.01-074 Genomic Analysis of Tumor and Plasma in T790M Mutant Positive EGFR Lung Cancer Patients before and after Osimertinib Treatment J.C. Yang,1 C. Yu,2 J. Shih,2 C. Ho,2 W. Liao,2 J. Lee,3 T. Tsai,2 K. Su,4 M. Shih,5 Y.L. Chang,5 Y. Bai,3 D. Huang,3 K. Thress,6 C. Lin3 1 Graduate Institute of Oncology, National Taiwan University, Taipei/TW, 2 Department of Internal Medicine, National Taiwan University Hospital, Taipei/TW, 3Department of Oncology, National Taiwan University Hospital, Taipei/TW, 4Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei/TW, 5 Department of Pathology, National Taiwan University, Taipei/TW, 6 Astrazeneca, Imed Oncology, Waltham, MA/US Background: Osimertinib is a third-generation, central nervous system active epidermal growth factor receptor (EGFR) e tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-sensitising and EGFR T790M resistance mutations. Osimertinib is approved for EGFR mutation positive non-small cell lung cancer (NSCLC) patients who develop EGFR T790M resistant mutation and resistant to prior EGFR TKI. Osimertinib resistance pattern and clinical outcome after osimertinib treatment are undergoing intensive investigation. Method: Seventy-one EGFR-TKI resistant patients received osimertinib in the AURA study in one medical center. We excluded patients treated as first-line or who do not have detectable T790M mutation. We collect available data of pre-osimertinib treatment plasma and tissue and postosimertinib plasma, tissue samples and tested for EGFR, HER2, K-ras, Braf, mutations, ALK fusion and cMET or HER2 gene amplification. Clinical and pathological characteristics before and after osimertinib treatment were collected. Result: Of the 53 T790M-positive patients, 6 did not progress. Three and 18 patients discontinued osimertinib due to side effect or progression, respectively; 26 received osimertinib beyond progression (1.1 to 20.5 months); 7 patients received osimertinib combination after progression. Fourteen patients are still alive. Median progression-free survival (PFS), overall survival(OS) and post-progression survival (PPS) were 11.1 months, 16.9 months and 5.0 months, respectively (only progression patients). In 47 progressive patients, post progression EGFR plasma tests were available in 40 patients. T790M was detected by BEAMing in 12 patients (4 patients combined with C797S) and not detected in 28 patients (70%). OS and PPS was longest for patients with no detectable EGFR activating mutation and T790M in the plasma before and/or after osimertinib