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T. Seto
Moderator of
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SC26 - Angiogenesis Inhibition: Advances & Perspectives (ID 350)
- Event: WCLC 2016
- Type: Science Session
- Track: Biology/Pathology
- Presentations: 4
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SC26.01 - Biology of Angiogenesis (ID 6709)
11:00 - 11:20 | Author(s): J. Heymach
- Abstract
- Presentation
Abstract not provided
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SC26.02 - Angiogenesis Inhibition in Lung Cancer: Recent Advances and Perspectives (ID 6710)
11:20 - 11:40 | Author(s): M. Boyer
- Abstract
- Presentation
Abstract:
Angiogenesis is an important process in the development and progression of tumours. Across a range of tumour types markers of angiogenesis, such as elevated VEGF levels or increased micro vessel density, have been shown to be associated with poorer patient outcomes. The recognition that VEGF mediated signalling is a key driver of angiogenesis within tumours led to the development of a range of anti-angiogenic approaches targeting this biological process. These approaches have included monoclonal antibodies (bevacizumab, ramucirumab), decoy receptors (aflibercept), and receptor tyrosine kinase inhibitors (nintedanib, sorafenib, sunitinib, motesanib, vandetanib, cediranib, pazopanib), all of which have been evaluated in lung cancer. Despite this volume of clinical research, only three of these agents have been shown to produce benefit in patients with advanced non-small cell lung cancer (NSCLC): bevacizumab, ramucirumab and nintedanib. No antiangiogenic agent has to date been shown to be of benefit in small cell lung cancer. Bevacizumab, an anti-VEGF monoclonal antibody, was the first antiangiogenic therapy to be evaluated in NSCLC. Early studies identified that patients with squamous cancers were at risk of increased toxicity due to haemorrhage so randomised trials have been restricted to patients with non-squamous tumours. The ECOG 4599 randomized trial evaluated treatment with carboplatin and paclitaxel with or without bevacizumab[1]. In this study, as in most other studies of antiangiogenics, bevacizumab was continued in a maintenance phase following the conclusion of chemotherapy. The study demonstrated an improvement in overall survival (HR 0.79, 95% CI 0.67 – 0.92 p = 0.003). A second phase 3 study, AVAiL, evaluated the addition of two different doses of bevacizumab to the combination of gemcitabine and cisplatin, in a double blind manner[2]. The study demonstrated an improvement in progression free survival, but with no difference in overall survival. Based on the results of these two trials, bevacizumab received approval in several jurisdictions, but there remained some doubts over the benefit to patients given the lack of a confirmatory trial showing improved overall survival. A recent meta-analysis[3] incorporating these and other randomised studies has shown that bevacizumab produces a modest, but statistically significant improvement in overall survival (HR 0.90, 95% CI 0.81 – 0.99; p=0.03). Subsequently, a further randomised trial, BEYOND[4], has been published, with bevacizumab added to the combination of carboplatin and paclitaxel in a purely Asian population. This trial showed an improvement in overall survival (HR 0.68, 95% CI 0.50 – 0.93 p=0.015), with median OS increasing from 17.7 to 24.3 months. Bevacizumab has also been evaluated in the second line setting in combination with erlotinib (in patients unselected for EGFR mutations), without significant impact on overall survival in the BeTa study[5]. Ramucirumab is a monoclonal antibody directed against the VEGFR2 receptor. It has been evaluated in a randomised trial in the second line setting. Patients were randomised to receive treatment with docetaxel with or without ramucirumab[6]. Treatment was continued till progression, with monotherapy ramucirumab continued if toxicity developed to docetaxel (and vice versa). The primary endpoint of the study was overall survival, and the results indicated an improvement in overall survival for patients receiving ramucirumab (HR 0.86, 95% CI 0.75 – 0.98; p=0.023), with median survival increasing from 9.1 to 10.5 months. By contrast to the various studies of bevacizumab, this study included patients with squamous cell cancer, as well as those with non-squamous tumours, with the magnitude of benefit being similar in both histologic types. Addition of ramucirumab resulted in an increase in toxicity, with more hypertension, bleeding, and febrile neutropenia. However the rate of serious adverse events and of deaths due to adverse events were similar between the two study arms. The results of this study led to the approval of ramucirumab for patients with previously treated in NSCLC in some parts of the world, including the USA and Europe. However, subsequently, the results of trials of immune checkpoint inhibitors in the same patient population has resulted in many of these patients not receiving docetaxel chemotherapy, making it difficult to assess the appropriate role for this agent. The addition of a tyrosine kinase inhibitor to chemotherapy has been evaluated extensively in patients with advanced NSCLC in both the first and second line settings. The results of these trials have been disappointing, with none of them demonstrating an overall survival benefit. Many, however, did show some improvement in progression free survival. Only one of these agents, nintedanib, is approved (in Europe) for the treatment of patients with NSCLC. This is based on the results of the LUME-1 study, which compared treatment with docetaxel alone with docetaxel plus nintedanib in patients with previously treated NSCLC[7]. In this study, progression free survival (the primary endpoint) was longer with the addition of nintedanib (3.4 vs. 2.7 months, HR 0.79, 95% CI 0.68 – 0.92; p=0.0019). Although there was no difference in overall survival in the whole study population, in the predefined subset of patients with adenocarcinoma and progression within 9 months of initial therapy median overall survival increased from 7.9 to 10.9 months (HR 0.75, 95% CI 0.60 – 0.92; p=0.007). Similar, though less extreme results occurred in all patients with adenocarcinoma. There was no effect on survival of patients with squamous histology. The combination resulted in an increase in the rate of adverse events, predominantly diarrhoea, liver function abnormalities and vomiting. To date, no biomarker of angiogenesis that allows the selection of patients for treatment with has been identified. As a consequence, patient selection (for bevacizumab) is based on the avoidance of toxicity, by excluding groups of patients known to be at higher risk (e.g. those with squamous cell histology, or a history of haemoptysis). Furthermore the inability to identify those patients most likely to benefit, along with the relatively small improvements in survival means that from an economic viewpoint, the cost per life year gained is high. This has resulted in antiangiogenics not being widely used in some countries. References 1. Paclitaxel Carboplatin alone or with bevacizumab for non-small-cell lung cancer. Sandler et al. N Engl J Med 2006; 355: 2542 – 2550 2. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for non-squamous non-small-cell lung caner: AVAiL. Reck et al. J Clin Oncol 2009; 27: 1227 – 1234 3.Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum based chemotherapy as first-line treatment in patients with advanced non-small cell lung cancer. Soria et al. Ann Oncol 2013; 24: 20 – 30. 4. BEYOND: A randomized, double-blind, placebo-controlled, multicentre phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent non-squamous non-cell lung cancer. Zhou et al. J Clin Oncol 2015; 33: 2197 – 2204 5. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind placebo-controlled phase 3 trial. Herbst et al. Lancet 2011; 377: 1846 – 1854 6. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre double-blind randomised phase 3 trial. Lancet 2014; 384: 665 – 673 7. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-1): a phase 3 double blind , randomised controlled trial. Reck et al. Lancet Oncol 2014; 15: 143- 155
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SC26.03 - Predictive Biomarkers for Angiogenesis Inhibitors: An Update (ID 6711)
11:40 - 12:00 | Author(s): M. Reck
- Abstract
- Presentation
Abstract:
The concept of tumor-induced neoangiogenesis has been shown to be a relevant factor for tumor proliferation and metastasis already a couple of years ago (1). Therefore interaction with proangiogenic pathways appears to be a promising therapeutic target across several solide tumors. In eligible patients with advanced non-squamous NSCLC the addition of the anti vascular endothelial growth factor (anti VEGF) antibody bevacizumab to platinum based chemotherapy has shown consistent improvement of response, progression free survival (PFS) and overall survival. However also the combination did increase the incidence of characteristic adverse events like hypertension, arterial and venous vascular events, bleeding events, proteinuria and other (2). Recently two large randomised phase III trials revealed a significant increase in efficacy by the combination of antiangiogenic agents and chemotherapy in pretreated patients with advanced NSCLC. In the LUME 1 trial the combination of the oral angiokinase inhibitor nintedanib and docetaxel revealed a significant improvement of PFS (median PFS 3.4 vs 2.7 months, HR 0.79, 95% CI 0.68-0.92) and OS in patients with adenocarcinoma histology (median OS 12.6 vs 10.3 months, HR 0.82, 95% CI 0.7-0.99) compared to docetaxel (3). The combination of the anti VEGF receptor 2 antibody ramucirumab and docetaxel did show a significant improvement of response (response rate: 23% versus 14%, p<0.0001), PFS (median PFS 4.5 versus 3.0 months, HR 0.76, 95% CI 0.68-0.86) and OS (median OS 10.5 versus 9.1 months, HR 0.86, 95% CI 0.75-0.98) compared to docetaxel in pretreated patients with NSCLC regardless of histology (4). The identification of potential predictive biomarkers remains a challenge due to the complexity of angiogenesis, the interaction between the tumor and the host and due to dynamic changes of the system. In a very large trial (Abigail), specifically designed to identify potential tissue based or blood based markers of efficacy, no predictive markers could be determined. However the relevant prognostic nature of angiogenesis marker could be confirmed (5). Recent analyses revealed that besides molecular markers clinical factors like rapid progressive diseases or tumors refractory to conventional chemotherapy could be associated with improved outcomes of angiogenesis inhibitors. Preplanned as well as exploratory analyses did show pronounced efficacy for the combination of antiangiogenic agents like nintedanib, ramucirumab and bevacizumab compared to chemotherapy alone supporting the hypothesis that fast progressing tumors are more dependant on neo angiogenesis. The translational exploration of these clinical findings is on the way in several programs and trials. The understanding of this correlation will be important for the optimal placement of antiangiogenic agents e.g. in the combination with immunotherapies. Folkman J, Merler E, Abernathy C et al. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971; 133: 275-288 Soria JC, Mauguen A, Reck M et al. Systematic review and meta-analysis of randomised phase II/III trials adding bevacizumab to platinum based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 2013; 24: 20-30 Reck M, Kaiser R, Mellemgaard A et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double blind, randomised controlled trial. Lancet Oncol 2014; 15: 143-50 Garon E, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665-773 Mok T, Gorbunova V, Juhasz E et al. A correlative biomarker analysis of bevacizumab and carboplatin-based chemotherapy for advanced nonsquamous non-small cell lung cancer: results of the phase II randomized ABIGAIL study (BO21015). J Thorac Oncol 2014; 9: 848-55.
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SC26.04 - Novel Imaging Technique (ID 6712)
12:00 - 12:20 | Author(s): S. Schönberg
- Abstract
- Presentation
Abstract:
Lung cancer is still the leading cause of cancer-related death in both men and women with 80% to 85% of cases being non-small-cell lung cancer (NSCLC).[1]The past fifteen years have brought significant breakthroughs in the understanding of the molecular biology of lung cancer. Signalling pathways and genetic driver mutations that are vital for tumour growth have been identified and can be effectively targeted by novel pharmacologic agents, resulting in significantly improved survival of patients with lung cancer.[2]Parallel to the progress in lung cancer treatment, imaging techniques aiming at improving diagnosis, staging, response evaluation, and detection of tumour recurrence have also considerably advanced in recent years.[3]However, standard morphologic computed tomography (CT) and magnetic resonance imaging (MRI) as well as fluor-18-fluorodeoxyglucose ([18]F-FDG) positron emission tomography CT (PET-CT) are still the currently most frequently utilized imaging modalities in clinical practice and most clinical trials.[4,5]Novel state-of-the-art functional imaging techniques such as dual-energy CT (DECT), dynamic contrast enhanced CT (DCE-CT), diffusion weighted MRI (DW-MRI), perfusion MRI, and PET-CT with more specific tracers that visualize angiogenesis, tumour oxygenation or tumour cell proliferation have not yet been broadly implemented, neither in clinical practice nor in phase I–III clinical trials [6]. In this context, Nishino et al.[4] published an article on personalized tumour response assessment in the era of molecular treatment in oncology. The authors showed that the concept of personalized medicine with regard to cancer treatment has been well applied in therapeutic decision-making and patient management in clinical oncology. With regard to imaging techniques, however, it was criticized that the developments in tumour response assessment that should parallel the advances in cancer treatment are not sufficient to produce state-of-the-art functional information that directly reflect treatment targets. Functional information on tumour response is highly required because there is growing evidence that the current objective criteria for treatment response assessment may not reliably indicate treatment failure and do not adequately capture disease biology. Molecular-targeted therapies and novel immunotherapies induce effects that differ from those induced by classic cytotoxic treatment including intratumorale haemorrhage, changes in vascularity, and tumour cavitation. Thus, conventional approaches for therapy response assessment such as RECIST or WHO criteria that exclusively focus on the change in tumour size are of decreasing value for drug response assessment in clinical trials.[7,8] Parallel to the development of novel imaging techniques automated and more detailed analysis of standard images is currently highly investigated and has led to the introduction of the term Radiomics. Radiomics refers to the comprehensive quantification of tumour phenotypes by applying a large number of quantitative image features that are standardized collected with specific software algorithms. Radiomics features have the capability to further enhance imaging data regarding prognostic tumour signatures, detection of tumour heterogeneity as well as the detection of underlying gene expression patterns which is of special interest in patients with metastatic disease. The aim of of this presentation is to provide an overview on state-of-the-art imaging techniques for the initial staging, response evaluation as well as surveillance in patients with lung cancer. The various techniques will be discussed regarding their pros and cons to further provide functional information that best reflects specific targeted therapies including anti-angiogenetic treatment, immunotherapies and stereotactic body radiation therapy. Moreover, imaging techniques and optimal time points after local minimally invasive treatments with microwave ablation or novel irreversible electroporation will be discussed. The second part of the presentation will focus on Radiomics and its potential value in lung cancer imaging. Literature: 1. Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 2009;15:4-9. 2. Rengan R, Maity AM, Stevenson JP, Hahn SM. New strategies in non-small cell lung cancer: improving outcomes in chemoradiotherapy for locally advanced disease. Clin Cancer Res 2011;17:4192-9. 3. Miles K. Can imaging help improve the survival of cancer patients? Cancer Imaging 2011;11 Spec No A:S86-92. 4. Nishino M, Jackman DM, Hatabu H, Janne PA, Johnson BE, Van den Abbeele AD. Imaging of lung cancer in the era of molecular medicine. Acad Radiol 2011;18:424-36. 5. Nishino M, Jagannathan JP, Ramaiya NH, Van den Abbeele AD. Revised RECIST guideline version 1.1: What oncologists want to know and what radiologists need to know. AJR Am J Roentgenol 2010;195:281-9. 6. Henzler T, Goldstraw P, Wenz F, et al. Perspectives of novel imaging techniques for staging, therapy response assessment, and monitoring of surveillance in lung cancer: summary of the Dresden 2013 Post WCLC-IASLC State-of-the-Art Imaging Workshop. J Thorac Oncol 2015;10:237-49. 7. Oxnard GR, Morris MJ, Hodi FS, et al. When progressive disease does not mean treatment failure: reconsidering the criteria for progression. J Natl Cancer Inst 2012;104:1534-41. 8. Stacchiotti S, Collini P, Messina A, et al. High-grade soft-tissue sarcomas: tumor response assessment--pilot study to assess the correlation between radiologic and pathologic response by using RECIST and Choi criteria. Radiology 2009;251:447-56.
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Author of
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ED14 - Small Cell Lung Cancer (ID 283)
- Event: WCLC 2016
- Type: Education Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:J.B. Sørensen, S. Zöchbauer-Müller
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall C2
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ED14.03 - Update on Prophylactic Cranial Irradiation in SCLC (ID 6503)
15:00 - 15:15 | Author(s): T. Seto
- Abstract
- Presentation
Abstract:
Background: A previous study has shown that prophylactic cranial irradiation (PCI) reduced the risk of brain metastases (BM) and prolonged the overall survival (OS) of patients (pts) with extended disease small cell lung cancer (ED-SCLC). However Japanese trial to reconfirm these results was stopped at first interim analysis (n=163 pts) because of futurity. According to this study protocol, final follow up was done. Materials and methods: From March 2009 pts with ED-SCLC who had any response to first-line chemotherapy (platinum agent plus irinotecan or etoposide) were randomized to either PCI (25Gy/10 fractions) or observation (Obs) alone. The patients were required to prove the absence of BM by MRI prior to enrollment. The primary endpoint was OS and a planned sample size of 330 was determined to detect the hazard ratio (HR) of 0.75 at a significance level of 0.05 and a power of 80%. Secondary endpoints included time to BM (evaluated every 3 months by imaging), progression-free survival (PFS), and adverse effects (AEs) and mini mental status examination (MMSE). Results: In Apr 2014, follow up analysis was conducted for the survival data of 224 all enrolled pts. One hundred fourth-five deaths were observed. The median OS was 11.6 and 14.1 months for PCI (n=112) and Obs (n=111), respectively (HR=1.28, 95%CI= 0.95-1.72; stratified log-rank test, P=0.107). PCI significantly reduced the risk of BM as compared to Obs (33.6% vs 59.7% at 12 months; Gray’s test, P<0.001), whereas PFS was comparable between the two arms (median, 2.3 vs. 2.4 months; HR=0.98, 95%CI=0.75-1.28). No significant difference in AEs greater than Grade 2 was observed between the two arms. At the MMSE there was no statistical difference between two arms, however in pts age 70 and older pts in PCI tended to be worse over time. Conclusion: PCI after response to chemotherapy could not show the OS impact in pts with ED-SCLC even in this follow up data.
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA07.03 - Alectinib (ALC) versus Crizotinib (CRZ) in ALK-Positive Non-Small Cell Lung Cancer (ALK+ NSCLC): Primary Results from Phase III Study (J-ALEX) (ID 5597)
11:12 - 11:18 | Author(s): T. Seto
- Abstract
- Presentation
Background:
ALK inhibitors are the standard treatment for ALK+ NSCLC and the comparison between 2 ALK inhibitors will be valuable in determining therapeutic strategy for ALK+ NSCLC patients (pts). We conducted the randomized open-label Phase III trial designed to prove the superior PFS of ALC to CRZ in ALK-inhibitor naïve ALK+ NSCLC.
Methods:
ALK+ NSCLC pts were randomized 1:1 either to receive ALC (300 mg b.i.d.) or CRZ (250 mg b.i.d.) and stratified by ECOG PS (0/1 vs 2), treatment line (1[st] vs 2[nd]), and clinical stage (IIIB/IV vs recurrence). Primary endpoint was PFS according to the blinded independent review board. Secondary endpoints included overall survival, objective response rate, and safety. Under an assumption of expected hazard ratio (HR) of 0.643, 164 events were required to have 80% power with 2-sided alpha of 0.05. Three interim analyses (IA) for early stopping due to efficacy were planned after 33%, 50%, and 75% of required PFS events occurred.
Results:
207 pts were enrolled at 41 centers in Japan between November 2013 and August 2015. Independent data monitoring committee recommended the release of study data because the superiority in PFS had been demonstrated for ALC based on second IA. The PFS HR of ALC arm to CRZ arm was 0.34 (99.6826% CI: 0.17-0.70, stratified log-rank p<0.0001). Median PFS was not reached (95% CI: 20.3-Not Reached (NR)) in ALC arm while it was 10.2 months (95%CI: 8.2-12.0) in CRZ arm. ALC demonstrated favorable result of PFS in each sub-group for instance, treatment line (1[st] line: HR = 0.30, ALC: NR vs CRZ: 10.2 months, 2[nd] line: HR = 0.39, ALC: 20.3 months vs CRZ: 8.2 months), brain metastases at baseline (yes: HR = 0.08, ALC: NR vs CRZ: 10.2 months, no: HR = 0.39, ALC: 20.3 moths vs CRZ: 10.0 months) and clinical stage (stage IIIb/IV: HR = 0.31 ALC: 20.3 months vs CRZ: 8.3 months, recurrence: HR = 0.49, ALC: NR vs CRZ: 11.6 months). Grade 3-4 AEs (ALC: 26% vs CRZ: 52%), discontinuation of study drug due to AEs (ALC: 9% vs CRZ: 20%) and dose interruptions due to AEs (ALC: 29% vs CRZ: 74%) occurred with lower rate in the ALC arm. There were no treatment-related deaths in either arm.
Conclusion:
ALC demonstrated prolonged PFS compared with CRZ in all sub-groups with a favorable AE profile representing a potential new standard treatment for 1[st] line ALK+ NSCLC pts.
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OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:O.T. Brustugun, S. Lu
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 2
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OA23.06 - Overall Survival (OS) of EGFR Mutation Positive Non-Small Cell Lung Cancer Patients: Real-World Treatment Patterns of 1,660 Japanese Patients (ID 5915)
15:15 - 15:25 | Author(s): T. Seto
- Abstract
- Presentation
Background:
Since the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) was launched in Japan, the survival periods of advanced/recurrent EGFR mutation positive (EGFR m+) non-small cell lung cancer (NSCLC) patients have been getting longer. However, clinical factors which contributed to the extension of survival periods of these patients remain unclear. We investigated overall survival, prognostic factors and treatments patterns of EGFR m+ NSCLC patients in real-world clinical practice.
Methods:
This is a multi-center, observational, retrospective study. Histologically or cytologically diagnosed EGFR m+ NSCLC patients who were started first-line treatment from 1/1/2008 to 31/12/2012 were enrolled. The primary objective was the estimated OS. The secondary objectives were to determine prognostic factors, real-world treatment patterns.
Results:
1,660 EGFR m+ NSCLC patients were enrolled from 17 hospitals in Japan (median age 67.0 years, female 64.8%, 38.9% had smoking history, ECOG-performance status 0, 1, 2, 3, 4 were 39.5%, 41.1%, 7.1%, 4.9%, 0.7%, respectively, adenocarcinoma 95.2%, 50.1% exon 19 deletion, 66.7% at stage IV). Median estimated OS was 29.7 months. Cox regression analysis revealed age, smoking history, performance status, histological diagnosis, EGFR mutation type and clinical stage were independently associated with OS. Five year survival rate of stage IV patients was 13.8%. The median number of treatment regimens was two. EGFR-TKI and platinum-doublet chemotherapy were most frequently used as first- and second-line treatments.
Conclusion:
Real world treatment of the large data-set of 1,660 EGFR m+ NSCLC patients was retrospectively investigated. Median OS was 29.7 months and EGFR-TKIs are major components of the treatment regimens for these patients in Japan. (NCT0247520)
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-002 - Phase I Study of DS-6051b, a ROS1/NTRK Inhibitor, in Japanese Subjects with Advanced Solid Tumors Harboring Either a ROS1 or NTRK Fusion Gene (ID 4366)
14:30 - 14:30 | Author(s): T. Seto
- Abstract
Background:
Oncogenic gene fusions of ROS1 or NTRK have been reported in various cancers. DS-6051b is an orally available small molecule receptor tyrosine kinase inhibitor with high affinity for the ROS1 and NTRK receptors. Non-clinical pharmacology studies demonstrated anticancer activity of DS-6051b against several types of human tumor harboring ROS1 or NTRK fusion gene in cultured cells and xenograft models.
Methods:
This is an ongoing phase 1 study in Japanese subjects with advanced solid tumors harboring either a ROS1 or NTRK fusion gene. Subjects receive doses of DS-6051b from 400mg to 800mg once daily (QD). Pharmacokinetics (PK) samples are collected from Day1 to Day22. Primary objective is to assess the safety profile and secondary objectives are to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and to assess the PK profile. The efficacy of DS-6051b is an exploratory assessment performed by investigator judgment per RECIST v.1.1.
Results:
As of June 27, 2016, a total of 9 subjects were enrolled. Median age was 51 (43-69) years, 56% were female, all 9 subjects were ROS1 fusion positive non-small cell lung cancer patients, and 3 subjects had prior crizotinib treatment. Subjects received DS-6051b at doses of 400mg QD (n=6) and 800mg QD (n=3). There were no DLTs in the 400mg QD cohort, and 2 out of 3 subjects in the 800mg QD cohort experienced DLT with grade 3 AST/ALT increased. To evaluate the MTD and RP2D more in detail, 600mg QD cohort is planned. Common adverse events were AST increased, ALT increased, diarrhea, and constipation. Among 7 patients who had target lesion, 4 subjects showed partial response, 3 subjects showed stable disease. PK data indicated the plasma drug concentration increases as the dose increases.
Conclusion:
This study is categorized as “Clinical Trial in Progress”. This study was initiated from February 2016 and estimated primary completion date will be September 2018.
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P2.08 - Poster Session with Presenters Present (ID 491)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Patient Support and Advocacy Groups
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.08-007 - Listen Advocate Voice - Web-Survey for the Japanese Model of Lung Cancer Advocacy by Society (ID 5651)
14:30 - 14:30 | Author(s): T. Seto
- Abstract
Background:
In Asian countries, the concept of cancer advocacy has not been sufficiently recognized. In Japan, Lung Cancer Society (JLCS) has led the lung cancer advocacy with a part of the NPO, and adopted the 2014 Kyoto Declaration. To evaluate the awareness and attitude of lung cancer advocacy activity among patients, medical workers, and the general population in Japan, web survey was planned for the perceptions of Kyoto declaration and JLCA (Japanese alliance for lung cancer advocacy) events which were carried out by JLCS in these 2 years.
Methods:
An internet survey using survey monkey was conducted which contained 6 closed-ended (selection one or free answers) and open-ended questions, depending on the JLCA network population in June 2016.
Results:
109 people of responded involving 36% of patients and their family, 25% of MD and medical worker, 19% of pharmaceutical company officials and 16% of news media. Perception of Kyoto declaration was 21% of attendee, 27% of well-known, 13% of partial known and 39% of non-awareness. Also the number of participants to the events of JLCA is, 49% of 0 times, 17% 0f 1-2 times, 24% of 3-4 times and 11% of more than 5 times. The most sympathy events ware voted to 1) lecture by a physician 57%, 2) lecture by survivor and the participants WCLC of cancer patients 46%, 3) information in the facebook and the web site 46% 4) citizen open lecture of lung cancer 39%, 5) Performance by society ambassador 38%, 6) advocacy program in annual meetings 26% and 7) Medical seminars around the country 26%. The proportion of respondents who have a certain reputation in the activities of JLCA was 76%. The requests to JLCA is, 1) is the most participation opportunities for information of new treatment and participation opportunities to clinical trial, followed by 2) wish to participate to all the programs in the Society.
Conclusion:
In Japan, awareness about the advocacy is improved, and it was found that the expect to Society for the diverse needs through the Internet survey.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-097 - Experience of Re-Biopsy (Biopsy at Progression) of EGFR Mutant Non-Small Cell Lung Cancer Patients in Japan: A Retrospective Study (ID 4049)
14:30 - 14:30 | Author(s): T. Seto
- Abstract
Background:
To confirm mechanisms of resistance to targeted therapy and to evaluate future treatment strategy, biopsy at progression is important and necessary. Since biopsy at progression is not standard of care, we investigated real-world clinical practice in Japanese patients with non-small cell lung cancer (NSCLC) patients harboring the epidermal growth factor receptor (EGFR) gene mutation.
Methods:
This was a retrospective, multi-center, observational study in Japan. EGFR mutation positive NSCLC patients who developed disease progression after treatment by EGFR tyrosine kinase inhibitor were enrolled. The primary objective was the success rate of re-biopsy (biopsy at progression). The secondary objectives were differences of between the first biopsy and re-biopsy (e.g. sampling method, target organ of biopsy) and complications associated with re-biopsy.
Results:
395 patients were evaluated, median age was 63 years, and the most common histological type was adenocarcinoma (96.2%). Success rate of re-biopsy was 79.5% (314/395) of patients. Compared with the first biopsy, surgical biopsy increased from 1.8% to 7.8%, percutaneous tissue biopsy increased from 7.6% to 29.1%. Most commonly performed gene mutation tests using specimen collected by re-biopsy were EGFR (94.3%), EML4-ALK (22.0%) and KRAS (14.3%). T790M mutation was detected in 147 (49.7 %) out of 296 patients. 23 patients (5.8%) had complications associated with re-biopsy, the most common complication was pneumothorax. A repeated re-biopsy was successful in 87.5% (28/32) of patients.Table. Re-biopsy success rate by site and sampling method No. of patients Success rate (%) By Site Primary site 220 168 (76.4%) Metastatic site 121 103 (85.1%) Lymphnodes 50 40 (80.0%) Others 4 3(75.0%) By sampling method Transbronchial biopsy; forceps 204 147(72.1%) Transbronchial biopsy; needle 41 34 (82.9%) Percutaneous needle biopsy under CT guidance 77 66 (85.7%) Percutaneous needle biopsy under ultrasonic guidance 36 34 (94.4%)
Conclusion:
The observed success rate of re-biopsy was approximately 80% in this study. T790M detection rate was comparable to the previously reported studies. Re-biopsy for the EGFR TKI failure NSCLC patients is feasible in Japan.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-001 - Phase I Study of Salazosulfapyridine Targeting Cancer Stem Cells in Combination with CDDP and Pemetrexed for Chemo-Naïve Advanced Non-Sq NSCLC (ID 4318)
14:30 - 14:30 | Author(s): T. Seto
- Abstract
Background:
Variant splicing isoforms of CD44 (CD44v) are a marker of cancer stem cells (CSCs) in solid tumors. CD44v stabilizes the glutamate-cystine transporter subunit xCT and thereby promotes synthesis of the intracellular antioxidant glutathione and protects CSCs from oxidative stress. Salazosulfapyridine (SASP) is an inhibitor of xCT activity, and, in combination with cisplatin (CDDP), it attenuates the increase in the proportion of CD44v-positive tumor cells during the growth of tumor xenografts in mice.
Methods:
Individuals with advanced (stage IIIB or IV) nonsquamous non–small cell lung cancer are eligible to enroll in a phase I dose-escalation study (standard 3+3 design) of SASP in combination with CDDP and pemetrexed (PEM) as first-line treatment. Patients receive SASP daily as well as CDDP (75 mg/m[2]) and PEM (500 mg/m[2]) on day 1 of a 21-day cycle. The primary end point is the percentage of patients who experience dose-limiting toxicity (DLT) between administration of the first dose of SASP (day 1) and day 21.
Results:
From April 2015 to January 2016, 15 patients were enrolled in the study (mean age, 64 years; age range, 42–74 years; male/female ratio, 10/5; ECOG performance status 0/1 ratio, 6/9). Immunohistochemical staining of tumor biopsy specimens revealed that the proportion of CD44v-positive cells was >10% in 9 patients before SASP treatment. No DLT was observed in the first three patients treated at SASP dose level 1 (500 mg TID) or those treated at dose level 2 (1000 mg TID). At dose level 3 (1500 mg TID), two of three patients experienced a DLT (anorexia of grade 3). We enrolled additional patients at dose level 2 and two of the total of five patients treated at this dose level experienced DLTs (hypotension or pneumonitis, each of grade 3). To confirm the safety of dose level 1, we enrolled additional patients at this dose level and one of the total of six patients treated at this dose level experienced DLTs (AST and ALT elevation, each of grade 3). Exposure of SASP following oral administration varied markedly among individuals according to ABCG2 and NAT2 genotypes as previously reported.
Conclusion:
SASP 500 mg TID was the recommended dose when administered with CDDP plus PEM.
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P3.05 - Poster Session with Presenters Present (ID 475)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Palliative Care/Ethics
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.05-007 - Prospective Evaluation for Combination Antiemetic Therapy on CINV in NSCLC Receiving Carboplatin-Based Chemotherapy of MEC (ID 3737)
14:30 - 14:30 | Author(s): T. Seto
- Abstract
Background:
The incidence of delayed chemotherapy-induced nausea and vomiting (CINV) for non-small cell lung cancer (NSCLC) patients receiving carboplatin (CBDCA) -based chemotherapy (CBDCA+pemetrexed (PEM) / CBDCA+ paclitaxel (PTX)) has not been clearly controlled.
Methods:
We used the combined data from the two prospective observational studies; A nationwide survey of CINV study group and the other prospective observational study in Japan. We assessed whether delayed CINV were controlled with combination antiemetic treatment. We also evaluate risk factors by logistic regression analysis.
Results:
A total of 240 patients were evaluable in this study. The median age was 66 (range:34-82) with 173 males and 67 females. Three antiemetics were used in 54 (22.5%) patients. Delayed nausea and vomiting were experienced more commonly in women than in men. Delayed nausea was well controlled with 3 antiemetics than with 2 antiemetics for women (45.0% vs. 72.3%; P=0.0506). Delayed vomiting was well controlled with 3 antiemetics than with 2 antiemetics for overall (11.1% vs. 23.1%; P=0.0571) and for women (20.0% vs. 44.7%; P=0.0962). We identified several risk factors; women (OR=2.903 ;95% confidence interval [CI], 1.607-5.242 ;P=0.0004) and age (OR=0.968 ;95%CI, 0.938-0.999 ;P=0.0442) for delayed nausea, and women (OR=4.252 ;95%CI, 2.154-8.394 ;P<0.0001) and 2 antiemetics (OR=3.140 ;95%CI, 1.205-8.179 ;P=0.0192) for delayed vomiting.
Conclusion:
Three antiemetics combination are encouraged for NSCLC patients treated with CBDCA-based chemotherapy to alleviate delayed vomiting.
