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P3.01-067 TP53 Mutations Could Involve in EGFR-TKI Primary Resistance in Advanced Non-Small Cell Lung Cancer
November 2017
Abstracts
S2227
Eligible pts had to be diagnosed with pulmonary adenocarcinoma harboring EGFR-activating mutations (Sanger sequencing performed in either archived or new, formalin-fixed and paraffin-embedded samples). CNS involvement was diagnosed based on CT scans, MRI and/or cerebrospinal fluid findings. All studied pts were treated with EGFRTKIs (erlotinib or gefitinib) and other multimodality therapies including radiation therapy (whole brain or stereotactic radiosurgery), metastasectomy and/or intrathecal methotrexate, based on the decision of the multidisciplinary team. Result: 35 pts were studied, with a median age 63 y.o. (35-90), being 26 (74%) female, 19 (54%) neversmokers, and 26 (74%) ECOG-PS 0-2. All pts received an EGFR-TKI (erlotinib or gefitinib), and 26 also were treated with radiation therapy, 11 were submitted to surgery, 2 to stereotactic radiosurgery and 1 received IT-MTX; 4/35 were treated with an EGFR-TKI only. Median treatment time with an EGFR-TKI was 7.6 mo. Median progression-free survival (mPFS) was 8.2 mo and the median overall survival (mOS) was 11.9 mo. Among those 25 pts whose tumors were diagnosed with an exon 19 deletion, mPFS was 8.2 mo. and mOS 11.9 mo., and among those 9 pts with L858R mutation, mPFS was 10.8 mo. and mOS 13.8 mo. Conclusion: Those pts diagnosed with pulmonary adenocarcinoma harboring EGFR-activating mutations treated with a multidisciplinary approach (including an EGFR-TKI) may derive promising PFS and OS results. The approach must be individualized, considering patient characteristics, tumor biology aspects and also the available healthcare resources. Keywords: brain metastases, lung cancer, EGFR
patients, 9 patients were observed long-term clinical benefit (PFS540 days) were into group 3; remaining 30 patients with PFS between 180 to 540 days were into group 4. Median PFS were 29, 95, 761 and 311 days from group 1 to 4, respectively. More signaling pathways were activated in group 1, relative to other groups, including bypass activation, downstream signal activation, apoptotic pathways disturbance and EMT activation. Meanwhile, the activation of more signaling pathways were found in samples after acquired resistance compared with paired baseline samples. In all of baseline samples, 60.0% patients harbored TP53 mutations, and these mutations distributed in exon 2,4,5,6,7,8 and 11, respectively. Interestingly, TP53 mutations of 23% patients were in exon 6 in group 1, mutations in exon 5 occurred in 33.3% patients with long-term clinical benefit (group 3). Patients with exon 6 mutation had more shorter PFS than those with exon 5 mutation (105 days vs 284 days). Conclusion: For patients resistant to EGFRTKI, more signal pathways were activation, and the heterogeneity of tumor cloning were complicated. TP53 mutations in different exons may have distinct effect on response to EGFR-TKI of patients with EGFR sensitive mutation. Keywords: TP53 mutation, non-small cell lung cancer, EGFR-TKI
P3.01-067 TP53 Mutations Could Involve in EGFR-TKI Primary Resistance in Advanced Non-Small Cell Lung Cancer
B. Lentrichia,1 H. Brown,2 M. Ratcliffe,3 A.M. Rachiglio,4 R. Pasquale,4 N. Normanno5 1Personalised Healthcare and Biomarkers, Astrazeneca Pharmaceuticals, Waltham/US, 2Personalised Healthcare and Biomarkers, Astrazeneca, Cambridge/GB, 3Personalised Healthcare and Biomarkers, Astrazeneca Pharmaceuticals, Waltham/MA/US, 4Cell Biology and Biotherapy, Istituto Nazionale Tumori “Fondazione Giovanni Pascale”, Naples/IT, 5Cell Biology and Biotherapy Unit, Instituto Nazionale Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Naples/IT
X. Li,1 C. Su,2 S. Ren,3 C. Zhao,4 T. Jiang,4 X. Chen,5 J. Li,4 W. Li,5 G. Gao,3 F. Zhou,4 Y. Shao,6 C. Zhou1 1Medical Oncology, Shanghai Pulmonary Hospital, Shanghai/CN, 2Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Pulmonary Cancer Institute, Shanghai/CN, 3Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Cancer Institute, Shanghai/CN, 4Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai/CN, 5Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China., Shanghai/CN, 6Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China, Nanjing/CN Background: Activating mutations in the epidermal growth factor receptor (EGFR) are strongly predictive of EGFR-tyrosine kinase inhibitor (TKI) activity in non-small cell lung cancer (NSCLC). However, primary resistance to EGFR-TKIs occurs in approximately 20-30% of NSCLC patients with EGFR mutations, acquired resistance is inevitable. The aim of study is to discover unknown resistant mechanisms and contribute to more precisely administrate advanced and metastatic NSCLC with EGFR mutations. Method: 60 NSCLC patients with EGFR sensitive mutation were enrolled this study. All of patients received EGFR-TKI treatment. 21 of patients were primary resistance and 39 acquired resistance according to Jackman standard. Tumor tissues of all of patients were collected before EGFR-TKIs treatment, and rebiopsy tissues were gained after acquired resistance in 39 NSCLC patients. Whole exome sequencing were performed in Illumina HiSeq2000 platform. The captured sequencing data was further processed to identify somatic mutations, including single nucleotide variants (SNVs), short insertions/deletions (indels) and copy number variations (CNVs). Result: In primary resistance patients, 13 patients occurred rapid progress (PFS 60 days) were put into group 1, and other 8 patients with PFS within 90-180 days were into group 2; in acquired resistance
P3.01-068 Investigation of Low Plasma/Tissue EGFR Concordance in Russia: Follow-up to the IGNITE Global Diagnostic Study
Background: IGNITE was a large multi-national, non-comparative, non-interventional diagnostic study whose objective was to in part determine the concordance in EGFR mutation status between tissue/ cytology and plasma testing in the real world setting1. Locally advanced or metastatic NSCLC patients were enrolled from 9 countries in AsiaPacific including Russia. A very significant difference was observed in performance of plasma testing in Russia (PPV¼39.3%) vs. Asia Pac (PPV¼92.5%) vs tissue results with only 51/84 ctDNA EGFR mutation positive results from Russian labs confirmed by the corresponding tissue result. No single lab appeared to contribute predominantly to the questionable overall performance. 1. Han, B et al.; ‘Determining the prevalence of EGFR mutations in Asian and Russian patients (pts) with advanced non-small-cell lung cancer (aNSCLC) of adenocarcinoma (ADC) and non-ADC histology: IGNITE study’ (ELCC 2015 Abstract No. 96O). Method: 142 of the 941 evaluable plasma samples from Russia were selected to include originally discordant samples and a similar number of concordant positive and concordant negative samples. All samples were shipped to an experienced lab and re-tested for TKI sensitizing mutations using the QIAamp Circulating Nucleic Acid Kit and the Therascreen® EGFR Plasma RGQ PCR test (Qiagen). The central laboratory was blinded to the origin of the samples and original EGFR mutation result. Result: Adhering to package insert defined criteria for the internal control, 38 of 112 (34%) of cases were re-classified (19 to pos. and 19 to neg.). By independent clinical laboratory interpretation of the results, 55 of 142 (39%) cases were re-classified (25 to pos. and 30 to neg.). A marked improvement was seen in concordance with the local tissue result after re-testing from 38% to 69% with the false positive rate decreasing from 18.8% to 3.6%. Re-classification of 17 (81%) original ‘false positive’ and 17 (35 %) original ‘false negative’
Abstracts
S2227
Eligible pts had to be diagnosed with pulmonary adenocarcinoma harboring EGFR-activating mutations (Sanger sequencing performed in either archived or new, formalin-fixed and paraffin-embedded samples). CNS involvement was diagnosed based on CT scans, MRI and/or cerebrospinal fluid findings. All studied pts were treated with EGFRTKIs (erlotinib or gefitinib) and other multimodality therapies including radiation therapy (whole brain or stereotactic radiosurgery), metastasectomy and/or intrathecal methotrexate, based on the decision of the multidisciplinary team. Result: 35 pts were studied, with a median age 63 y.o. (35-90), being 26 (74%) female, 19 (54%) neversmokers, and 26 (74%) ECOG-PS 0-2. All pts received an EGFR-TKI (erlotinib or gefitinib), and 26 also were treated with radiation therapy, 11 were submitted to surgery, 2 to stereotactic radiosurgery and 1 received IT-MTX; 4/35 were treated with an EGFR-TKI only. Median treatment time with an EGFR-TKI was 7.6 mo. Median progression-free survival (mPFS) was 8.2 mo and the median overall survival (mOS) was 11.9 mo. Among those 25 pts whose tumors were diagnosed with an exon 19 deletion, mPFS was 8.2 mo. and mOS 11.9 mo., and among those 9 pts with L858R mutation, mPFS was 10.8 mo. and mOS 13.8 mo. Conclusion: Those pts diagnosed with pulmonary adenocarcinoma harboring EGFR-activating mutations treated with a multidisciplinary approach (including an EGFR-TKI) may derive promising PFS and OS results. The approach must be individualized, considering patient characteristics, tumor biology aspects and also the available healthcare resources. Keywords: brain metastases, lung cancer, EGFR
patients, 9 patients were observed long-term clinical benefit (PFS540 days) were into group 3; remaining 30 patients with PFS between 180 to 540 days were into group 4. Median PFS were 29, 95, 761 and 311 days from group 1 to 4, respectively. More signaling pathways were activated in group 1, relative to other groups, including bypass activation, downstream signal activation, apoptotic pathways disturbance and EMT activation. Meanwhile, the activation of more signaling pathways were found in samples after acquired resistance compared with paired baseline samples. In all of baseline samples, 60.0% patients harbored TP53 mutations, and these mutations distributed in exon 2,4,5,6,7,8 and 11, respectively. Interestingly, TP53 mutations of 23% patients were in exon 6 in group 1, mutations in exon 5 occurred in 33.3% patients with long-term clinical benefit (group 3). Patients with exon 6 mutation had more shorter PFS than those with exon 5 mutation (105 days vs 284 days). Conclusion: For patients resistant to EGFRTKI, more signal pathways were activation, and the heterogeneity of tumor cloning were complicated. TP53 mutations in different exons may have distinct effect on response to EGFR-TKI of patients with EGFR sensitive mutation. Keywords: TP53 mutation, non-small cell lung cancer, EGFR-TKI
P3.01-067 TP53 Mutations Could Involve in EGFR-TKI Primary Resistance in Advanced Non-Small Cell Lung Cancer
B. Lentrichia,1 H. Brown,2 M. Ratcliffe,3 A.M. Rachiglio,4 R. Pasquale,4 N. Normanno5 1Personalised Healthcare and Biomarkers, Astrazeneca Pharmaceuticals, Waltham/US, 2Personalised Healthcare and Biomarkers, Astrazeneca, Cambridge/GB, 3Personalised Healthcare and Biomarkers, Astrazeneca Pharmaceuticals, Waltham/MA/US, 4Cell Biology and Biotherapy, Istituto Nazionale Tumori “Fondazione Giovanni Pascale”, Naples/IT, 5Cell Biology and Biotherapy Unit, Instituto Nazionale Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Naples/IT
X. Li,1 C. Su,2 S. Ren,3 C. Zhao,4 T. Jiang,4 X. Chen,5 J. Li,4 W. Li,5 G. Gao,3 F. Zhou,4 Y. Shao,6 C. Zhou1 1Medical Oncology, Shanghai Pulmonary Hospital, Shanghai/CN, 2Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Pulmonary Cancer Institute, Shanghai/CN, 3Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Cancer Institute, Shanghai/CN, 4Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai/CN, 5Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China., Shanghai/CN, 6Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China, Nanjing/CN Background: Activating mutations in the epidermal growth factor receptor (EGFR) are strongly predictive of EGFR-tyrosine kinase inhibitor (TKI) activity in non-small cell lung cancer (NSCLC). However, primary resistance to EGFR-TKIs occurs in approximately 20-30% of NSCLC patients with EGFR mutations, acquired resistance is inevitable. The aim of study is to discover unknown resistant mechanisms and contribute to more precisely administrate advanced and metastatic NSCLC with EGFR mutations. Method: 60 NSCLC patients with EGFR sensitive mutation were enrolled this study. All of patients received EGFR-TKI treatment. 21 of patients were primary resistance and 39 acquired resistance according to Jackman standard. Tumor tissues of all of patients were collected before EGFR-TKIs treatment, and rebiopsy tissues were gained after acquired resistance in 39 NSCLC patients. Whole exome sequencing were performed in Illumina HiSeq2000 platform. The captured sequencing data was further processed to identify somatic mutations, including single nucleotide variants (SNVs), short insertions/deletions (indels) and copy number variations (CNVs). Result: In primary resistance patients, 13 patients occurred rapid progress (PFS 60 days) were put into group 1, and other 8 patients with PFS within 90-180 days were into group 2; in acquired resistance
P3.01-068 Investigation of Low Plasma/Tissue EGFR Concordance in Russia: Follow-up to the IGNITE Global Diagnostic Study
Background: IGNITE was a large multi-national, non-comparative, non-interventional diagnostic study whose objective was to in part determine the concordance in EGFR mutation status between tissue/ cytology and plasma testing in the real world setting1. Locally advanced or metastatic NSCLC patients were enrolled from 9 countries in AsiaPacific including Russia. A very significant difference was observed in performance of plasma testing in Russia (PPV¼39.3%) vs. Asia Pac (PPV¼92.5%) vs tissue results with only 51/84 ctDNA EGFR mutation positive results from Russian labs confirmed by the corresponding tissue result. No single lab appeared to contribute predominantly to the questionable overall performance. 1. Han, B et al.; ‘Determining the prevalence of EGFR mutations in Asian and Russian patients (pts) with advanced non-small-cell lung cancer (aNSCLC) of adenocarcinoma (ADC) and non-ADC histology: IGNITE study’ (ELCC 2015 Abstract No. 96O). Method: 142 of the 941 evaluable plasma samples from Russia were selected to include originally discordant samples and a similar number of concordant positive and concordant negative samples. All samples were shipped to an experienced lab and re-tested for TKI sensitizing mutations using the QIAamp Circulating Nucleic Acid Kit and the Therascreen® EGFR Plasma RGQ PCR test (Qiagen). The central laboratory was blinded to the origin of the samples and original EGFR mutation result. Result: Adhering to package insert defined criteria for the internal control, 38 of 112 (34%) of cases were re-classified (19 to pos. and 19 to neg.). By independent clinical laboratory interpretation of the results, 55 of 142 (39%) cases were re-classified (25 to pos. and 30 to neg.). A marked improvement was seen in concordance with the local tissue result after re-testing from 38% to 69% with the false positive rate decreasing from 18.8% to 3.6%. Re-classification of 17 (81%) original ‘false positive’ and 17 (35 %) original ‘false negative’