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Y. Wu

Moderator of

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    CALC - Chinese Alliance Against Lung Cancer Session (ID 79)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track: Other Topics
    • Presentations: 15
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      Morning Tea and Chinese Poster Review (ID 3870)

      • Abstract

      Abstract not provided

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      CALC.01 - Welcome (ID 3865)

      Y. Wu, C. Bai

      • Abstract
      • Slides

      Abstract

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      CALC.02 - Keynote: Epidemiology and Burden of Smoking Related Diseases in China (ID 3866)

      C. Bai

      • Abstract
      • Slides

      Abstract
      Epidemiology and Burden of Smoking Related Diseases in China Prevalence of Smoking in China Being the largest producer and consumer of tobacco across the globe, China produces one-third (2.66 million tons/year) of the global tobacco leaves [1] and consumes 30% of the world’s cigarettes [2]. According to the Global Adult Tobacco Survey (GATS) Collaborative Group, China had the highest number of tobacco users (300.8 million) and a low quit ratio compared to 16 countries [3]. The International Collaborative Study of Cardiovascular Disease in Asia showed that 147,358,000 Chinese male and 15,895,000 Chinese female aged 35–74 years had been current cigarette smokers [4]. Regardless of gender difference, such prevalence was higher in the rural population compared to the urban population (male 61.6% vs 54.5% P <0.001; female 7.8% vs. 3.4% P<0.001) [4]. A growing prevalence of smoking was also observed in women [5], adolescents and young adults [2,6-8]. Even among non-smokers, the threat of tobacco smoke remained because airborne nicotine had been detected in 91% of the 273 public locations sampled in rural and urban China [9]. Specifically, an estimated 50-72% of Chinese non-smokers had been exposed to secondhand tobacco smoke [10,11]. Considering active and passive smoking altogether, 72% of the Chinese population were tobacco exposed [12]. Such common exposure has aggravated tobacco-related morbidity and mortality which create a direct economic burden accounting for 42.31 billion yuan [13]. By increasing mortality from cancer, respiratory disease and cardiovascular disease [14-18], smoking currently costs over 1 million Chinese lives per year. If the trend continues, a predicted sum of 2 million Chinese may die of tobacco-related diseases in 2025 [19]. COPD and Smoking Chronic obstructive pulmonary disease (COPD) had an estimated prevalence of 8.2% (>43 million) in the Chinese population > 40 years old [20] and was ranked the fourth/third leading cause of death in urban/rural area respectively [21]. Prompted by the causative roles of active [22-24] and passive smoking [25], a yet increasing prevalence of COPD would be expected in the Chinese population. In the meantime, the expensive treatments and compromised productivity of COPD patients had already created an enormous economic burden equaling to 110% and 34% of the annual incomes in rural areas and urban areas respectively [26]. Even so, the situation might have been undermined due to premature mortality and impaired working capabilities within affected families. Anti-smoking measures could be the best solution since the absolute risks of COPD would fall by 56% in Chinese male and 63% in Chinese female 5 years after smoking cessation [27]. Lung Cancer and Smoking Smoking is the main risk factor for lung cancer regardless of smoking experience (ever, current and ex smoking), tobacco product variety (pipes, cigars and cigarettes) and histological subtypes [28].\\Lee et al. demonstrated the dose-response relationship between smoking and lung cancer pathogenesis [28]. Specifically, risk of lung cancer decreased with duration of smoking cessation but increased with an earlier age of smoking and elevations in (i) the amount and fraction of smoking; (ii) duration of smoking; and (iii) tar level. Analyzing data from10 cancer registries, the crude incidence rate of lung cancer in China was estimated to be 49.35 per 100,000 population (63.7 per 100,000 men and 35.0 per 100,000 women) in 2005 [29]. Compared to lifelong non-smokers, the mortality rate of lung cancer was found to be approximately 23 times and 13 times higher in current male smokers and current female smokers respectively [30]. As prevalence of smoking rose during the past 3 decades, lung cancer mortality also increased by 464.84% [31]. Since 2008, lung cancer has surpassed other malignant tumors to become the most common cause of death in Chinese cancer patients [32]. At present, the mortality rate of lung cancer is 600,000 per year [33]. If the current trend continues, it may reach 1 million by 2025 [33]. With an increased prevalence of lung cancer and more advanced technology, the total number of lung cancer inpatients increased from 174,066 to 364,484 while medical costs increased from 2.16 billion yuan to 6.33 billion yuan between 1999 to 2005 as illustrated in the China Statistical Yearbook. Nonetheless, such dedication did not effectively prove its worth since the 5-year survival rate of lung cancer remained relatively low (10% - 14%) [34]. To relieve the socioeconomic burden, measures should be taken to reduce the incidence of lung cancer and relevant medical costs. CAD and Smoking Smoking has been associated with increased risk of coronary artery disease (CAD). In China, the reported crude odd ratio varied between 1.37 - 5.19 in former and current smokers [35-38]. In a study about risk ratio for CAD mortality, former smokers and current smokers had a risk ratio of 0.68 and 1.81 respectively when compared to never smokers [37]. Nonetheless, such figures bore no significant difference if stratified by co-morbidity of diabetes. Perhaps not surprisingly, passive smoking was verified to independently increase the risk of cardiovascular heart disease (CHD) by 25% - 30% [39,40]. While the prevalence of coronary artery disease (CAD) have fallen in developed countries through control of preventable risk factors, China witnessed an opposite trend as CAD climbed from the fifth most common heart disease in 1948-1957 to the most common in 1980-1989 [41]. As reported, CAD caused 51.4% and 32.8% of mortality related to cardiovascular disease (CVD) in urban and rural areas respectively. Projected from 1990, 72.7 million Chinese male and 72.1 million Chinese female will have been diagnosed with CAD in 2020 [42]. Smoking, one of the modifiable risk factors of CAD, should be tightly controlled in China if the socioeconomic burden has to be alleviated. Conclusion COPD, lung cancer and CAD are common smoking related chronic diseases which occupy a large share of medical resources yet cost a massive number of lives in China. In order to improve the current situation, smoking cessation should be reinforced in China through introduction of effective measures supported by favorable policy. Reference 1. Wang H. Tobacco control in China: the dilemma between economic development and health improvement. Salud Publica Mex. 2006; 48(Suppl. 1): S140–7.

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      CALC.03 - Pathogenesis and Pathology of Never Smoking Lung Cancer (ID 3867)

      A.F. Gazdar, C. Zhou

      • Abstract
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      Abstract
      Lung cancer (LC) is the leading cause of cancer deaths in the world. While smoking is universally accepted as the major cause of lung cancer in tobacco users, lung cancer in lifetime never smokers (LCNS) is among the 10 major causes of cancer deaths. LCNS is a very different disease than LC arising in ever smokers (LCES), and these differences are discussed in this Abstract. Because LCNS is highly influenced by gender and ethnicity, we put special emphasis on LCNS arising in East Asians. The reader is referred to several recent review articles on this subject [1-5] Etiology: Unlike LCES, the etiology of LCNS is not fully elucidated. The suspected factors include exposure to environmental tobacco smoke (ETS), exposure to industrial or domestic carcinogens including coal smoke and volatile cooking oils, radon exposure, viruses including HPV, and genetic factors. While these factors may individually or in combination contribute to the pathogenesis of LCNS, none of them is likely to be the major causative factor. Further investigation of causation is required. Clinico-patholgoical differences. While adenocarcinoma is the predominant form of NSCLC, the vast majority of LCNS are of adenocarcinoma histology, or large cell carcinomas (which may represent poorly differentiated adenocarcinomas). Squamous cell histology is rare and small cell carcinomas almost never occur. A retrospective study from Singapore identified significantly better performance status, younger age at diagnosis, and higher proportion of females (68.5% vs. 12-13%) and more advanced stage at diagnosis in never smokers compared with current and former smokers [6]. The disease stage variation at diagnosis might be explained by late presentation of symptoms and delayed diagnosis by physicians. The survival outcome of never smokers was significantly better than smokers, with the 5-year overall survival rate of LCES, respectively [6]. The differences in the treatment response and survival outcome between never smokers and smokers with lung cancer may be attributed to the differences in molecular pathogenesis and tumor biology (see below). Genetics: While lung cancer prone families have been well described, the risk of affected subjects is greatly increased after smoke exposure. Recently the interest has focused on single nucleotide polymorphisms (SNPs). Genome wide association studies (GWAS) identified a locus in chromosome region 15q25 that was strongly associated with lung cancer. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits [7]. Such subunits are expressed in neurons and other tissues, including alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to potential lung carcinogens. Thus variants in this region undoubtedly code for increased susceptibility to smoke and are unlikely to be associated with LCNS. Not unexpectedly, GWAS studies indicate different patterns of susceptibility for Asians and never smokers and possibly related to gender [8, 9]. Molecular differences: The molecular differences between LCES and LCNS show marked differences and characteristic patterns. While TP53 mutations are common to all types of lung cancer, the mutational spectra are very different [10]. KRAS mutations are largely limited to LCES, and, along with TP53, show the typical smoking associated characteristic G to T transversions. In addition, the total numbers of non-synonymous and synonymous mutations in LCES tumors are much higher than that in LCNS, indicating that tobacco exposure results in in widespread genomic instability. Paradoxically, some of the most responsive currently available or potential molecular targets for precision medicine are more frequent in never smokers, including EGFR, BRAF and HER2 mutations and ALK translocations. Therapeutic options and precision medicine: While the overall treatment strategy is the same for LCES and LCNS, the differences in molecular profiles dictate differences in precision medicine and, response to targeted agents and overall survival. These factors are also influenced by gender and ethnicity. For instance, one study found that the frequency of driver mutations (EGFR, HER2, ALK, KRAS, or BRAF) in lung adenocarcinoma from female never-smokers in China was over 87% [11]. Summary: The differences between LCES and LCNS are major, and cover etiologic factors, clinic-pathological changes, genetic susceptibility genes, mutational and molecular changes and precision medicine. These differences are vast enough so that we can regard lung cancers arising in ever and never smokers as two different diseases. References: 1. Rudin CM, Avila-Tang E, Harris CC, et al. Lung cancer in never smokers: molecular profiles and therapeutic implications. Clin Cancer Res 2009;15(18):5646-61. 2. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers - a different disease. Nat Rev Cancer 2007;7(10):778-90. 3. StatBite lung adenocarcinoma in smoker vs. never smokers. J Natl Cancer Inst 2010;102(10):674. 4. Lee YJ, Kim JH, Kim SK, et al. Lung cancer in never smokers: change of a mindset in the molecular era. Lung Cancer 2011;72(1):9-15. 5. Subramanian J, Govindan R. Lung cancer in never smokers: a review. J Clin Oncol 2007;25(5):561-70. 6. Toh CK, Gao F, Lim WT, et al. Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J Clin Oncol 2006;24(15):2245-51. 7. Hung RJ, McKay JD, Gaborieau V, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 2008;452(7187):633-7. 8. Shiraishi K, Kunitoh H, Daigo Y, et al. A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. Nat Genet 2012;44(8):900-3. 9. Lan Q, Hsiung CA, Matsuo K, et al. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat Genet 2012;44(12):1330-5. 10. Pfeifer GP, Besaratinia A. Mutational spectra of human cancer. Hum Genet 2009;125(5-6):493-506. 11. Zhang Y, Sun Y, Pan Y, et al. Frequency of driver mutations in lung adenocarcinoma from female never-smokers varies with histologic subtypes and age at diagnosis. Clin Cancer Res 2012;18(7):1947-53

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      CALC.04 - SBRT for Lung Cancer (ID 3868)

      D. Liu, M. Fan

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      Abstract
      Approximately 20% of patients with NSCLC present with early stage diseases. While with the advances in imaging and the success in low-dose CT screening in high risk patients, the proportion of patients diagnosed of stage I disease may increase. Radical surgery has been well established as the primary treatment for localized disease. However, a substantial number are ineligible for resection because of comorbidities that are associated inoperable medical condition or advanced age. Conventional fractionated therapy has had disappointing outcomes for stage I NSCLC, with reported local failure rates as high as 60–70% in some series, likely due of inadequate doses. Prior dose escalation study suggested that 70 Gy in 2 Gy fractionation would predict a local-progression free survival of only 24% at 30 months, while dose of 80 to 90 Gy were needed to achieve a recurrence-free survival rate of 50%. Utilizing the advances in radiotherapy planning and tumor targeting techniques, stereotactic body radiation therapy (SBRT) using ablative-range daily doses of 7.5–30 Gy (1-8 fractions), has achieved a biologically effective dose above 100 Gy. This biological unique treatment is associated with notable increases in tumoricidal effect. Reported local control rates have been repeatedly around 90% at 3 years. There is some uncertainty equating SBRT doses and fractionations. In a recent systemic review involving 1076 patients with stage I NSCLC with a follow up of at least 30 months (15 studies), no positive dose–response relationship for tumor control was revealed within different schemes. Current dose to eradicate stage I disease might thus be overestimated. Treating central lesions with hypo-fractionated radiotherapy or SBRT at lower biologically effective doses may be justified. Survival after SBRT is, in general, worse than that after surgery in indirect comparisons, probably because of the frail nature of the patients who receive SBRT. In a population-based study, SEER data showed that even though lobectomy were associated with the best long term outcomes in fit patients with early-stage NSCLC, the survival after SBRT was similar to that after lobectomy in the propensity-score matched analysis, suggesting comparable efficacy with in select populations. Further, the introduction of SBRT reduced the proportion of stage I NSCLC patients who received no local therapy. In north Netherlands population, the application of SBRT corresponded to a 16% absolute increase in the proportion of patients receiving radiotherapy, and this shift was associated with a 6-month median survival improvement SBRT is characterized by both high conformality of the ablative dose delivered to the target, and a sharp dose gradient at the edge of the target volume. This enables possibility for the physician to minimize treatment toxicity. Rate of symptomatic pneumonitis is usually less than 20%. Common, self-limited toxicities were revealed in approximately up to 40% of patients including fatigue, cough, dyspnea and chest pain. Hemoptysis and rib fracture can occur, whereas life-threatening complications are rare. Dose constraints have been investigated for SBRT, though the basic data are now being accrued. Nevertheless, clinical factors like gender, smoking history, and larger gross PTV may equally important or even overweight dosimetric metrics. Further research is required to better understand the tolerance of normal tissues and the long term quality of life after SBRT.

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      CALC.05 - COPD and Lung Cancer (ID 3869)

      I.A. Yang

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      Abstract
      Lung cancer and COPD frequently occur together in smokers, and COPD increases the risk of developing lung cancer in at-risk individuals. Exposure to cigarette smoke is clearly the most important causative factor. Other biological mechanisms for susceptibility to both lung cancer and COPD may involve inflammation, abnormal repair, oxidative stress, cellular proliferation, and epithelial-mesenchymal transition. In addition, genomic and epigenomic changes - such as single nucleotide polymorphisms, copy number variation, promoter hypermethylation and microRNAs - could alter biological pathways and enhance susceptibility to lung cancer and COPD. Approaches of studying genomics, epigenomics and gene-environment interaction will yield greater insight into the shared pathogenesis of lung cancer and COPD, leading to new diagnostic and therapeutic modalities. In addition to smoking cessation and preventing smoking initiation, understanding shared mechanisms in these smoking-related lung diseases is critical, in order to develop new methods of prevention, diagnosis and treatment of lung cancer and COPD.

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      CALC.06 - Diagnosis of Lung Nodules by CT-Guided Lung Biopsy (ID 3873)

      Y. Song

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      Abstract
      CT-guided percutaneous needle biopsy(CT-guided PTNB) of the lung, with its high sensitivity, specificity, and accuracy, is an important diagnostic tool in the evaluation of pulmonary lesion, especially in malignant disease . And it’s specificity can reach 95 percent to 100 percent in malignant disease. Although PTNB of the lung is a mature technique, careful case selection is necessary to increase diagnostic yield and avoid unnecessary complications. It is indicated for indeterminate pulmonary nodules or masses, particularly those that will likely require chemotherapy or radiation rather than surgery. Pneumothorax and pulmonary hemorrhage are the most common complications of PTNB, whereas air embolism and tumor seeding are extremely rare. Attention to biopsy planning and technique and postprocedural care help to prevent or minimize most potential complications. A retrospective investigation of patients with CT-guided PTNB in Jinling Hospital between January 2000 to October 2010 was performed. The risk factors for complications were determined by multivariate analysis of variables related to patients’ demographics, lung lesions, biopsy procedures, and individual radiological features.1014 biopsy prcedures were enrolled. The total complication rate was 18.5 percent with pneumothorax 12.9 percent (131/1014), hemoptysis 5.6 percent (57/1014), and with no mortality. The diagnosis was cofirmed by PTNB in 961 patients (94.8 percent) with 639 patients as malignant disease (63 percent) and 322 patients as benign diease (31.8 percent). Taken into all the evidence, CT-guided percutaneous needle biopsy is a safe and effective means in the diagnosis of pulmonary occupying lesions.

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      CALC.07 - Molecular Signatures for the Accurate Classification of NSCLC and Neuroendocrine Tumors and Cell Lines (ID 3874)

      A.F. Gazdar, L. Girard

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      Abstract
      Until recently the oncologist was only interested to know whether a lung cancer was SCLC or NSCLC. However, recent changes, particularly during this century, require more precise classification of lung cancer, and, in some cases, for subclassification [1]. The different classes of lung cancer respond differently to conventional therapy and to precision medicine. The patterns of driver mutations are highly tumor type dependent, with very little overlap between classes. Thus mutation testing depends of accurate classification. Other reasons for accurate classification include: 1) Adenocarcinoma histology is a strong predictor of response to pemetrexed therapy in patients with advanced disease; and 2) Serious hemorrhagic complications after bevacizumab therapy have been reported in patients with squamous histologies. With the development and application of newer agents for precision medicine, the need for accurate classification will only increase. Complicating the increased need for accurate classification is the fact that currently 70% of lung cancers are diagnosed from small biopsies or cytological samples. Thus more accurate diagnoses are demanded from smaller amounts of materials [1, 2]. A further complication is that large international clinical trials often require that tumor materials be reserved for entry requirements or various tests. In routine pathology practice, immunostains are often used to classify poorly differentiated lung carcinomas. While many immunostains have been proposed, a simple algorithm utilizing TTF1 and Napsin A for adenocarcinoma and p63 (or its isoform p40) and high molecular weight keratins have is effective [3]. However, even with excellent pathology practices, over 10% of cases will be incorrectly classified or be unclassified (undifferentiated large cell carcinoma or NSCLC-not other wise specified (NSCLC-NOS). Pathology practices and quality may vary from institution to institution or country to country. The SEER data on cancer incidence indicates that over 20% of lung cancer cases in the USA are not further classified. For these reasons we developed highly specific and sensitive RNA expression signatures as an adjunct test for routine pathological classification. The signatures not only classify the smaples, but provide a numeric scor ranging from 0-1.0, indicating the degree of differentiation. We utilized expression arrays from multiple public and private sources including The Tumor Cell Genome Atlas (TCGA), which used several platforms including Illumina, Affymetrix and RNA-Seq. For complete identification, four signatures had to be developed and validated and can be utilized independently or in combination. These signatures are: 1) Adenocarcinoma-squamous cell carcinoma discrimination, 2) lung specific neuroendocrine (NE)-non neuroendocrine lung cancer discrimination, 3) Non-malignant lung- lung carcinoma discrimination and 4) lung respiratory cell-lung carcinoma cell discrimination. The adenocarcinoma signature includesTTF1, the squamous cell carcinoma signature includes p63 and several high molecular weight keratins, and the NE cell signature includes chromgranin A, synaptophysin and dopa decarboxyase, adding credence to the signatures. These signatures have <10% discrepancy rates with expert pathology review and have helped n the correct classification of NSCLC, large cell and NSCLC-NOS carcinomas, NE lung tumors and lung cancer cell lines. John Minna and Alex Augustyn, in collaboration with us, have utilized their modification of the NE cell signature, and have identified two potential major clinical applications. These include identification of the full NE expression signature in a subset (5-10%) of NSCLC. While some of these may represent misclassified large cell neuroendocrine carcinomas, others appear to be typical adenocarcinomas. In addition, they have identified that BCL2 is one of the downstream targets of ASCL1, the driving force for NE differentiation in the lung, and that inhibition of BCL2 results in apoptosis of SCLC and NSCLC-NE tumors. Practical application of our signatures requires modification to a more practical platform such as Nanostring technology, and application to formalin fixed paraffin embedded small biopsies. These are currently in development. We are grateful to Drs. William Travis and Natasha Rehktman, members of the TCGA pathology panel and Ignacio Wistuba, John Minna and Alex Augustyn for their invaluable assistance. References 1. Gazdar AF. The evolving role of the pathologist in the management of lung cancer. Lung Cancer Management 2012;1(4):1-9. 2. Travis WD, Brambilla E, Noguchi M, et al. Diagnosis of Lung Cancer in Small Biopsies and Cytology: Implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification. Arch Pathol Lab Med 2012. 3. Travis WD, Rekhtman N. Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing. Semin Respir Crit Care Med 2011;32(1):22-31.

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      CALC.08 - Targeted Therapies for Adenocarcinoma, Now and Future (ID 3875)

      C. Zhou

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      Abstract
      Lung cancer remains as the most fatal disease world-wide.Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers. Incidence of pulmonary adenocarcinoma has been increasing in most countries and becomes a major histology. We had, up to the recent past, treated patients with chemotherapy without any clinical or biological selection. Unfortunately, the improvement in overall survival (OS) with platinum-based doublets is modest, although statistically significant when compared to best supportive care. We now, however, understand that adenocarcinoma could be divided into several subsets according to oncogenic drivers and each subset of adenocarcinoma has a different biology. So, targeted therapies against these drivers have been extensively studied and will play more and more important roles in treatment of advanced adenocaricnoma of the lung. Oncogenic drivers Adenocarcinoma is different in oncogenic drivers between East Asian and Caucasian patients. East Asian patients have more frequent epidermal growth factor receptor (EGFR) mutation but less frequent KRAS mutation. Incidence of EGFR mutation is about 50% - 78.8% but of KRAS mutation about 1.9% to 12%. Other oncogenic drivers include ALK or ROS1 rearrangement, BRAF mutation, HER2 amplification or mutation, c-MET amplification, etc, and arecomparable in their incidencesbetween Asian and Caucasian patients. These oncogenic drivers are mutually exclusive in majority cases. EGFR TKI Several phase II/III studies have investigated the efficacy of EGFR tyrosine kinase inhibitors (TKI) as front-line therapy of patients with advanced NSCLC. EGFR TKI is not appropriate for front-line therapy in unselected populations, in those without EGFR mutation, or those with unknown EGFR mutation status. Improvement in PFS with EGFR TKI is confined to those with EGFR mutation. In fact, first-line EGFR TKI seems to have a detrimental effect in those without an EGFR mutation. Clinical characteristics alone are not sufficient to correctly predict benefit from EGFR TKIs. Treatment with EGFR TKI in EGFR mutant NSCLC patients has also been found to be associated with improvement of progression-free survival (PFS) and quality of life and less toxicity profile. Both first-generation and second-generation EGFR TKIs are effective. Treatment of patients with acquired resistance to EGFR-TKI is wildly being studied. Switching to standard chemotherapy, continuation of an EGFR TKI beyond disease progression and/or plus local therapy, afatinib plus cetuximab are some options of treatment. ALK inhibitors Crizotinib proves effective in adenocarcinoma with ALKorRos1 rearrangement. Several studies (Profile 1001, 1005 and 1007) investigated crizotinib in advanced NSCLC with ALK rearrangement. Tumor response is about 51-61% and PFS 41.9-48.1 weeks. Second-line crizotinib was found more effective than chemotherapy in terms of tumor response rate and PFS. The compound was also found to be effective in those with ROS1 rearrangement. Among 35 patients, its tumor response rate was 60% and PFS was not reached. LDK 387 is a second-generation ALK inhibitor. Phase I study showed its promising efficacy in the patients with ALK rearrangement. It could overcome acquired resistance of NSCLC to crizotinib. Antiangiogenicagents Bevacizumab is approved to be combined with doublet chemotherapy as 1[st] line treatment of non-squamous NSCLC. The combination significantly improves tumor response, PFS and OS. But up to now, there is no biomarker for selection of non-squamous NSCLC patients to receive bevacizumab therapy. Many small molecular anti-angiogenicinhibitors plus standard chemotherapy have been investigated but failed in improvement of OS. Recently, LUME-Lung 1 trials suggested ninetedanib plus docetaxelsignificantly improved PFS and OS of patients with advanced adenocarcinoma of the lung in second line setting compared with docetaxel + placebo. KRAS inhibitors Some compounds are being investigated in those with KRAS mutation. Selumetinib, MKE1/2 inhibitor, combined with docetaxel significantly improved tumor response (37% vs 0%) and PFS (5.2 months vs 2.1 months, HR 0.58), compared with docetaxel alone.Trametinib plus second line chemotherapy produced about 12 to 28% of tumor response rate and 2.9 to 4.1 months of PFS. BRAF inhibitor Dabrafenib has been approved for treatment of melanoma harboringBRAF V600E mutation. Incidence of BRAF V600E mutation is about 1% in NSCLC. A phase II study investigated dabrafenib in adenocarcinoma of the lung withBRAF V600E mutation. Preliminary results in 20 patients showed 40% of tumor response rate and 60% of disease control rate with the compound. c-MET inhibitors c-METamplification is one of major mechanisms for acquire resistance of NSCLC to EGFR TKI. Several small molecular inhibitors of cMET and monoclonal antibodies against cMET are under clinical development. METmab plus erlotinib significantly improved PFS than erlotinib in those with MET high patients in the phase II trial. Crizotinib led to tumor shrinkage in a patient with MET amplification. HER2 inhibitors HER2 mutation and amplification are not frequently observed in adenocarcinoma of the lung. Mazieres and the colleagues reported that HER2-targeted therapies in additional lines of treatment produced 50% of overall response rate, 82% of disease control rate and 5.1 months of PFS. The disease control rate was 96% with trastuzumab-based therapies and 100% with afatinib monotherapy. The relative efficacy of these compounds deserves prospective evaluation in larger international clinical trials. Inhibitors of other oncogenic drivers Many inhibitors of other drivers including PDGFR, FGFR, RET rearrangement, PI3K, mTOR, MEK, AKT, STAT3, etc are under clinical development. We are just waiting for their results of clinical trials. In summary, EGFR TKI and ALK inhibitors are important agents for EGFR mutant and ALK or ROS1 rearranged adenocarcinoma of the lung, respectively. They become standard 1[st] line therapy for these patients. Bevacizumab plus doublet chemotherapy could be 1[st] line therapy for those with advanced adenocarcinoma harboring no oncogenic drivers. Many inhibitors of other oncogenic drivers are under clinical development and will become standard therapy for these patients in near future.

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      CALC.09 - Targeted Therapies for SCC, Now and Future (ID 3876)

      T. Mok

      • Abstract
      • Slides

      Abstract not provided

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      CALC.10 - Second Line Treatment of NSCLC: Needed to Detect Driven Gene Mutation Status (ID 3877)

      B. Han

      • Abstract
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      Abstract
      Despite progressive advances in biomarker-driven personalised therapeutic approaches to non-small cell lung cancer (NSCLC) in recent years, the efficacy of first-line treatment remains suboptimal. Most chemotherapy-treated patients experience disease progression within 3–6 months[1,2] and even those who initially benefit from tyrosine kinase inhibitor (TKI) therapy inevitably progress after 10–14 months.[3–6] However, 40–50% of patients have a good performance status at progression and are suitable for subsequent therapy.[7,8] Thus, improving second-line treatment has the potential to significantly impact patient outcomes. The success of several molecularly targeted therapies in the first-line setting in clinical trials has stimulated research interest in similar applications in the second-line setting. Data from the DELTA[9] and CTONG0806[10] studies presented at ASCO 2013 corroborate findings from the TAILOR[11] study which suggest that chemotherapy may be a marginally better option than epidermal growth factor receptor (EGFR)-TKI for EGFR wild-type patients beyond the first-line setting. It is now clear that treatment response varies widely between patients with different biomarker profiles and this underscores the increasing importance of biomarker testing prior to second-line therapy. For patients with unknown mutation status in the first-line setting, biomarker analysis upon progression is essential to guide second-line treatment decisions to optimise treatment response, both for targeted therapies and chemotherapy. In the pivotal BR.21 trial of erlotinib versus placebo in the second-line setting, response to erlotinib increased from 8.9% in the unselected population to 27.0% in the EGFR mutation-positive sub-population. Similarly, overall survival (OS) increased from 6.7 months to 10.9 months when the EGFR genotype was known.[12,13] In patients with anaplastic lymphoma kinase (ALK)-positive tumours, crizotinib has demonstrated superiority to chemotherapy in the second-line setting with improved progression-free survival (PFS; 7.7 vs. 3.0 months; p<0.001) and quality of life, an important second-line outcome.[14] Although improvements in chemotherapy efficacy seem to have reached a plateau, the use of molecular testing to identify patients who will benefit most from chemotherapy is being actively investigated. A recent study exploring the predictive role of BRCA1 and ERRC1 genes in patients receiving second-line platinum-based chemotherapy showed that low mRNA levels of both genes correlated with increased OS (16.0 vs. 5.4 months; p<0.001) and PFS (4.1 vs. 2.0 months; p=0.002) compared with high levels.[15] Although clinically validated biomarkers have not been identified for most therapies, they remain a critical focus of research and currently available information offers clinicians new insights into second-line management. For patients with known mutation status who experience disease progression following first-line therapy, biomarker testing prior to therapy allows identification of mechanisms of acquired resistance to enable clinicians to tailor subsequent treatment strategies. The most common mechanism of acquired resistance to EGFR-TKIs is the T790M mutation, which has been reported in up to 60% of patients with acquired EGFR-TKI resistance.[16–19] Oxnard et al. demonstrated favourable prognosis and more indolent disease progression in patients with T790M-mediated acquired resistance compared with other mechanisms of acquired resistance, and customised subsequent treatment based on these findings. Over 80% of T790M-positive patients were maintained on TKI therapy, along with chemotherapy, to help maintain the indolent characteristics of T790M-associated progression.[17] A re-response phenomenon has also been described in T790M-positive patients in whom TKI-sensitive cells repopulate upon cessation of TKI therapy, allowing the tumour to regain sensitivity to EGFR-TKI. Thus, re-treatment with EGFR-TKI and chemotherapy may be well suited to target both sensitive and resistant cell populations.[20] Other mechanisms of acquired EGFR-TKI resistance include secondary c-MET overexpression/amplification via HER3/erbB3 or KRAS activation (5–19%), AXL upregulation (20–25%) and phosphatidylinositol-3-kinase mutations (5%).[21,22] Similarly, secondary genetic alterations have been demonstrated in crizotinib-resistant ALK-positive tumours.[23,24] For patients with known mutation status who are still on first-line treatment, biomarker testing provides real-time information to monitor for the development of mutations and to uncover additional targetable tumour characteristics that may impact treatment response and warrant a change in therapy. Tumour characteristics may evolve following first-line treatment as tumour heterogeneity may exist at both genomic and morphological levels. Bai et al. investigated the impact of chemotherapy on EGFR mutation in advanced NSCLC patients who received first-line chemotherapy and patients with stage IIb–IIIb disease who received neoadjuvant chemotherapy, and found that mutation-positive rates were lower post-chemotherapy in both cohorts (p<0.01 and p=0.13, respectively). Importantly, patients who lost EGFR mutation positivity post-chemotherapy had a better partial response than patients with a reverse change (p=0.037).[25] Morphological tumour heterogeneity following first-line therapy has been increasingly reported in the literature. EGFR mutation-positive adenocarcinomas have been reported to transform to small cell histology with maintained EGFR mutation following progression.[16,18] In a study by Sequist et al., these observations allowed investigators to switch patients to small cell lung cancer chemotherapy regimens, with 75% responding to treatment.[18] Epithelial-mesenchymal transitions have also been reported.[18,26] Biomarker testing in the second-line setting is important to detect any changes in tumour characteristics before significant clinical deterioration when alterations to regimens might be most effective. The growing number of biomarker-targeted treatment options may create a need for biopsy or re‑biopsy during treatment. Recent guidelines by the College of American Pathologists, the International Association for the Study of Lung Cancer and the Association for Molecular Pathology recommends re-biopsies for EGFR and ALK mutation analysis to guide treatment decisions beyond the first-line setting.[27] Although re-biopsy may be challenging due to patients’ and/or clinicians’ reluctance, it has shown to be feasible and provides sufficient material for mutation analysis in most patients. High-sensitivity sequencing methods can detect T790M mutation in up to 68% of re-biopsy samples from patients with acquired resistance.[16,17,28,29] Nevertheless, promising surrogates for tumour tissue DNA, such as circulating blood biomarkers, are being investigated and may represent a less invasive approach. The BATTLE-1 trial, which employed real-time biopsies to match patients to targeted therapies, proved that a biomarker-driven treatment approach is feasible.[30] BATTLE-2, which involves more drug combinations, and real-time selection and validation of predictive biomarkers, is currently ongoing;[31] the highly anticipated results hold promise for revolutionising NSCLC treatment.

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      CALC.11 - MicroRNA Biomarkers in Lung Cancer (ID 3878)

      S. Lu, W. Huang, D. Yang, J. Hu, C. Bai, Y. Wu, H. Zhu

      • Abstract
      • Slides

      Abstract
      ABSTRACT Rationale: Effective treatment for lung cancer requires accuracy in sub-classification of carcinoma subtypes. Objectives: To identify microRNAs in bronchial brushing specimens for discriminating small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC) and for further differentiating squamous cell carcinoma (SQ) from adenocarcinoma (AC). Methods: Microarrays were used to screen 723 microRNAs in laser-captured, microdissected cancer cells from 82 snap-frozen surgical lung tissues. Quantitative reverse-transcriptase PCR was performed on 153 macrodissected formalin-fixed, paraffin-embedded (FFPE) surgical lung tissues to evaluate 7 microRNA candidates discovered from microarrays. Two microRNA panels were constructed based on a training cohort (n = 85) and validated using an independent cohort (n = 68). The microRNA panels were applied as differentiators of SCLC from NSCLC and SQ from AC in 207 bronchial brushing specimens. Measurements and Main Results: Two microRNA panels yielded high diagnostic accuracy in discriminating SCLC from NSCLC (miR-29a and miR-375, AUC 0.991 and 0.982 for training and validation dataset, respectively) and in differentiating SQ from AC (miR-205 and miR-34a, AUC 0.977 and 0.982 for training and validation dataset, respectively) in FFPE surgical lung tissues. Moreover, the microRNA panels accurately differentiated SCLC from NSCLC (AUC 0.947) and SQ from AC (AUC 0.962) in bronchial brushing specimens. Conclusion: We found 2 microRNA panels that accurately discriminated between the 3 subtypes of lung carcinoma in bronchial brushing specimens. The microRNA panels could have considerable clinical value in differential diagnosis and play an important role in determining optimal treatment strategies based on the lung carcinoma subtype.

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      CALC.12 - IPF Caused by EGFR-TKIs in Asia (ID 3879)

      Q. Hong

      • Abstract
      • Slides

      Abstract
      Drug-associated interstitial lung disease (ILD) is not uncommon, but it may developed to fatal acute respiratory distress syndrome, so an accurate diagnosis based on clinical, radiological and histological manifestations is important. As an EGFR-TKI, Gefitinib or Erlotinib has been widely used in advanced NSCLC, although it may prolong the patient’s survival, the possibility of ILD associated with EGFR-TKI remains a big problem that we need to confront especially in Asian NSCLC patient. Diagnosis For the assignation of ILD, patient usually need to accord with the following requirements: (1) progressive dyspnea with or without cough or fever, (2) radiographic findings(HRCT recommended) show bilateral, diffuse, or patchy interstitial and/or alveolar opacifications, (3) lack of evidence of infection and progression of underlying lung cancer, (4) consistent pathologic findings if available. Establishing a diagnosis on EGFR-TKI associated ILD is often difficult, and is particularly challenging in a patient having been given chemotherapy and/or radiotherapy, chemotherapy and radiotherapy, either alone or in combination, have been associated with the development of ILD. In addition, infections, and other environmental exposures can also mimic ILD. The characteristic images of EGFR-TKI associated ILD were of patchy diffuse ground-glass shadows; several other characteristic HRCT patterns can also been observed. In acute forms of ILD, ground-glass attenuation is usually seen bilaterally in the lung fields. In chronic forms of the disease, “honeycombing” is seen that results from extensive pulmonary fibrosis and loss of acinar architecture of the lungs. Although ILD can occur during the first 3 months of treatment, the median time to onset was actually 24 to 42 days, and ILD developed in most patients within the first 4 weeks of treatment, with possibly rapid progression.On the other hand, ILD can develop in patients who are retreated with EGFR-TKI after a period of interruption. Therefore, all patients receiving EGFR-TKI who present with an acute onset of dyspnea, regardless of the presence of cough or low-grade fever, should be promptly evaluated, especially during the first month of treatment. Epidemiology There are more frequent reports of EGFR TKI-associated ILD in Japan than elsewhere in the world. The causes for this worldwide differences are unknown and require further scientific investigation. Several reasons have been suggested for this difference, including differences in follow-up period, the clinical characteristics of the study population, and the applied diagnostic criteria for ILD. Pre-existing ILD, including usual interstitial pneumonia, has been found in the reported EGFR-TKI induced ILD patients,the presence of IPF seems to be an important risk factor. Alternatively, there may be a specific increased genetic susceptibility to ILD among the Japanese population. However, this ethnic difference in reporting rates does not extend to other Asian countries, where the frequency of ILD is comparable with the rest of the world Mechanism of ILD The molecular mechanisms leading to ILD are also unclear. The distribution of EGF and EGFR in normal adult human lung has been demonstrated by immunohistochemistry, with expression observed in the basal cell layer of the bronchial epithelium . EGF signaling probably represents an important mechanism that helps coordinate the process of recovery from lung injury by stimulating epithelial repopulation and restoration of barrier integrity. Some investigator have suggested that EGFR-TKI therapy may augment any underlying pulmonary fibrosis via a decrease in EGFR phosphorylation with a coincident decrease in regenerative epithelial proliferation. Therefore, it is possible that EGFR inhibition will at least in part reduce the ability of pneumocytes to respond to lung injury. Compared with other EGFR inhibitors, the largest amount of information regarding the association with ILD is available for gefitinib, as this agent has been given to more patients than any other EGFR-TKIs. Treatment Treatment of EGFR TKI–induced ILD include supplemental oxygen, empirical antibiotics, and mechanical ventilation depending on the severity of the situation. Immediate discontinuation of the TKI drug is recommended . Acute pneumonitis commonly resolves on discontinuation of therapy, although in severe cases patients , systemic corticosteroids are usually prescribed, Prognosis with treatment is good if the diagnosis is made early; however, once fibrosis has occurred, the damage may be permanent with irreversible loss of lung function.

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      CALC.13 - Novel Lung Cancer Plasma Immunoinflammatory Complexes (ID 3880)

      J. Hu

      • Abstract
      • Slides

      Abstract
      The plasma protein complexes level was measured by electrophoresis analyses in 31 patients with advanced NSCLC treated with 125 or 150 mg/day icotinib hydrochloride until disease progression or unacceptable toxic effects or the patient refused further treatment. Eligibility criteria include performance status≤2, age≥18 years, and stage ⅢB-Ⅳ disease. Herein we found more than 87 % of the change in plasma IIRPCs appears at earlier time than histopathology occurs during the treatment with icotinib hydrochloride: (1) having a crest; (2) having a trough. The increasing or discreasing point always appears at earlier time in the treatment before histopathology occurs. There are no significant differences of the median PFS among the other clinical information groups, including: ages, gender, smoking history and EGFR mutation. Therefore, we showed that measurement of plasma protein complexes level during the treatment in patients with NSCLC may be a new surrogate marker for monitoring the therapeutic efficacy of icotinib and predicting the progression of the disease.

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      CALC.14 - Summary and Close, Thanks to CALC, Speakers and Sponsors (ID 3881)

      D.C. Lam, C. Bai

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS05 - Modern Management of Neuroendocrine Tumours (ID 22)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Surgery
    • Presentations: 5
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      MS05.0 - N/A - Chair Intro (ID 475)

      • Abstract

      Abstract not provided

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      MS05.1 - Bronchopulmonary Carcinoids (ID 476)

      A. Iyoda, S. Koezuka, T. Makino, H. Otsuka, F. Sato, K. Tamaki, Y. Hata, N. Tochigi, K. Shibuya, T. Mikami, K. Isobe, S. Homma

      • Abstract
      • Presentation
      • Slides

      Abstract
      In the 1970s, pulmonary neuroendocrine tumors were classified into three histologically defined categories: typical carcinoid (TC), atypical carcinoid (AC) and small cell lung carcinoma (SCLC) [1)] . Later, a fourth high-grade neuroendocrine tumor of the lung, large cell neuroendocrine carcinoma (LCNEC) was recognized [2)] , and in 1999, the World Health Organization (WHO) classified LCNEC as a variant of large cell carcinoma [3)] . To date, in neuroendocrine tumors of the lung, the major categories of morphologically identifiable neuroendocrine tumors are TC, AC, LCNEC, and SCLC. Lung tumors with neuroendocrine morphology by light microscopy encompass a three-grade spectrum of low grade TC, intermediate-grade AC, and high-grade LCNEC and SCLC. WHO criteria show that the mitotic range for TC was less than two mitoses per 2 mm[2] (10 high-power field [10 HPF]), and that for AC was between two and ten mitoses per 10 HPF. A mitotic count of eleven or more mitoses per 10 HPF is the main criterion for distinguishing LCNEC and SCLC from AC. A criterion for distinguishing AC from TC is necrosis. Therefore, we classify TC as a tumor with carcinoid morphology, lacking necrosis with less than two mitoses per 2 mm[2]. Tumors with carcinoid morphology, areas of necrosis and/or 2-10 mitoses per 2 mm[2 ]are classified as AC [4)] . Immunohistochemically, neuroendocrine markers such as chromogranin, synaptophysin, and N-CAM are typically positive in TC [4)] . Analyses of molecular markers revealed that low-grade TC and intermediate-grade AC exhibit a low proliferative rate compared with high-grade LCNEC and SCLC [5)] , and TC and AC have different genetic alterations from high-grade LCNEC and SCLC [6)] . Analyses of their genetic alterations show that neuroendocrine lung tumors may represent a spectrum ranging from low-grade TC and intermediate-grade AC to highly malignant LCNEC and SCLC tumors [6)] . Carcinoid tumors can be diagnosed by cytology of bronchoscopic fine needle aspiration or bronchoscopic biopsy specimens. Distinguishing TC from AC requires examination of a surgical specimen, unless mitoses between two and ten per 10 HPF and/or necrosis are seen on a bronchoscopic biopsy [4)] . Preoperative FDG-PET imaging is frequently positive in carcinoid tumors [7)] . TC and AC occur equally in males and females, and patients with TC and AC are younger than those with LCNEC and SCLC. TC is classified as a malignant epithelial tumor of the lung [3,4)] . However, the overall survival rate is better for TC than for AC [4,8)] , and the frequency of lymph node metastases in TC is lower than in high-grade LCNEC and SCLC [8)] . Therefore, some investigators have advocated limited resection in patients with carcinoid [9, 10)] . Some reports revealed that sublobar resection was noninferior to lobectomy for survival in patients with carcinoid tumor [10)] . However, other reports advised that radical oncologic surgery with radical node dissection was needed, and segmental and other limited procedures had to be avoided because of the high frequency of lymph node involvement and multicentric forms[11,12)] . A randomized controlled trial is the best method to compare surgical efficacies. However, it may be impractical due to the rarity of carcinoid tumors. Moreover, AC has a poorer prognosis and a higher frequency of lymph node metastases than TC, and preoperative diagnoses and/or diagnoses of intraoperative frozen sections are often difficult for differentiating AC from TC because small amounts of necrosis or few mitoses are sometimes unclear in those specimens. Therefore, sublobar resection for TC might be the optimal surgical method because of lung preservation and lower mortality than lobectomy; however, limited resection for TC remains an area of controversy. References 1) Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 1972;64:413-21 2) Travis WD, Linnoila RI, Tsokos MG, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. Am J Surg Pathol 1991;15:529-53 3) Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, editors. Histological Typing of Lung and Pleural Tumours. World Health Organization International Histological Classification of Tumors, XIII, 3rd ed. Berlin/Heidelberg: Springer-Verlag; 1999 4) Travis W.D, Brambilla E, Müller-Hermelink H.K, Harris C.C (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. IARC Press:Lyon 2004 5) Rusch VW, Klimstra DS, Venkatraman ES. Molecular markers help characterize neuroendocrine lung tumors. Ann Thorac Surg 1996;62:798-810 6) Onuki N, Wistuba II, Travis WD, et al. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer 1999;85:600-7 7) Moore W, Freiberg E, Bishawi M, Halbreiner MS, Matthews R, Baram D, Bilfinger TV. FDG-PET Imaging in Patients With Pulmonary Carcinoid Tumor. Clin Nucl Med. 2013;38:501-5 8) Iyoda A, Hiroshima K, Baba M, Saitoh Y, Ohwada H, Fujisawa T. Pulmonary large cell carcinomas with neuroendocrine features are high-grade neuroendocrine tumors. Ann Thorac Surg. 2002 ;73:1049-54 9) Afoke J, Tan C, Hunt I, Zakkar M. Is sublobar resection equivalent to lobectomy for surgical management of peripheral carcinoid? Interact Cardiovasc Thorac Surg. 2013;16:858-63 10) Fox M, Van Berkel V, Bousamra M II, Sloan S, Martin RC II. Surgical management of pulmonary carcinoid tumors: sublobar resection versus lobectomy. Am J Surg. 2013;205:200-8 11) Daddi N, Ferolla P, Urbani M, Semeraro A, Avenia N, Ribacchi R, Puma F, Daddi G. Surgical treatment of neuroendocrine tumors of the lung. Eur J Cardiothorac Surg. 2004;26:813-7 12) Chen F, Sato T, Fujinaga T, Sakai H, Miyahara R, Bando T, Date H. Surgical management of bronchopulmonary typical carcinoid tumors: an institutional experience. Interact Cardiovasc Thorac Surg. 2010;11:737-9

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      MS05.2 - Combined Modality for LCNEC and Atypical Carcinoids (ID 477)

      E. Lim

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      • Abstract
      • Presentation
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      Abstract
      INTRODUCTION Mediastinal Neuroendocrine Tumors occur most frequently in the thymus. Primary Thymic Neuroendocrine Tumors (NETs) are rare and highly aggressive neoplasms; a little more than 350 cases have been described in the literature, many of which are single case reports. We collected one of the largest series ever reported through a multicenter International study, with the aim to evaluate factors influencing survival and recurrence development in patients with Thymic NETs. MATERIAL AND METHODS A multicenter retrospective study of patients operated for NETs between 1989 and 2012 in 9 high-volume International Thoracic Surgery Institutions, was conducted. According to the International Thymic Malignancy Interest Group (ITMIG) outcome measures, primary and secondary outcome were Cause Specific Survival (CSS) and Disease Free Survival (DFS). Competing-risks regression models (Fine and Gray method), taking into account death by any causes as competing event, were used to identify the association between individual factors and tumor related death. Cox proportional hazards regression models were used to define association between individual factors and DFS, considering R0 cases only. Univariate and multivariate analyses were also performed. RESULTS There were 52 patients (41 males –79%-, median age 49 years). The tumor was asymptomatic in 22 cases (42%). Endocrine paraneoplastic syndromes were observed in 23 cases (44%): 13 Cushing’s syndrome and 10 MEN-1 syndrome. Well differentiated neuroendocrine carcinoma (Typical and Atypical Carcinoid) was the commonest histological subtype (30 cases –58%-). Eight patients (15%) received induction therapy (3 chemotherapy, 2 chemo+radiotherapy, 2 biological therapy and 1 chemo+radio+biological therapy), because of their radiological invasiveness. Median sternotomy was the commonest surgical approach (29 cases). The median tumor size was 8 cm (range 1 – 31 cm); a complete resection (R0) was achieved in 48 cases (92%). Advanced Masaoka-Koga stage (III-IV) was observed in 35 patients (67%). Postoperative treatment was offered to 26 (50%): radiotherapy in 17, chemotherapy in 1, chemo+radiotherapy in 5 and chemo+radio+biological therapy in 3 patient, respectively. Three, 5 and 10-year survival rates were 89%, 76% and 51% (Figure 1). Recurrences were observed in 32 cases (62%): 11 local, 10 intrathoracic and 11 distant. Cumulative incidence of recurrence was 41% at 2 years and 70% at 3 years (Figure 2). Variables influencing survival were: tumor size (p< 0.00) and recurrences (p=0.01). Independents DFS predictors were: age > 50 (p= 0.02), paraneoplastic syndromes (p=0.02), symptoms at presentation (p= 0.01) and poor differentiated histology (p= 0.04). CONCLUSIONS We have confirmed that Thymic NETs are rare mediastinal tumors presenting with an aggressive biological behavior; surgery remains the mainstay of treatment and it should be proposed whenever possible, even in case of advanced diseases. Recurrences are frequent, especially in the first years after operation. Survival is statistically related to the tumor size and to the presence of recurrences, whereas, surprisingly, it is not influenced by induction/adjuvant treatment. A global International effort is needed to collect larger series and to confirm these conclusions. Figure 1: Thymic NETs overall survival curveFigure 1Figure 2: Thymic NETs: cumulative incidence of tumor recurrencesFigure 2

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      MS05.4 - Advances in Radionuclide Therapy (ID 479)

      D. Kwekkeboom

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    CALC - Chinese Alliance Against Lung Cancer Session (ID 79)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track: Other Topics
    • Presentations: 1
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      CALC.01 - Welcome (ID 3865)

      Y. Wu

      • Abstract
      • Slides

      Abstract

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    E13 - High Risk Patients and Low Risk Surgeons (ID 13)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Surgery
    • Presentations: 1
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      E13.3 - Micrometastases: Magic or Mainstream? (ID 434)

      Y. Wu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.13 - BEYOND: a randomized, double-blind, placebo-controlled, multicentre, phase III study of first-line carboplatin/paclitaxel (CP) plus bevacizumab (Bv) or placebo (Pl) in Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) (ID 2756)

      Y. Wu

      • Abstract
      • Slides

      Background
      Bevacizumab, a monoclonal antibody that inhibits angiogenesis via the vascular endothelial growth factor (VEGF) pathway, has proven efficacy in extending overall survival (OS) (Sandler et al, 2006) and progression-free survival (PFS) (Sandler et al, 2006; Reck et al, 2009) when added to platinum-doublet chemotherapy as first-line treatment for advanced non-squamous NSCLC. These pivotal studies included mainly Caucasian patients, however subgroup analyses in Asian patients also reported efficacy of the first-line Bv+CP regimen (Reck et al, 2009). The BEYOND study was initiated to confirm efficacy in a Chinese population.

      Methods
      Patients aged ≥18 years with histologically or cytologically confirmed, locally advanced, metastatic or recurrent advanced non-squamous NSCLC and an ECOG performance status of 0–1 were randomised 1:1 to receive CP (paclitaxel 175mg/m[2] i.v. and carboplatin AUC6 i.v. on day 1 of each 3-week cycle for up to 6 cycles), plus either Pl or Bv 15mg/kg i.v. on day 1 of each cycle, until progression, unacceptable toxicity, withdrawal of patient consent or death. Patients had no prior treatment for advanced NSCLC. Patients were stratified by gender, smoking status and age. The primary endpoint was PFS in the intent-to-treat (ITT) population; secondary endpoints included objective response rate (ORR), OS, exploratory biomarkers and safety. Collection of blood samples for biomarker analyses was mandatory (at baseline, every two cycles during treatment, at progression, and 4–6 weeks post-progression); tissue samples were optional.

      Results
      276 patients were randomised into the study, 138 to each arm. Baseline characteristics were similar in both treatment groups. PFS was prolonged with Bv+CP versus Pl+CP: hazard ratio 0.40 (95% CI 0.29–0.54); median 9.2 versus 6.5 months; p<0.0001 (ITT population). ORR was also improved with the addition of Bv to CP: 54.4% versus 26.3% with Pl+CP. Disease control rate was 94.4% versus 88.7% with Bv+CP and Pl+CP, respectively. Median duration of response was 8.0 months with Bv+CP versus 5.3 months with Pl+CP. OS data are not yet mature. Safety data were similar to previous studies of Bv+CP in NSCLC; no new safety signals were observed. Treatment discontinuation due to adverse events was 18.4% (Bv+CP) and 15.0% (Pl+CP). Treatment-related deaths were low in both arms (Bv+CP: 2.2%; Pl+CP: 0.0%). Detailed safety data and biomarker analyses will be reported.

      Conclusion
      This study confirms that the addition of bevacizumab to first-line platinum-based chemotherapy appears to provide similar PFS benefits in Chinese patients with advanced non-squamous NSCLC compared with global populations. No new safety concerns were reported.

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    MS06 - Surgeons as Drivers of NSCLC Research (ID 23)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Surgery
    • Presentations: 1
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      MS06.2 - Clinical Trial and Research Cooperation (ID 482)

      Y. Wu

      • Abstract
      • Presentation
      • Slides

      Abstract
      Clinical research in non-small-cell lung cancer is a rapidly evolving field. We conducted a survey of lung cancer surgical clinical trials listed on clinicaltrials.gov. 658 records were found, which were mainly consisted of trials studying the surgical procedure and (neo) adjuvant therapy. Phase III trials account for 15.5%. Only 34.9 %( 230 records) trials were completed, and 43 studies present results in clinicaltrials.gov. The median time to completion (MTC) of Ph III surgical procedure trials was 9.4 years. The MTC of Ph III neo-adjuvant and adjuvant trials had not been reached but are longer than 10 years. In comparison, the MTC of Ph III trials in first line setting were only 4.5 years. We summarized the characteristics of these trials with real-world case examples. Our analyses reveal that it is critically needed for regulatory authorities, clinical trial sponsors, collaborative research groups, and academic institutions to work together to build the infrastructure and research cooperation for clinical trials with surgical components. In 2007, a national collaborative clinical research group, Chinese Thoracic Oncology Group (CTONG), was established. CTONG is a network of researchers, physicians and healthcare professionals in public institutions across China. Currently, there are 22 member hospitals in the group. A CTONG-sponsored trial (CTONG1104) is discussed to illustrate our experience with surgical clinical trials. In summary, to expedite clinical research in early stage lung cancer, it is necessary for investigators to collaborate in cooperative clinical trials. As cancer treatment is multidisciplinary, while retaining a surgical focus, surgical trials require multidisciplinary collaboration.

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    O01 - Prognostic and Predictive Biomarkers I (ID 94)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O01.06 - Dynamic change in plasma EGFR mutation DNA in response to first line therapy for advanced stage non-small cell lung cancer (NSCLC) (ID 2496)

      Y. Wu

      • Abstract
      • Presentation
      • Slides

      Background
      Diagnostic utility study of EGFR mutation analysis of tumor and plasma from FASTACT 2 confirmed that the plasma EGFR mutation DNA (pEGFRmut) is a sensitive and specific biomarker. (Wu et al, Lancet Oncology 2013; T. Mok, ASCO 2013). Primary objective of this study is to investigate the dynamic change in pEGFRmut during course of treatment. Secondary objective is to study the diagnostic utility of pEGFRmut in patients with distant organ metastasis whom we assumed to have higher level of plasma DNA.

      Methods
      Retrospective EGFR mutation testing of FFPET and plasma from FASTACT 2 were performed with two allele-specific assays, cobas® 4800 EGFR_FFPET test and cobas® EGFR_blood test (in Development). Both tests are designed to detect one or more of the 42 known EGFR mut. One FFPET section was used for tissue test and 2-ml plasma was used for blood test. We studied the plasma samples collected at baseline, post cycle 3 (C3) and at tumor progression according to RECIST criteria (PD).

      Results
      Complete analysis of plasma samples at baseline, C3 and PD was available in 305 of 451 pts(67.6%). Incidence of pEGFRmut positive at baseline, C3 and PD was 35% (106/305),15% (47/305)and 27% (81/305), respectively. 98 of 106 pEGFRmut patients harbor the Exon 19 deletion or L858R at baseline. (C arm 51; CE arm 47). At C3, 21 (41%) pts lose pEGFRmut positivity in C arm comparing to 39 (83%) in CE arm. At PD, 8 of the 21pts in C arm and 18 of the 39 in CE arm regained pEGFRmut positivity. Table 1 summarized the median pEGFRmut copies/PCR. There was a considerable decline at C3 in both C and CE arm. However, pEGFRmut copies/PCR rebounded to high level at PD in C arm only and remained low in CE arm. Correlation of dynamic change in pEGFRmut copies/PCR with clinical tumor response and PFS will be presented at the meeting. We have also identified 93 (out of 224 matched tissue and plasma samples) patients with known distant organ metastasis. Sensitivity of pEGFRmut in this patient subgroup is 91% (41/45), specificity at 98% (47/48) and overall concordance at 95% (88/93). Table 1

      Median pEGFRmut copies/PCR Baseline C3 PD
      C (Exon 19) 27.6 2.3 35.8
      CE (Exon 19) 43.2 0 2.7
      C(Exon 21) 40.9 2.6 63.9
      CE (Exon 21) 87.1 0 3.5

      Conclusion
      This is the first study demonstrating the quantitative dynamic change in pEGFRmut in pts who received C or CE for advanced NSCLC. At RECIST progression, pEGFRmut remained low in patients who received erlotinib but not in patients who received chemotherapy only. pEGFRmut is a potential biomarker for monitoring tumor response.

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    O03 - NSCLC - Targeted Therapies I (ID 113)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O03.05 - Activity of afatinib in uncommon epidermal growth factor receptor (EGFR) mutations: Findings from three trials of afatinib in EGFR mutation-positive lung cancer (ID 1114)

      Y. Wu

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR (ErbB1) mutations define a lung cancer subtype with exquisite sensitivity to EGFR tyrosine kinase inhibitors (TKIs). While in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21 are the two most common sensitizing EGFR mutations in non-small cell lung cancer (NSCLC), approximately 10% of EGFR mutation-positive tumours harbour uncommon mutations. These mutations represent a heterogeneous group of rare molecular alterations (or combinations) within exons 18–21, whose oncogenicity and sensitivity to EGFR TKIs may vary and has not been prospectively studied. Here we present the first prospective data series on activity of afatinib, the irreversible ErbB Family Blocker, in patients with tumours harbouring uncommon EGFR mutations.

      Methods
      This analysis is based on data from EGFR mutation-positive patients included in the LUX-Lung 2 (Phase II), LUX-Lung 3 and LUX-Lung 6 (both Phase III) studies. EGFR mutations were identified prospectively by direct sequencing in LUX-Lung 2 and by central testing with TheraScreen EGFR RGQ PCR kit (TheraScreen29) in LUX-Lung 3 and 6. Patients were classified as having common (Del19 or L858R) or uncommon (all other single or complex) mutations. Uncommon mutations were categorized into three groups: de novo T790M (alone or in combination with other mutations); exon 20 insertions; and other. Objective response rate (ORR), disease control (DCR), duration of response and progression-free survival (PFS) were assessed by independent review.

      Results
      Seventy-five patients (LUX-Lung 2: n=23; LUX-Lung 3: n=26; and LUX-Lung 6: n=26) had uncommon mutations, accounting for 12.5% of all afatinib patients in these studies. The majority of patients received afatinib first line; 13 patients from LUX-Lung 2 received afatinib after chemotherapy. Breakdown into the three groups was T790M: n=14; Exon 20 insertions: n=23; other: n=38 (most frequent types were L861Q: n=12; G719X: n=8; G719X+S768I: n= 5; G719X+L861Q: n=3). Efficacy results for each group are shown below. Further details by mutation status will be presented.

      Mutation ORR, % (n=) Median duration of response, months (95% confidence interval) DCR (ORR + stable disease), % (n) Median PFS, months (95% confidence interval) Median survival, months (95% confidence interval)
      De novo T790M alone or in combination with other mutations (n=14) 14.3 (2) Individual response durations: 4.1, 12.4 64.2 (9) 2.9 (1.2−8.3) 14.9 (8.1−24.9)
      Exon 20 insertions (n=23) 8.7 (2) Individual response durations: 4.2, 10.1 65.2 (15) 2.7 (1.8−4.2) 9.4 (4.1−21.0)
      Other (n=38) 71.1 (27) 11.1 (4.1, 15.2) 84.2 (32) 10.7 (5.6−14.7) 18.6 (16.4−not estimable)

      Conclusion
      Afatinib was active in lung tumours harbouring uncommon EGFR mutations, such as G719X, L861Q, S768I. Rate and duration of response was comparable with that previously observed in patients with common mutations in these trials. The response rate was low in tumours with de novo T790M mutations and insertions in exon 20 but durable tumour control was achieved in some patients. To date this is the largest analysis of data for prospectively identified patients with uncommon EGFR mutations; treatment options in this heterogeneous group of tumours will be discussed.

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    O15 - NSCLC - Chemotherapy II (ID 109)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O15.07 - Final results of CTONG 0806: a phase II trial comparing pemetrexed with gefitinib as second-line treatment of advanced non-squamous NSCLC patients with wild-type EGFR (ID 1920)

      Y. Wu

      • Abstract
      • Presentation
      • Slides

      Background
      Both Pemetrexed and gefitinib are standard second-line treatments for advanced non-squamous NSCLC in East Asia. The CTONG 0806, a multi-center, randomized, controlled, open-label phase II trial was designed to explore the efficacy of pemetrexed versus gefitinib as second-line treatment in advanced non-squamous NSCLC with wild-type EGFR.

      Methods
      Patients with locally advanced or metastatic non-squamous NSCLC previously treated with platinum-based chemotherapy and with wild-type EGFR detected by direct sequencing were randomized to receive gefitinib orally 250 mg/day (G arm) or pemetrexed 500 mg/m[2] iv day 1 every 21 days (P arm) until disease progression or unacceptable toxicity. Primary endpoint was progression-free survival (PFS). Secondary endpoints included 4-month and 6-month PFS rate, overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life and safety. Independent Review Committee (IRC) evaluated all pictorial data.

      Results
      From Feb. 2009 to Aug. 2012, 161 patients were enrolled and 157 were evaluable (81 in G arm and 76 in P arm). Baseline characteristics were balanced between arms. The primary endpoint of median PFS was met with 4.8 months in P arm versus 1.6 months in G arm(HR 0.54, 95% CI 0.40~0.75, P<0.001), which was confirmed by IRC evaluation (5.6 vs. 1.7 months, HR 0.53, 95% CI 0.38~0.75, P<0.001). Significant difference between two arms was also seen in terms of 4-month PFS rate, 6-month PFS rate and DCR (Table 1). Median OS showed the trend of superiority in P arm (12.4 vs. 9.6 months, HR 0.72, 95% CI 0.49 ~ 1.04, P=0.077). In 108 patients having enough tumor tissue, EGFR mutation status was tested again by Scorpion amplification refractory mutation system (ARMS) and 32 were found to be positive. In 76 patients with wild-type EGFR confirmed by ARMS (35 in P arm and 41 in G arm), median PFS was 4.0 vs. 1.3 months (HR 0.42, 95% CI 0.26~0.67, P<0.001). More skin rash and diarrhea were seen in G arm while more fatigue and ALT increase were in P arm. CTCAE grade 3 or 4 adverse events was 12.3% in G arm and 32.9% in P arm (P=0.002). The detailed survival analysis and biomarkers analysis will be presented on the ground.

      Table1. Efficacy of pemetrexed and gefitinib evaluated by investigators and IRC
      Evaluated by Investigators Evaluated by IRC
      Pemetrexed arm Gefitinib arm P Pemetrexed Gefitinib arm P
      PFS 4.8months 1.6months <0.001 5.6months 1.7months <0.001
      HR 0.54,95% CI 0.40 ~ 0.75 HR 0.53, 95% CI 0.38 ~ 0.75
      4-month PFS rate 59.0% 33.0% <0.001 62.0% 37.0% <0.001
      6-month PFS rate 43.0% 23.0% <0.001 48.0% 27.0% <0.001
      ORR 13.2% 13.6% 0.938 14.5% 12.3% 0.695
      DCR 60.5% 29.6% <0.001 61.9% 30.8% <0.001
      OS 12.4months 9.6months 0.077
      HR 0.72,95% CI 0.49 ~ 1.04

      Conclusion
      CTONG0806 is the first trial to show significant improvement in PFS, DCR and a trend of improving OS with pemetrexed compared with gefitinib in second-line setting for EGFR wild-type advanced non-squamous NSCLC.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P1.11-021 - First-line erlotinib versus cisplatin/gemcitabine (GP) in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC): interim analyses from the phase 3, open-label, ENSURE study (ID 1849)

      Y. Wu

      • Abstract

      Background
      Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor, has proven efficacy in second-/third-line advanced NSCLC, and provides superior first-line efficacy to chemotherapy for patients whose tumors harbor activating EGFR mutations. The phase 3, randomized, open-label ENSURE study evaluated erlotinib vs GP in patients from China, Malaysia and the Philippines with EGFR mutation-positive NSCLC.

      Methods
      Patients ≥18 years with histologically or cytologically confirmed stage IIIB/IV EGFR mutation-positive NSCLC and an ECOG PS of 0–2 were randomized 1:1 to receive either erlotinib (oral; 150mg qd until progression/unacceptable toxicity) or GP (G 1250mg/m[2] iv d1 & 8 q3w; P 75mg/m[2] iv d1 q3w for up to 4 cycles). Patients were stratified by EGFR mutation type, PS, gender, and country). Primary endpoint is progression-free survival (PFS) by investigator, with Independent Review Committee (IRC) assessment for sensitivity analysis; other endpoints include objective response rate (ORR), overall survival (OS), and safety. A pre-planned interim analysis was conducted after 73% of PFS events (cut-off 20 July 2012). An additional exploratory updated analysis (cut-off of 19 November 2012), included all planned PFS events.

      Results
      In total, 217 patients were randomized: 110 to erlotinib and 107 to GP. Baseline characteristics were similar in both groups. Efficacy data by treatment arm for the interim and updated analyses are presented (Table 1). PFS by investigator in EGFR exon 19 deletion and exon 21 L858R mutation subgroups is also presented (Table 1). Erlotinib was better tolerated than GP, with treatment-related serious adverse events (SAEs) occurring in 2.7% vs 10.6% of patients, respectively. The most common grade ≥3 AEs of any cause were neutropenia (25.0%), leukopenia (14.4%) and anemia (12.5%) in the GP arm, and rash in the erlotinib arm (6.4%). At the updated analysis (19 November 2012), erlotinib remained better tolerated than GP, with treatment-related SAEs occurring in 3.6% vs 11.5% of patients, respectively. Median duration of follow-up was 10.3 months and 11.7 months for the GP and erlotinib arms, respectively, at latest cut-off. OS data are not yet mature.

      Efficacy Outcome Interim analysis (cut-off 20 July 2012) Updated analysis (cut-off 19 November 2012)
      E GP E GP
      Investigator-assessed PFS Events, n 35 66 61 87
      Median, months 11.0 5.5 11.0 5.5
      HR (95% CI) 0.34 (0.22–0.51) 0.33 (0.23–0.47)
      log-rank p-value <0.0001 <0.0001
      IRC-assessed PFS Events, n 33 47 51 55
      Median, months 11.0 5.6 11.1 5.7
      HR (95% CI) 0.42 (0.27–0.66) 0.43 (0.29–0.64)
      log-rank p-value 0.0001 <0.0001
      ORR % 62.7 33.6 68.2 39.3
      p-value 0.0001 <0.0001
      Disease control rate (DCR) % 89.1 76.6 91.8 82.2
      p-value 0.015 0.0354
      EGFR exon 19 deletion subgroup PFS Median, months 11.1 4.2 11.1 4.3
      HR (95% CI) 0.20 (0.11–0.37) 0.20 (0.12–0.33)
      EGFR exon 21 L858R subgroup PFS Median, months 8.3 7.1 8.3 5.8
      HR (95% CI) 0.57 (0.31–1.05) 0.54 (0.32–0.90)
      p-value significance level: alpha=0.05

      Conclusion
      These analyses demonstrate that erlotinib provides statistically significant and clinically meaningful improvement in both investigator-assessed and IRC-assessed PFS compared with GP in Asian patients with EGFR mutation-positive NSCLC. Primary efficacy results were also supported by secondary endpoints including ORR and DCR.

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      P1.11-044 - Progression-free survival is a poor surrogate endpoint for overall survival in the first line EGFR-TKI treatment in advanced non-small-cell lung cancer with EGFR mutation (ID 2969)

      Y. Wu

      • Abstract

      Background
      (Although epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs), gefitinib and erlotinib have shown antitumor activity in patients with non-small cell lung cancer (NSCLC) , it is unclear if progrssion-free survival(PFS)could be a good surrogate endpoint for overall survival(OS) in the clinical trials of first-line EGFR-TKIs treatment in patients with advanced NSCLC, especially with activating EGFR mutation.)

      Methods
      A PubMed search identified 12 randomized trials comparing first-line EGFR-TKIs treatment with chemotherapy in patients with advanced NSCLC. A total of 1816 patients were enrolled and EGFR mutation status was known in 554 patients. Linear regression analysis was carried out to estimate the correlation of PFS, response rate (RR), and survival post-progression (SPP) with OS

      Results
      PFS, RR and PPS were all strongly associated with OS(r=0.942, 0.982 and 0.895, respectively, P< 0.01) for all trials. But in trials enolled patients with EGFR mutation, PFS and RR were poor correlate with OS (r =-0.121 and 0.131, respectively, P< 0.01), while PPS strongly associated with OS (r =0.849, P<0.01 )PFS, RR and PPS were all strongly associated with OS(r=0.942, 0.982 and 0.895, respectively, P< 0.01) for all trials. But in trials enolled patients with EGFR mutation, PFS and RR were poor correlate with OS (r =-0.121 and 0.131, respectively, P< 0.01), while PPS strongly associated with OS (r =0.849, P<0.01 )

      Conclusion
      Our findings indicate that PFS is a poor surrogate endpoint for OS in the first line EGFR-TKI treatment in advanced EGFR mutation NSCLC. Further studies are needed to search for appropriate surrogate endpoint for OS.

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    P2.01 - Poster Session 2 - Cancer Biology (ID 145)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.01-017 - Gene expression of MAGE-A3 tumor antigen and EGFR mutational status in Chinese NSCLC patients (ID 2781)

      Y. Wu

      • Abstract

      Background
      The MAGE-A3 tumor antigen is expressed in non-small cell lung cancer (NSCLC), and is a potential target for cancer immunotherapy. NSCLC patients may also have specific epidermal growth factor receptor (EGFR) gene mutations, which are responsible for sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in metastatic NSCLC patients. In Asian populations, a relatively low MAGE-A3 expression (Therasse et al. ASCO 2012) and a relatively high frequency of EGFR mutations (An et al. 2012) have been reported compared to Caucasian populations. Three phase III studies, one with MAGE-A3 cancer immunotherapeutic and two with EGFR-TKIs, are ongoing in patients with early-stage, resected NSCLC. However, to date, a direct association between MAGE-A3 expression pattern and EGFR mutational status has not been investigated. Here, we evaluate a potential link between MAGE-A3 expression and frequency of EGFR mutations in Chinese NSCLC patients.

      Methods
      This single-center, non-interventional, retrospective study was conducted at Guandong Lung Cancer Institute, China. Adenocarcinoma and squamous cell carcinoma (SCC) fresh frozen (FF) stage IB, II or IIIA NSCLC tumor samples were collected. MAGE-A3 transcript levels were determined using quantitative real-time PCR. The presence of EGFR mutations was detected using bidirectional Sanger sequencing on genomic DNA extracted from the same FF tumor samples.

      Results
      MAGE-A3 was expressed in 15.6% of adenocarcinoma (N=96) and 31.6% of SCC (N=95) samples. EGFR mutations were found in 43.8% of adenocarcinoma and 5.3% of SCC samples. MAGE-A3 expression rates and EGFR mutational status are shown (table). Figure 1

      Conclusion
      In this study, mutated EGFR status was observed in more than half of MAGE-A3-positive adenocarcinoma samples. However, due to a small number of samples analyzed, no statistical association could be concluded. Additional larger studies, especially in Asian patients with adenocarcinoma, are needed to confirm the findings. This study was funded by GlaxoSmithKline Biologicals SA.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-043 - CYP1A1*2A Polymorphism is correlate with EGFR Exon 19 Mutation and is an Independent Prognostic indicator for the Advanced Lung Cancer Patients Treated with EGFR-TKI (ID 3053)

      Y. Wu

      • Abstract

      Background
      The EGFR mutated status becomes a very important factor for NSCLC patients considering of the treatment, but the mechanism of the mutation is still unknown.Our study aimed to detect the correlations among EGFR mutations and polymorphisms of EGFR and CYP1A1 genes and their associations with clinical outcome of NSCLC patients treated with EGFR-TKI.

      Methods
      We evaluated the EGFR mutations, the genotypes for EGFR Intron1 (CA) n, R497K and CYP1A1 *2A, *2C polymorphisms in 70 Chinese patients with NSCLC. Genetic polymorphisms were correlated to EGFR mutations. As to subgroup of 36 patients who accepted the EGFR-TKI treatment and had systemic 5 years follow up data, the associations among the somatic EGFR mutations, the genomic polymorphisms of EGFR and CYP1A1 and clinical outcome of the EGFR-TKI were analyzed.

      Results
      The data show that EGFR Intron1 (CA) n and CYP1A1*2A, *2C polymorphisms were correlated with EGFR mutations (P=0.006, P=0.001, and P=0.008, respectively) and all the three polymorphisms were also associated with EGFR 19 exon delection (P=0.007, P=0.033, and P=0.006, respectively); whereas the multivariate analysis demonstrated that only CYP1A1*2A polymorphism was associated with EGFR somatic mutations (P=0.021). For 36 patients treated with EGFR-TKI, the EGFR mutation and CYP1A1*2A polymorphism showed correlation with clinical response of EGFR-TKI(P=0.001, and P=0.011, respectively); However, the multivariate analysis confirmed that the EGFR mutation is still the most effective predictive factor (P=0.006) ; Either the log-rank test and Cox regression analysis demonstrated that the CYP1A1*2A polymorphism is independent prognostic factor for patients’ overall survival treated with EGFR-TKI( P=0.000 for both statistical analysis).

      Conclusion
      The results demonstrate that the CYP1A1*2A polymorphism is correlated with EGFR somatic mutation; for advanced NSCLC patients with EGFR-TKI therapy, the EGFR mutation status is still most effective predictor for clinical response of EGFR-TKI, whereas the CYP1A1*2A polymorphism is an independent prognostic factor. The inner mechanisms deserve thorough study.

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    P3.07 - Poster Session 3 - Surgery (ID 193)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P3.07-026 - A non-interventional study on EGFR mutation status and clinical outcomes of Chinese patients with completely resected lung adenocarcinoma (ICAN study) (ID 2187)

      Y. Wu

      • Abstract

      Background
      ICAN study (NCT01106781) investigated EGFR mutation status, clinical outcomes and recurrent risk factors in Chinese lung adenocarcinoma (ADC) patients after complete resection. Here we report analysis results for the profile of surgery, adjuvant therapy and 2-year disease free survival (DFS) rate in the real-world practice.

      Methods
      Patients were aged ≥18 years, with histological diagnosed lung ADC, and received surgical complete resection. Tumor sample EGFR mutation status was determined according to clinical routine practice. All eligible patients would be followed up to collect the clinical information and the outcomes till 3 years after operation.

      Results
      Of 571 patients from 26 sites, 315 (55.2%) patients were EGFR mutation positive. The most common mutations were exon19 deletion and L858R mutation found in 140 (24.52%) and 132 (22.59%) patients respectively. There were 50.79% of patients who received adjuvant therapy, in which 45.37% received chemotherapy, 4.55% received radiotherapy and 1.93% received TKI therapy, respectively. The 2-year DFS rate was 68.83%. There was statistically significant difference of 2-year DFS among the patients with different postoperative pathologic stage (P <0.0001). There was no statistically significant difference of 2-year DFS among the patients with age, gender, smoking history and EGFR mutation status. Operation method and adjuvant therapy correlated significantly with 2-year DFS, but was not significant when adjusted for postoperative pathologic stage.

      Conclusion
      The overall EGFR mutation positive rate in operable Chinese ADC was 55.2%. 2-year DFS rate was 68.83%. Postoperative pathologic stage had a statistically significant association with 2-year DFS, while age, gender, smoking history and EGFR mutation status didn’t show statistically significant association.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-044 - Overall Survival analysis results of TFINE Study (CTONG 0904): Different Dose Docetaxel plus Cisplatin as First-line Chemotherapy and Then Maintenance Therapy with Single Agent Docetaxel for Advanced non-Small Cell Lung Cancer (ID 2524)

      Y. Wu

      • Abstract

      Background
      Docetaxel (75mg/m[2]) has been reported as first-line and maintenance treatment for Western population with advanced NSCLC. Different doses of docetaxel (60mg/m[2]) are currently delivered in Asian population. Pharmacogenomics alterations in taxanes disposition in different ethnic groups may explain this difference. TFINE study was to evaluate the efficacy, safety, and tolerability of Docetaxel in the maintenance setting, and to identify the preferable dose of docetaxel in Asian population. TFINE study demonstrated significant superiority in tolerability and similar efficacy for dose of 60mg/m2 of Docetaxel versus that of 75mg/m2 in first-line Chinese advanced NSCLC patients. And maintenance treatment with docetaxel significantly prolonged PFS compared with BSC. Here we report Overall Survival (OS) data from TFINE (ClinicalTrials.gov NCT01038661).

      Methods
      Previously untreated patients, aged between 18 and 75 years, histologically or cytologically confirmed advanced NSCLC with PS of 0-1 were included. Patients were initially randomized (R1, 1:1) to receive cisplatin (75mg/m2) plus docetaxel of 75 mg/m2 or 60mg/m2 for 4 cycles. Patients with disease control after the initial treatment were subsequently randomized (R2, 1:2) to best supportive care (BSC) or maintenance docetaxel of 60mg/m2 for up to 6 cycles. Genomic DNA was prospectively collected from all enrolled patients. The primary endpoint was PFS since R2, and the secondary endpoints included ORR, overall survival (OS), and toxicity. OS was defined as the time lasting from R2 to death of any cause. The subgroup analysis about OS included gender, historical category, smoking, ECOG PS. The maintenance treatments of every patient were recorded.

      Results
      This randomized study was undertaken in 15 centers in China. Between Dec 2009 and Aug 2011, a total of 382 patients were enrolled to R1 and 179 patients (46.8%) were enrolled to R2 (61 vs. 118). The median follow-up time for OS was 23.5 months (range 20.5, 28.1 months) for patients receiving BSC and 24.4 months (range 22.6, 25.3 months) for patients receiving maintenance docetaxel of 60mg/m2 for up to 6 cycles. Median OS of BSC group (13.7months, [95%CI:12.0, 15.7]) was not significantly different from that of docetaxel group(12.3months,[95%CI:11.2,14.1]) (p=0.77). No difference was found in the subgroup analysis. Post-discontinuation therapy was given at the discretion of the investigator. Numerically more patients in BSC group (n=35, 57.4%) received second-line treatments, including docetaxel, EGFR-TKI or pemetrexed, than those in maintenance group (n=56, 45.5%), although the difference is statistically insignificant (p=0.13). The failure observation of PFS gains translating into OS gains is partially related to post-progression therapy. Preliminary pharmacogenomics analysis demonstrated the CYP3A5*3C(6986 AG/GG) genotype associated with poor PFS and ABCB1:2677 GG genotype demonstrated less neutropenia in Chinese NSCLC patient treated with Docetaxel/DDP regiment, which did not correlated with OS.

      Conclusion
      Although there is no significant benefit in terms of OS with Docetaxel maintenance treatment, our finding for better tolerability suggest that Decetaxel maintenance treatment could be of some benefit to patients with advanced non-small cell lung cancer.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-023 - Comparative safety profile of afatinib in Asian and non-Asian patients with EGFR mutation-positive (EGFR M+) non-small cell lung cancer (NSCLC) (ID 2141)

      Y. Wu

      • Abstract

      Background
      Afatinib is an oral, irreversible ErbB Family Blocker which showed superior efficacy to standard first-line chemotherapy in two large randomized Phase III trials in global (LUX-Lung 3) and Asian (LUX-Lung 6) EGFR M+ patients. In both trials, median progression-free survival on afatinib was 11 months by independent review. This was also reflected in median treatment duration of 11–12 months in both trials. With long-term treatment duration, the safety profile of afatinib becomes particularly relevant to patients and physicians, and needs to be well characterized. Furthermore, differences in the pattern of some adverse events (AEs; notably interstitial lung disease [ILD]) have been previously described in Asian and non-Asian patients with reversible EGFR tyrosine kinase inhibitors. Here, we present a detailed review of afatinib’s safety profile in Asian and non-Asian patients.

      Methods
      229 (LUX-Lung 3) and 239 (LUX-Lung 6) EGFR M+ patients were treated with afatinib 40mg daily until progression or intolerable AEs. Afatinib dose could be escalated to 50mg daily or reduced to 30mg or 20mg based on predefined study criteria. Patients from both trials were grouped according to ethnicity: Asian vs. non-Asian. On-treatment AEs were summarized by preferred/grouped terms and graded using NCI-CTCAEv3.0.

      Results
      404 Asian (66% China/Taiwan; 16% Southeast Asia; 13% Japan; 5% Korea) and 64 non-Asian patients (95% Caucasian; 3% American-Indian; 2% African-American) received afatinib, with median exposure of 359 and 261 days, respectively. There was no difference in afatinib pharmacokinetic exposure in Asian vs. non-Asian patients. All patients reported at least one AE. Most common AEs were EGFR-mediated and are summarized in the table. Figure 1 Drug-related AEs leading to discontinuation were slightly higher in Asian patients, but at a rate lower than with chemotherapy (28%). Related ILD-like events occurred in four Asian patients (three Grade ≥3) and no non-Asian patients.

      Conclusion
      Most common drug-related AEs with afatinib were EGFR mediated and occurred at similar frequency in Asian and non-Asian patients. Treatment discontinuation due to EGFR-related AEs was low in both groups, indicating that afatinib has a manageable safety profile in both populations and is suitable for long-term treatment of EGFR M+ NSCLC patients.