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T. Mitsudomi
Moderator of
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PLEN 03 - Science Drives Lung Cancer Advances (ID 52)
- Event: WCLC 2015
- Type: Plenary
- Track: Plenary
- Presentations: 5
- Moderators:T. Mitsudomi, T. Mok
- Coordinates: 9/09/2015, 08:15 - 09:45, Plenary Hall (Bellco Theatre)
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PLEN03.01 - Lung Cancer Genomes - Adenocarcinoma (ID 2043)
08:20 - 08:35 | Author(s): M. Meyerson
- Abstract
- Presentation
Abstract not provided
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PLEN03.02 - Lung Cancer Genomes - Squamous Cell Carcinoma/Small Cell (ID 2044)
08:35 - 08:50 | Author(s): R.K. Thomas
- Abstract
- Presentation
Abstract not provided
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PLEN03.03 - Molecular Mechanisms of Drug Resistance (ID 2045)
08:50 - 09:10 | Author(s): P.A. Jänne
- Abstract
Abstract not provided
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- Abstract
- Presentation
Abstract:
Platinum-based doublet chemotherapy is the standard first-line treatment for non-selected patients with advanced non-small cell lung cancer (NSCLC) who have a good performance status . However, some tumors are highly dependent on the function of specific oncogenes for proliferation and survival. This “oncogenic addiction” has leaded the development of targeted anticancer therapies and their ad hoc biomarkers as predictors of their efficacy. This fact has changed the diagnostic and treatment approach in NSCLC . Moreover, this ‘‘personalized medicine’’ approach, in which tumors might potentially benefit from a biology-guided treatment, has an impact in patients’ outcome . Personalized medicine is also feasible in other malignancies such as metastatic breast cancer, even for patients with rare genomic alterations (SAFIR01 trial) , and in other refractory malignancies (SHIVA trial) , reinforcing that the establishment of a comprehensive tumour molecular profile is feasible and compatible with clinical practice. Unlike “basket trials”, where researchers test the effect of a single drug on a single mutation in a variety of cancer types, “umbrella” trials are designed to test the impact of personalized medicine with different drugs on different mutations in a single type of cancer on the basis of a centralized molecular portrait . The phase II BATTLE (Biomarker-integrated Approaches of Targeted Therapy for lung Cancer) trial was the first prospective, biopsy-mandated, biomarker-based study, that adaptively randomised 255 pre-treated NSCLC patients to erlotinib, sorafenib, erlotinib plus bexarotene, or vandetanib, based on molecular biomarker analysed in fresh core needle biopsy specimens. Overall results included a 46% 8-week disease control rate (primary endpoint). This trial established the feasibility of “real-time” biopsies and personalized treatment in lung cancer. BATTLE-2 (NCT01248247), a phase II, randomised, multi-arm study in advanced pre-treated EGFR wild type and ALK non-rearranged NSCLC patients is currently ongoing. The SPECTA-lung (NCT02214134), included within the SPECTA-platform, is a program aiming at Screening Patients with thoracic tumors (lung cancer, malignant pleural mesothelioma, thymoma or thymic carcinoma at any stage) to identify the molecular characteristics of their disease for Efficient Clinical Trial Access. Second-generation trials encompass within the trial design to access to targeted therapies and usually incorporate a randomization process. SAFIR02-Lung (NCT02117167) is an open-label, multicentric randomised, phase II trial. Advanced no EGFR-activating mutation or ALK translocation NSCLC patients are biopsied during the two initial platinum-based chemotherapy cycles. A comparative genomic hybridisation (CGH) array and a next-generation sequencing are performed and analysed during the two subsequent cycles as a therapeutic decision tool. Only patients with a molecular alteration are randomized to maintenance targeted drug arm (AZD8931, Vandetanib, Selemutinib, AZD5363, AZD4547, AZD2014); or standard maintenance treatment (pemetrexed or erlotinib) after completion of four cycles of chemotherapy to test an improvement in progression free survival (PFS). Lung-MAP (NCT02154490) trial is a phase II/III multidrug, multi-sub-study, and biomarker-driven clinical trial in advanced second-line squamous lung cancer patients. Patients are randomized to standard second-line treatment (docetaxel / erlotinib) or five experimental drugs (four targeted therapies according NGS results and an anti-PDL1 immunotherapy based on immunochemistry results). The primary end-point of the trial is PFS. Approximately 500 and 1000 patients will be screened per year for over 200 cancer-related genes for genomic alterations. ALChEMIST trial (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials) is designed to assess whether adjuvant therapy with erlotinib (ALCHEMIST-erlotinib, NCT02193282) or crizotinib (ALCHEMIST-crizotinib, NCT02201992) for 2 years will improve survival over placebo for patients with completely resected stage IB-IIIA EGFR-mutant or ALK-rearranged NSCLC tumors following standard post-operative therapy. ALCHEMIST-screening trial (NCT02194738) will screen about 6,000 to 8,000 participants over 5 to 6 years, with 400 patients enrolled per arm. The RTOG1306 is a phase II trial in EGFR-mutant or ALK-rearranged unresectable stage IIIA (pN2) or IIIB (pN3) NSCLC patients. The aim of the study is to asses whether induction therapy with erlotinib or crizotinib for 12 weeks prior to chemo-radiotherapy improves PFS compared to those treated with standard care therapy alone. Molecular screening is also tested across prospective trials in different malignancies. The MOSCATO trial (NCT01566019) includes metastatic solid tumors and the primary objective is to use high throughput molecular analysis (CGH Array and sequencing) to guide treatment of patients with targeted therapeutics in order to improve the PFS compared to the previous treatment line. IMPACT trial (Initiative for Molecular Profiling in Advanced Cancer Therapy Trial, NCT00851032), is an umbrella protocol in 5,000 patients with advanced malignancies. The goal is to correlate the molecular profile with response to phase I therapies. The NCI-MATCH trial (Molecular Analysis for Therapy CHoice) trial is an umbrella protocol for multiple single-arm, phase II trials. Biopsies from as many as 3,000 patients will be screened by next-generation DNA sequencing to identify 100 actionable mutations, with 1000 participants being enrolled (25% of whom will have rare cancers). Co-primary end-points are overall response rate and PFS rate at 6 months. Finally, for advanced and refractory cancer patients who do not have recognised genetic abnormalities WINTHER trial (NCT01856296) aims at selecting rational therapeutics based on the analysis of matched tumors and normal biopsies according to micro arrays and gene expression profiling results. The main objective is to compare the PFS of the current treatment versus the previously prescribed treatment. Models of personalized medicine implementation (no organized compared with organized framework) , optimal technology for molecular profile , and the optimal patients’ selection are some of challenges to be overcome in personalized medicine. Moreover, the actual model of personalized medicine does not take in account secondary events, which will be involved in cancer resistance. A major challenge in molecular medicine will be to target these secondary events early enough, in order to avoid treatment resistance . Intratumoral heterogeneity plays a critical role in tumor evolution. However, molecular characterization of the tumor is provided from a single biopsy and at single time point. Multiregional evaluations to determine geographical heterogeneity, and molecular characterization of different samples collected over space and time to ascertain clonal evolution are not routinely carried out . The prospective TRACERx trial (TRAcking non-small cell lung Cancer Evolution through therapy [Rx], NCT01888601) in NSCLC patients, aims to define the evolutionary trajectories of lung cancer in both space and time through multi-region and longitudinal tumor sampling and genetic analysis by following cancer from diagnosis to relapse. The study aims to recruit 842 patients . Incorporating an analysis of the tumor immune contexture is also a key challenge and need for the design of new precision medicine trials . In the near future most patients with metastatic tumors will receive targeted therapies or immune modualtors delineated by tumor genotyping and analysis of immune contexture and all of these trials will help to validate current biomarkers facilitating rapid access to innovative therapies.
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PLEN03.05 - Mouse Models of SCLC and NSCLC (ID 2047)
09:30 - 09:50 | Author(s): A. Berns
- Abstract
- Presentation
Abstract:
Lung cancer and mesotheliomas belong to the most lethal human malignancies with poor prognosis. The majority of these tumors is associated with carcinogen exposure (smoking and asbestos). Small cell lung cancer (SCLC) and mesothelioma patients show very poor survival statistics due to their late detection, invasive and high metastatic potential, and chemo-resistance. Using the Rbf/f;p53f/f mouse model for SCLC, we found that the tumors are often composed of phenotypically different cells, characterized by mesenchymal and neuroendocrine markers. These cells often share a common origin. Crosstalk between these cells can endow the neuroendocrine component with metastatic capacity, illustrating the potential relevance of tumor cell heterogeneity in dictating functional tumor properties. Also specific genetic lesions appear to be associated with metastatic potential. We have studied the nature of this crosstalk and identified the components responsible for paracrine signaling and the downstream effector pathway critical for promoting metastatic spread. We have also evaluated the relevance of additional lesions that were frequently acquired in the mouse SCLC, such as amplification of Myc and Nfib. Therefore, we have derived ES cells from Rbf/f;p53f/f, equipped these cells with an exchange cassette in the ColA1 locus, and shuttled a conditional L-Myc and Nfib under a strong promoter into this locus. This accelerated tumorigenesis and resulted also in a shift in the metastatic phenotype. To investigate the cell-of-origin of thoracic tumors, we have inactivated a number of tumor suppressor/oncogene combinations (Trp53, Rb1, Nf2, Cdkn2ab-p19Arf, mutant Kras) in distinct cell types by targeting Cre-recombinase expression specifically to Clara cells, to neuroendocrine cells, alveolar type II cells and cells of the mesothelial lining (origin of malignant mesothelioma) using adenoviral or lentiviral vectors with Cre recombinase driven from specific promoters. Dependent on the induced lesions and the cell-type specific targeting, SCLC, NSCLC, or mesothelioma could be induced. We show that multiple cell types can give rise to these tumors but that the cell-of-origin is an important factor in determining tumor phenotype. Our data indicate that both cell type specific features and the nature of the oncogenic lesion(s) are critical factors in determining the tumor initiating capacity of lung (progenitor) cells. Furthermore, the cell-of-origin appears to influence the malignant properties of the resulting tumors. Sutherland, K., Song, J-Y., Kwon, M-C, Prooost and Berns A. (2014). Multiple cells-of-origin in K-RasG12D induced mous lung adenocarcinoma. Proc. Natl. Acad. SCi. USA, 111, 4952-4957. Kwon, M-C, and Berns, A. (2013) mouse models of Lung Cancer. Mol. Oncol. 7, 65-177. Sutherland, K.D., Proost, N., Brouns, I., Adriaensen, D., Song, J-Y., and Berns, A. (2011). Cell of Origin of Small Cell Lung Cancer: Inactivation of Trp53 and Rb1 in Distinct Cell Types of Adult Mouse Lung. Cancer Cell 19, 754-64. Calbo, J., van Montfort, E., Proost, N., van Drunen, E., Beverloo, H., Meuwissen, R., and Berns, A. (2011) A functional role for tumor cell heterogeneity in a mouse model of Small Cell Lung Cancer. Cancer Cell, 19, 244-56.
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Author of
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.08 - AZD9291 in Pre-Treated T790M Positive Advanced NSCLC: AURA2 Phase II Study (ID 1406)
17:25 - 17:30 | Author(s): T. Mitsudomi
- Abstract
- Presentation
Background:
The epidermal growth factor receptor (EGFR) T790M mutation is found in about half of patients who have developed resistance to EGFR-tyrosine kinase inhibitors (TKIs), gefitinib or erlotinib. AZD9291 is an oral, potent, irreversible EGFR-TKI selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. In the Phase I AURA study, AZD9291 80 mg (dose selected for further evaluation) was found to be clinically active, with an acceptable tolerability profile. This ongoing AURA2 Phase II study (NCT02094261) investigates the efficacy and safety of AZD9291 80 mg once daily after previous EGFR-TKI treatment in patients with EGFRm and T790M positive advanced NSCLC.
Methods:
AURA2 (NCT02094261) is a global, open-label, single-arm Phase II study. To be eligible, all patients had a mandatory tumor sample taken after disease progression on the most recent line of therapy, for confirmation of T790M positive status by central laboratory testing using the cobas™ EGFR Mutation Test. Further inclusion criteria included measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. Patients receive AZD9291 at 80 mg once daily until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (assessed by independent central review, ICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and safety. Planned enrollment was 175 patients to give an ORR with 95% confidence interval (CI) within ±8%. The data cut-off was January 9, 2015.
Results:
Recruitment is complete and 210 patients were enrolled; 12 patients did not have measurable disease at baseline by ICR and are excluded from the evaluable-for-response set. By central testing, in addition to T790M, patients had background EGFR mutation: Ex19del, 65%; L858R, 32%; other, 3%. Baseline characteristics: median age, 64 years; female, 70%; WHO PS 0/1, 40%/60%; Asian, 63%; second-/≥third-line, 32%/68%. Median treatment exposure was 4.0 months and 183 patients remain on treatment at the data cut-off. ORR by ICR was 64% (127/198; 95% CI 57, 71) and DCR was 90% (95% CI 85, 94). Investigator-assessed ORR was 64% (135/210; 95% CI 57, 71). Median DoR and median PFS have not been reached (maturity 6% and 20%, respectively). The estimated proportion of patients who are alive and progression free is 82% and 70% at 3 and 6 months, respectively. The most common all-causality adverse events (AEs) were diarrhea, 34% (1% Gr≥3) and grouped rash terms 40% (0.5% Gr≥3); 38 (18%) patients experienced Gr≥3 AEs. Interstitial lung disease grouped terms were reported in four (1.9%) patients, one of which was fatal (0.5%) and considered possibly causally related to AZD9291 by the investigator. Eight patients (4%) discontinued treatment due to an AE. Updated results from a later data cut-off will be available for presentation.
Conclusion:
AZD9291 80 mg once daily demonstrates clinical activity and manageable tolerability in patients with EGFRm, T790M mutation positive advanced NSCLC that has progressed on or after EGFR‑TKI treatment. AZD9291 is being investigated in the randomized AURA3 Phase III study (NCT02151981) in comparison with platinum-based doublet chemotherapy.
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MS 18 - Advocacy Snapshots (ID 36)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Advocacy
- Presentations: 1
- Moderators:P. Mondragon, K. Norris
- Coordinates: 9/08/2015, 14:15 - 15:45, 703
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MS18.02 - Advocates Making a Responsible Case for High-Risk Screening (ID 1927)
14:35 - 14:50 | Author(s): T. Mitsudomi
- Abstract
- Presentation
Abstract:
Purpose: The purpose is to discuss how to advocate to make a Responsible Case for the Screening of lung cancer high risk group. Background and fact: Screening is looking for cancer at an early stage before a person has any symptoms. For the better screening, efficiency is determined as well as sensitivity and specificity. In these forty years, three screening tests have been studied to find if they decrease the risk of dying from lung cancer. Chest X-rays were evaluated at the earliest time in the lung cancer screening history while it is no longer recommended for screening.. Sputum cytology is a procedure in which a sample of sputum is viewed under a microscope to check for cancer cells, so it is required to good mucus that is coughed up from the lungs. Now, it is used as a non-invasive examination of a patient with a sputum symptoms rather than screening. Low-dose spiral CT (LDCT) scan is a special kind of x-ray that takes many pictures as you lie on a table that slides in and out of the machine. A computer then combines these pictures into a detailed picture of a slice of your body. In this procedure, low-dose radiation is used to make a series of very detailed pictures of areas inside the body with reduction of radiation exposure.. The National Lung Screening Trial (NLST) provided the first evidence that lung screening can reduce cancer deaths, when data from the study was published in 2011. The National Lung Screening Trial began in 2002 and enrolled more than 53,000 participants who were current or former heavy smokers, ages 55 to 74. The trial randomly assigned people to receive lung screening either by low-dose helical CT scans or chest X-rays. The trial was sponsored by the National Cancer Institute, and the University of Michigan was one of 33 places across the country to take part. U-M enrolled 850 participants. The study found that screening individuals with low-dose CT scans could reduce lung cancer mortality by 20 percent compared to chest x-ray. Now, it is concluded that the only recommended screening test for lung cancer is LD-CT, which result Medicare's decision to cover lung cancer screening in US. However, the evidence at the present time in LD-CT screening is only one report from US, the results of additional studies from Europe (NELSON) and Japan (Sagawa team) is awaited. Discussion: To raise up the efficiency of screening, It is important who is suitable as subjects. According to “ the Lung Cancer Screening Guidelines and Recommendations” by CDC, many organizations in US definite that lung cancer screening with LDCT is recommended for people of age 55 to 74 years with ≥ 30 pack year smoking history, who either currently smoke or have quit within the past 15 years while some difference of subjects who are in relatively good health or age 55 to 80 years across organizations. However, major obstacles are lying that smokers are lack of awareness or information for risks and benefits with attention to the specifics of each person making a decision about screening as well as the risk of lung cancer, in order to operate LD-CT screening effectively. GLCC poll in 2013 showed that in Australia and Great Britain current smokers are less aware of the symptoms of lung cancer than former smokers and people who have never smoked regularly. Even if screening system was developed, the risk of death due to lung cancer can not be reduced unless the people of high risk group do not visit to appropriate screening service that has been ensurring quality. In addition, Assessment of smoking and the provision of smoking cessation services must be part of any lung cancer screening program. Advocate movement based on research is urgently needed to develop approaches that will maximize cessation rates among smokers undergoing screening. Even more, it is required to enlightenment for smokers in cooperation with the international community by utilizing a variety of public relations means. In November 2014, lung cancer awareness month, Japan Lung Cancer Society approved the Kyoto Declaration. This declaration has been included that the tackle in the prevention of lung cancer and development of effective treatment by alliance with lung cancer Society, lung cancer patient, government, people, medical personnel, advocacy organizations, and healthcare industry. While the evidence from the NLST supports the implementation of lung cancer screening for high-risk individuals via LDCT, the experience to date also must validates the prior recommendations around institutional approaches to lung cancer screening, including the need for the availability of multidisciplinary clinical teams. In order to advocate making responsible case, several ways should be developed like a “Shared Decision-Making” toolkit(s) by the Lung Association that would act as a “consumers’ guide” for those considering lung cancer screening. After examine such a tool, it is also one of the ideas to take advantage according to the circumstances of each country.
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ORAL 03 - New Kinase Targets (ID 89)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:F. Blackhall, R. Juergens
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 4a-4f
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ORAL03.03 - EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Sensitivity to Afatinib or Neratinib but Not to Other EGFR-TKIs (ID 1748)
11:07 - 11:18 | Author(s): T. Mitsudomi
- Abstract
- Presentation
Background:
Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs),whereas exon 20 insertions (Ins20) are known to be resistant to these drugs. However, little is known about the role of mutations in exon 18. Inspired by clinical observation that a patient with adenocarcinoma harboring exon 18 deletion (Del18: delE709_T710insD) responded to afatinib, this study aimed to establish a rational therapeutic strategy for lung cancers harboring exon 18 mutations.
Methods:
The mutational status of lung cancers registered in Aichi Cancer Center (ACC) database between 2001 and 2015 was reviewed. Three representative mutations in exon 18, Del18, E709K, and G719A, were introduced into Ba/F3, NIH3T3, and HEK293 cells using retroviral vector. The 90% inhibitory concentrations (IC90s) of first generation (1G) (gefitinib and erlotinib), second generation (2G) (afatinib, dacomitinib, and neratinib), and third generation (3G) TKIs (AZD9291 and CO1686) in these cells were determined and compared with the corresponding IC90s in cells expressing exon 19 deletion (Del 19) and with the trough concentration (C~trough~) at the recommended doses for each drug. Clinical data on the treatment response of tumors harboring exon 18 mutations were collected from the ACC and Catalogue of Somatic Mutations in Cancer (COSMIC) databases.
Results:
Among the 1355 EGFR mutations registered in the ACC database, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Of note, exon 18 mutations including G719X, E709X, and Del18 were present in 3.2% (n=43), accounting for 38% of the remaining. According to the COSMIC database, exon 18 mutations accounted for 4.1% (654/16,138) of all EGFR mutations present from exons 18-21. Mutations at codons 709 and 719 accounted for 84% of all exon 18 mutations. Ba/F3 cells expressing Del18, E709K, or G719A grew in the absence of interleukin 3, and NIH3T3 cells transfected with these mutations formed foci with marked pile-up, indicating that these mutations act as oncogenic drivers. IC90s of 1G and 3G TKIs in cells transfected with Del18, E709K and G719A were much higher than those in cells transfected with Del19 (by >50-, >25-, and >11-fold, respectively). In contrast, IC90 of afatinib in these three mutations ranged from only 2- to 6-fold greater than that in Del19 and was <1/40 of its C~trough~. Notably, cells transfected with exon 18 mutations exhibited higher sensitivity to neratinib (by 25-fold for E709K, by 5-fold for G719A, and by a comparable extent for Del 18) than those expressing Del19. Western blot analyses showed that these differential sensitivities corresponded to different degrees of suppression of EGFR phosphorylation in HEK293 cells. Furthermore, analyses of the ACC and COSMIC databases clearly indicated that patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (~80%) than to 1G TKIs (35-56%).
Conclusion:
Our data indicated that lung cancers harboring exon 18 mutations, although rare, should not be overlooked in clinical practice and that these cases are best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits do not detect all exon 18 mutations.
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ORAL 17 - EGFR Mutant Lung Cancer (ID 116)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:P. Meldgaard, E. Felip
- Coordinates: 9/08/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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ORAL17.09 - Discussant for ORAL17.05, ORAL17.06, ORAL17.07, ORAL17.08 (ID 3334)
12:12 - 12:22 | Author(s): T. Mitsudomi
- Abstract
- Presentation
Abstract not provided
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ORAL 42 - Drug Resistance (ID 160)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:R.C. Doebele, J.V. DeGregori
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 4a-4f
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ORAL42.02 - Qualitative and Quantitative Heterogeniety in Acquiring Resistance to EGFR Kinase Inhibitors in Lung Cancer (ID 572)
18:41 - 18:52 | Author(s): T. Mitsudomi
- Abstract
- Presentation
Background:
Acquisition of resistance to EGFR- tyrosine kinase inhibitors (TKIs) is one of important issues in lung cancer researches. Several resistance mechanisms have been identified. However, inter-tumor heterogeneity in acquisition of resistance to EGFR-TKIs is currently unclear.
Methods:
Eleven autopsied patients who developed acquired resistance to EGFR-TKI monotherapy were included in this study. All patients harbored activating EGFR mutations (exon 19 deletion or L858R mutation), and developed acquired resistance to EGFR-TKI after initial response to the drug. Details of patient characteristics are summarized in Table 1. The resistance mechanisms of seven patients have been reported in our previous analyses (Suda K, et al. Clin Cancer Res 2010, and Suda K, et al. APLCC 2014). In this study, we analyzed acquired resistance mechanisms in twenty-eight tumor samples obtained from the four additional patients using target sequencing technique by next-generation sequencer.
Results:
Among eleven patients, four developed T790M EGFR secondary mutation in all TKI-refractory lesions. One patient developed MET amplification in all TKI-refractory lesions. Three patients harbored both TKI-refractory lesions with T790M mutation and those with MET amplification. The other three patients showed respective resistance mechanisms (Table 1).Table 1. Summary of resistant mechanisms in eleven patients.
In the target sequence analysis, allele count data were further analyzed in tumor samples with T790M mutation, and we observed diverse T790M/activating EGFR mutation allele ratio ranging from 2 – 51%. In the analysis for time to treatment failure (TTF), we observed longer TTF in patients who developed single resistance mechanism compared with those who developed multiple resistance mechanisms (Fig. 1; p = 0.055). Figure 1Pt. ID Age/Sex Pack-Year Resistant Mechanisms TTF (m) C1 57/F 0 T790M or MET 13.8 C2 48/F 0 T790M or MET 11.0 C3 58/M 34 MET 14.5 C4 75/M 0 T790M 43.9 C5 93/F 0 T790M 14.8 C6 62/M 26 T790M 9.1 P1 86/F 0 T790M 10.8 P2 72/M 27 T790M or MET 3.8 P3 89/F 0 EGFR loss with MET or Unknown 9.0 P4 84/F 0 Unknown 22.6 A1 76/F 0 SCLC transformation or T790M 5.0
Conclusion:
In this study, we observed qualitative heterogeneity and quantitative heterogeneity of T790M allele ratio in acquisition of resistance to EGFR-TKIs in lung cancers. Qualitative heterogeneity in resistance mechanisms would have a correlation with TTF of EGFR-TKIs.
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P1.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 209)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.02-016 - Prevalence of Preoperative DVT in Japanese Patients Who Underwent Thoracic Surgery by Intensive Screeng (ID 3038)
09:30 - 09:30 | Author(s): T. Mitsudomi
- Abstract
Background:
Pulmonary thromboembolism (PTE) is a well-recognized potentially fatal complication after thoracic surgery. In Japan, PTE had been relatively uncommon. However, it has recently been increasing probably due to changes in lifestyle. Therefore the first guideline for the prevention of venous thromboembolism (VTE) were published in February 2004 in Japan. In this guideline, the patients with history of VTE are classified as highest risk group for PTE. Recently, it has been reported that the presence of normal D-dimer levels can exclude acute-phase deep vein thrombosis (DVT). Therefore, in our institution, DVT had been intensively screened by measuring preoperative D-dimer. The objective of this study was to investigate prevalence of preoperative DVT in Japanese patients scheduled for thoracic surgery.
Methods:
A total of 276 patients who underwent thoracic surgery from June 2013 through July 2014 in our institution were reviewed. The patients who were deemed high-risk for DVT (those with elevated preoperative D-dimer (≧1.0μg/ml), with past history of thrombosis, or with varicose veins in their lower extremities) were defined as preoperative screening positive. They were examined with venous ultrasonography of lower extremities. Those with DVT underwent contrast-enhanced computed tomographic scan (CT) for PTE.
Results:
Of all patients, only 1 failed to undergo preoperative measurement of D-dimer because of emergency surgery. Among the remaining 275 patients, a total of 113 patients ( 95 with elevated D-dimer, 15 with varicose veins in their lower extremities, one with swelling in his extremities, one with paralyzed inferior limbs, and one with previously diagnosed PTE ) were examined with venous ultrasonography of lower extremities. Of them, 34 patients (12.6%) were diagnosed DVT (Figure 1) Proximal and distal DVT were diagnosed in ten patients ( three with isolated DVT, three with multiple DVT, and four with a wide range of huge clots ) and 24 patients ( 15 with isolated DVT and nine with multiple DVT ) , respectively. Of them, none was diagnosed preoperative PTE. For a peri-operative management, all the patients received unfractionated heparin. In addition, of four patients with a wide range of huge clots, three had prophylactic inferior vena cava filter placed. Of 34 patients, one was diagnosed asymptomatic exacerbation of DVT by ultrasonography one week after surgery, but none developed symptomatic PTE. Figure 1
Conclusion:
This study showed an DVT prevalence of 12.6% in patients undergoing thoracic surgery in Japan. However, none developed symptomatic PTE in the peri-operative period.
