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W. Eberhardt

Moderator of

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    ED10 - Locally Advanced NSCLC: State-of-the-Art Treatment (ID 279)

    • Event: WCLC 2016
    • Type: Education Session
    • Track: Locally Advanced NSCLC
    • Presentations: 4
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      ED10.01 - Chemoradiotherapy of Stage III NSCLC (ID 6481)

      16:00 - 17:30  |  Author(s): F. Mornex

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ED10.02 - The Role of Surgery in Stage III NSCLC (ID 6482)

      16:00 - 17:30  |  Author(s): W. Klepetko

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease characterized by either locally advanced tumor infiltration and/or mediastinal lymph node involvement. Due to improvements in chemo (CT)- and combined chemoradiation (CRT) therapy protocols, patients with locally advanced stage III NSCLC become potential candidates for curative resection more frequently. According to the TNM-7 classification, stage III NSCLC can be defined by the following T and N subsets: stage IIIA: T3 N1-2, T4 N0-1, T1-2 N2; stage IIIB: T4 N2, T1-4 N3. Five-year survival of stage III is generally around 25% taken all different therapy strategies together. Several studies have shown that induction treatment before surgery is beneficial in resectable cases and selected patients undergoing radical resection may have encouraging 5-year survival rates up to 60%. However, to date, no worldwide consent exists on the general role of surgery in curative attempt. Furthermore, it is still unclear if resectable patients might have greater benefit from induction CT compared to combined induction CRT and if concomitant CRT should be preferred over a sequential treatment. Only a small number of prospective phase II/III trials are available addressing these issues. A phase III trial comparing induction CRT plus surgery (S) with definitive CRT in patients with stage IIIA/N2 published in 2009 has questioned the role of surgery since there was no difference in overall survival (OS) between the two groups [1]. However, the 30-day mortality was unacceptably high (26%) in the subgroup of patients undergoing pneumonectomy and thus patients with CRT and lobectomy had significantly improved OS compared to those with CRT alone. Moreover, several other retrospective series have reported encouraging long-term survival in selected patients undergoing induction treatment followed by radical surgery. The benefit of adding sequential RT to CT prior to surgery (S) in stage IIIA/N2 has been investigated in a recent phase III trial [2]. Patients undergoing CRT/S had a non-significant superior median OS of 37 months compared to 26 months with CT/S. Both groups had similar disease free survival (DFS) and it was concluded that RT did not add any benefit to induction CT prior to surgery. However, those with CRT/S had an objective response, pathological complete response, a R0 resection rate and a mediastinal downstaging more frequently and less local progression compared to CT/S. The question whether to apply RT concomitantly or sequentially to CT has been investigated in a recent meta-analysis [3]. Pooled data from six prospective trials suggested that concomitant CRT, as compared with sequential CRT, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control. However, these patients were treated without surgery and caution should be taken when transferring these conclusions to the neoadjuvant setting before surgery. From the surgical point of view, patients with local tumor invasion (T3-4 N0-1 including Pancoast tumors) have to be treated by different oncological principles than those with mediastinal lymph node (LN) involvement (N2). In patients with T3 tumors invading the chest wall, diaphragm, mediastinal pleura, phrenic nerve or parietal pericardium and N1 involvement, primary resection can be undertaken. Induction therapy may improve local control rates in larger tumors but it remains unclear if systemic treatment is beneficial prior to or after local resection. Intraoperative frozen section of resection margins should be mandatory and reconstruction of resected structures with synthetic material may be necessary. T4 tumors with invasion to the mediastinal structures or vertebral bodies are a unique subset of locally advanced NSCLC and multidisciplinary treatment can be challenging. Well selected patients may benefit from multimodality therapy including surgery and should be treated in well experienced centers [4, 5]. In patients with suspected N2 disease, invasive staging for histological confirmation has been widely accepted as a standard procedure [6]. In case of multilevel and/or bulky N2 disease, surgery should be avoided due to the expected poor outcome. However, it has been well shown that patients in good performance status with single or two level N2 disease with good response after induction therapy may have improved OS when undergoing curative resection [7, 8]. On the other hand, patients with persistent N2 disease after induction treatment tend to have worse OS and high recurrence rates and thus should not undergo surgery. This finding strengthens the impact of invasive re-staging after induction treatment as proposed by recent staging guidelines. In conclusion, selected patients with stage III NSCLC may have beneficial outcome after surgery combined with CT or CRT. However, this holds truth only for cases with response to induction treatment, nodal downstaging and when R0 resection is deemed achievable. Surgery should be avoided in patients with multilevel/bulky N2 disease or persistent mediastinal LN after induction treatment due to the expected poor outcome. The optimal sequence and modality of induction treatment has yet to be defined in larger prospective trails. References [1] Albain KS, Swann RS, Rusch VW, Turrisi AT, Shepherd FA, Smith C, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374:379-86. [2] Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386:1049-56. [3] Aupérin A, Le Péchoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:2181-90. [4] Collaud S, Fadel E, Schirren J, Yokomise H, Bolukbas S, Dartevelle P, et al. En Bloc Resection of Pulmonary Sulcus Non-small Cell Lung Cancer Invading the Spine: A Systematic Literature Review and Pooled Data Analysis. Ann Surg. 2015;262:184-8. [5] Rusch VW. Management of Pancoast tumours. Lancet Oncol. 2006;7:997-1005. [6] De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. 2014;45:787-98. [7] Friedel G, Budach W, Dippon J, Spengler W, Eschmann SM, Pfannenberg C, et al. Phase II trial of a trimodality regimen for stage III non-small-cell lung cancer using chemotherapy as induction treatment with concurrent hyperfractionated chemoradiation with carboplatin and paclitaxel followed by subsequent resection: a single-center study. J Clin Oncol. 2010;28:942-8. [8] Hancock J, Rosen J, Moreno A, Kim AW, Detterbeck FC, Boffa DJ. Management of clinical stage IIIA primary lung cancers in the National Cancer Database. Ann Thorac Surg. 2014;98:424-32; discussion 32.

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      ED10.03 - New Developments in Radiotherapy of Stage III NSCLC (ID 6483)

      16:00 - 17:30  |  Author(s): J. Jassem

      • Abstract
      • Presentation
      • Slides

      Abstract:
      NSCLC accounts for 80-85% of all lung cancers, and stage III disease constitutes about 40% of the total cases. The main treatment modality in these patients is radiotherapy, usually combined with concurrent chemotherapy. Five-year overall survival in stage III disease is merely 10-15%. Radiotherapy of thoracic tumors poses several challenges, such as tissue heterogeneity, tumor and organ motion and changing anatomy over the treatment course. Main approaches addressing these problems include dose intensification, altered fractionation and advanced radiotherapy techniques. Until recently, dose escalation was considered the main means to increase radiotherapy efficacy. Despite encouraging results of phase I–II studies, the results of recent RTOG trial 0617 were disappointing (1). This study compared high-dose radiotherapy (74 Gy/37 fractions) to a standard-dose (60 Gy/30 fractions) concurrently with weekly paclitaxel/carboplatin, with or without cetuximab. Surprisingly, median overall survival in the high-dose arms was significantly shorter (20 months vs. 29 months in the standard-dose arms; p=0.004) (1). It was speculated that the inefficacy of high-dose radiotherapy could be due to long overall treatment time and accelerated tumor repopulation. Shortening treatment time may be accomplished by accelerated radiotherapy. A phase III study investigating continuous hyperfractionated accelerated radiotherapy (CHART; 54 Gy/36 fractions of 1.5 Gy delivered 3 times daily over 12 consecutive days) showed increased efficacy compared to conventional fractionation (2). A CHARTWEL study, using the same fractionation but with weekend breaks, was not superior to conventional fractionation (3). A meta-analysis of 10 trials (2000 patients) demonstrated an absolute 5-year survival benefit of 2.5% with hyperfractionated and/or accelerated radiotherapy over conventional fractionation, at the expense of significantly increased grade 3–4 acute esophagitis (4). Important developments in lung radiotherapy represent new imaging techniques. PET-CT, currently a routine procedure, allows better patient selection for radical radiotherapy and facilitates selective irradiation of involved volumes (5). Image guided radiation therapy (IGRT), such as daily volumetric kilovoltage cone-beam computed tomography (CBCT), provides actual positional information, allowing for online repositioning and more precise tumor localization. Image-guided adaptive radiotherapy (IGART) additionally accounts for changes and deformations occurring during the radiotherapy course, thus allowing treatment re-planning (6). Currently, dose delivery in NSCLC is commonly accomplished by intensity modulated radiotherapy (IMRT). This technique improves the conformality of radiotherapy by modulating the radiation beam intensity profile, and allows decreasing the mean lung dose, particularly in patients with larger tumor volumes (7). The problem of intrafraction motion in thoracic malignancies has been traditionally managed by extension of treatment margins, leading to excessive radiation to normal tissues. Currently, tumor motion may be managed individually by respiratory-correlated 4-dimensional CT (4DCT) based on the acquisition of organ and tumor imaging data at extreme phases of the breathing cycle. An innovative option allowing for safe dose intensification is isotoxic therapy (8). This approach includes dose prescription defined by the maximal doses achievable to normal tissues. More recently, several clinical studies investigated the role of proton beam therapy in NSCLC. A dosimetric advantage of proton- over conventional photon radiotherapy is mediated by its unique properties: low doses upon tissue penetration, maximal dose deposition towards the end of the beam’s path (Bragg peak) and finite range with minimal dose beyond the tumor. Retrospective data and phase II studies suggested promising survival rates, and reduced pulmonary and esophageal toxicity with protons. However, the results of recent phase III trial did not confirm the superiority of this method over IMRT (9). In summary, recent diagnostic and therapeutic advances the use of radiation in stage III NSCLC allow for more accurate treatment planning, more precise dose delivery and managing tumor and organ motion. Some of these developments have been adopted in clinical practice, despite relatively few evidence of their advantages in terms of better local control and survival. The paucity of phase III trials testing new radiotherapy approaches is partly due to relying on better dose distribution and reduced exposure of normal tissues, making comparisons with less advanced techniques an ethical dilemma (10). References 1. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16:187-99. 2. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. Lancet 1997;350:161–5. 3. Baumann M, Herrmann T, Koch R, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97–1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol 2011;100:76–85. 4. Mauguen A, Le Pe´choux C, Saunders MI, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol 2012;30:2788–97. 5. Chang JY, Dong L, Liu H, et al. Image-guided radiation therapy for non-small cell lung cancer. J Thorac Oncol 2008;3:177–86. 6. Sonke JJ, Belderbos J. Adaptive radiotherapy for lung cancer. Semin Radiat Oncol 2010;20:94-106. 7. Bezjak A, Rumble RB, Rodrigues G, and al. Intensity-modulated radiotherapy in the treatment of lung cancer. Clin Oncol 2012;24:508–20. 8. De Ruysscher D, van Baardwijk A, Steevens J, et al. Individualised isotoxic accelerated radiotherapy and chemotherapy are associated with improved long term survival of patients in stage III NSCLC: a prospective population-based study. Radither Oncol 2012;102:228-233. 9. ZX Liao, J. JJ Lee, R Komaki, et al. Bayesian randomized trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non-small cell lung cancer. J Clin Oncol 2016;34(15S):435s. 10. Dziadziuszko R, Jassem J. Randomized clinical trials using new technologies in radiation oncology: ethical dilemma for medicine and science. J Thor Oncol 2007;7:3-4.

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      ED10.04 - New Developments for Systemic Therapies in Stage III NSCLC (ID 6484)

      16:00 - 17:30  |  Author(s): E.E. Vokes

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Concomitant chemoradiotherapy is currently the most widely accepted standard of care for patients with locoregionally advanced NSCLC. Induction chemotherapy represents an evidence-based alternative and is a particular attractive prior to surgery in patients with marginally resectable disease (1). Over the past two decades, the regimens of cisplatin and etoposide and carboplatin and paclitaxel with concurrent radiotherapy, respectively have been most widely used, with cisplatin and vinorelbine with radiotherapy as possible alternative. More recently interest in the cisplatin/pemetrexed/radiotherapy combination has gained interest based on the superior toxicity and efficacy profile of this regimen in the stage IV setting for patients with non-squamous cell malignancies (2). In addition, it is possible to administer this combination of drugs at systemic doses together with radiotherapy (3). In the randomized phase III PROCLAIM study, this regimen was directly compared with etoposide and cisplatin. The goal of this trial was to establish superiority of this regimen. The trial was closed prior to full enrollment with approximately 300 patients per arm evaluated, due to futility for superiority. Median survival for both study groups was very similar at 26.8 and 25.0 months, respectively and better than statistically assumed (4). Additional chemoradiotherapy regiments of current interest include the addition of the PARP inhibitor veliparib to chemoradiotherapy as recently presented (5). Over the last decade, systemic therapy for patients with metastatic lung cancer has been transformed through the use of tumor mutation analyses and targeted therapies as well as the emergence of immune-oncology. However, application of these strategies to the stage III setting has been slow and no definitive data exist currently to support these strategies in the curative intent setting. The addition of cetuximab to chemoradiotherapy did not result in a survival benefit in RTOG 0612 (6). There are, however several ongoing trials that will be described, including RTOG 1306-Alliance 31101. In this trial patients with EGFR mutation or an alk translocation are randomized to either induction chemotherapy with the appropriate targeted agent (erlotinib and crizotinib, respectively) followed by concurrent chemoradiotherapy or concurrent chemoradiotherapy alone. This trial is actively accruing patients. Regarding immune-oncology, a trial evaluating a liposome-based MUC vaccine (tecemotide) has been completed. MUC1 is a mucinous glycoprotein that is overexpressed and aberrantly glycosylated in NSCLC and a vaccination strategy was supported by preclinical studies as well as clinical data in a stage III subgroup analysis of an earlier exploratory trial. Butts et al (7) reported on a randomized trial in which patients completing locoregional sequential or concurrent therapy were randomized to placebo versus tecemotide vaccination therapy reporting a trend for improved overall survival that was statistically significant in the subset analysis of patients receiving concurrent radiotherapy as their primary therapy. Further investigations of this agent however were halted following emergence of additional negative data from a Japanese phase II trial that remains unpublished. Regarding PD-1 or PD-L1 inhibitors, trials have recently been activated investigating the addition of such agents in the consolidation setting following primary treatment of patients with unresectable SCLC. For example, in the ‘Pacific’ trial patients are randomized in a 2-1 fashion to durvalumab for up to 12 months or placebo. In the Alliance, a trial looking at induction chemotherapy with atezolizumab is currently in the process of activation. Here patients will receive induction chemotherapy with atezolizumab for up to four cycles followed by concurrent chemoradiotherapy and additional adjuvant immune therapy. These strategies are well supported by preclinical data showing irradiation upregulating PD1 expression on myeloid and tumor cells and synergistic amplification of radiation antitumor effects by PD-L1 blockade (8). Updated information on these trials and relevant preclinical data will be presented. References: 1. Schild SE, Vokes EE. Pathways to improving combined modality therapy for stage III nonsmall-cell lung cancer. Ann Oncol 2016 Apr;27(4):590-9. 2. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. 3. Govindan R, Bogart J, Stinchcombe T, Wang X, Hodgson L, Kratzke R, Garst J, Brotherton T, Vokes EE. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol. 2011 Aug 10;29(23):3120-5. 4. Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. 5. Cristea MC, Miao, J, Argiris A, Chen AM, Daly ME, Decker RH, Garland LL, Wang D, Koczywas M, Moon J, Kelly K, Gandara DR. SWOG S1206: A dose-finding study of veliparib added to chemoradiotherapy with carboplatin and paclitaxel for unresectable stage III non-small cell lung cancer. J Clin Oncol. 2016 34:(suppl; abstr 8537). 6. Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. 7. Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, Nawrocki S, Ciuleanu TE, Bosquée L, Trigo JM, Spira A, Tremblay L, Nyman J, Ramlau R, Wickart-Johansson G, Ellis P, Gladkov O, Pereira JR, Eberhardt WE, Helwig C, Schröder A, Shepherd FA; START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Jan;15(1):59-68. 8. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014 Feb;124(2):687-95.

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Author of

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    MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA08.02 - Clinical Research Platform into Molecular Testing, Treatment, Outcome (CRISP): A Prospective German Registry in Stage IV NSCLC AIO-TRK-0315 (ID 5911)

      11:00 - 12:30  |  Author(s): W. Eberhardt

      • Abstract
      • Presentation
      • Slides

      Background:
      Treatment in non-small cell lung cancer is quickly evolving and new agents make it to the routine practice at a rapid pace. Whether outcome and PRO data generated in clinical trials with often narrow inclusion and exclusion criteria will hold up in the routine practice is of high interest, especially due to the increasing costs of new drugs. Therefore registry data are of ever increasing importance to patients, physicians and reimbursement institutions.

      Methods:
      Therefore, we have started a prospective, clinical registry for patients with metastatic non-small cell lung cancer. The purpose of CRISP is to set up a national clinical research platform to document representative data on molecular testing, sequences of systemic therapies and other treatment modalities, course of disease in patients with advanced or metastatic NSCLC in Germany not amenable to curative treatment. A particular focus is on molecular biomarker testing of patients before the start of first-line treatment. The data shall be used to assess the current state of care and to develop recommendations concerning topics that could be improved. PRO assessment will provide large-scale data on quality of life and anxiety/depression for real-life patients in routine practice. In addition, two questionnaires (concerning individual quality of life and patient-caregiver communication) will be validated in German patients with metastatic NSCLC. Furthermore CRISP will set up a decentral tissue annotation for future collaborative, investigational scientific biomarker testing.

      Results:
      This study will be carried out in up to 150 representative cancer centers in all therapeutic sectors in Germany. More than 8000 patients will be recruited and followed up to a maximum of 3 years, respectively until death. The first patients have been included as of December 2015. As of yet, 82 centers have been initiated, 211 patients have been recruited. Preliminary data will be presented at the meeting in terms of molecular test rates, demographic data as well as treatment stratification in the 1[st] line setting.

      Conclusion:
      The registry CRISP will be the first to present representative real life data, covering all treatment settings of patients with NSCLC in Germany. ClinicalTrials.gov Identifier: NCT02622581 CRISP is supported by Grants from AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Celgene GmbH, MSD Sharp & Dohme GmbH, Novartis Pharma GmbH, and Pfizer Pharma GmbH.

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    P1.07 - Poster Session with Presenters Present (ID 459)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      P1.07-003 - A Phase II Study Evaluating the Combination of Everolimus with Carboplatin/Paclitaxel as 1st Line Treatment in Patients with Advanced LCNEC (ID 4370)

      14:30 - 15:45  |  Author(s): W. Eberhardt

      • Abstract
      • Slides

      Background:
      Approximately 3% of all lung cancers are made up of large cell neuroendocrine carcinoma of the lung (LCNEC). These tumors in general have a bad prognosis and currently there are only very limited treatment options, including platinum derivatives and etoposide. The PI3/AKT/mTOR pathway is known to be dysregulated in neuroendocrine tumors (NETs). Since the mTOR inhibitor RAD001 (everolimus) already has proven effectiveness in different types of NETs, we tested whether everolimus might be also an effective treatment option in advanced LCNEC patients.

      Methods:
      In this multi-center, open-label, phase II study, everolimus was combined with platin-based chemotherapy in patients with histologically confirmed stage IV LCNEC according to WHO criteria. Further inclusion criteria were measurable disease according to RECIST 1.1 and adequate bone marrow, renal, and liver function. Main exclusion criteria were symptomatic CNS metastases and prior treatment for advanced LCNEC. Enrolled patients received everolimus once a day in combination with 4 cycles of carboplatin and paclitaxel, followed by daily everolimus maintenance therapy. The primary objective was to evaluate the efficacy by assessing the proportion of progression-free patients after three months of treatment.

      Results:
      Ten German trial sites enrolled altogether 49 patients (mean age: 62 ± 9 years; 71% men). The primary endpoint (proportion of pts progression-free at month 3) was achieved by 24 patients (49%), assessed by an independent central imaging reviewer. Further efficacy evaluation showed an overall response rate (ORR) until month 3 of 45%, a disease control rate (DCR) until month 3 of 73.5%, a median progression-free survival (PFS) of 4.3 months, and a median overall survival (OS) of 9.8 months. At least one toxicity occurred in 86% of all enrolled patients with grade 3/4 toxicities in 51%. Most frequent toxicities were diarrhea, fatigue, anemia, and neutropenia.

      Conclusion:
      The results show that a combined therapy of carboplatin and paclitaxel with the mTOR inhibitor everolimus is an alternative treatment option for LCNEC patients. When comparing to other trials, the effectiveness is comparable to a treatment regimen of cisplatin and etoposide.

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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
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      P3.02b-025 - Rapid and Highly Sensitive EGFRdelEx19 and KRAS Exon 2 Mutation Detection in EBUS-TBNA Specimen of Lung Adenocarcinoma (ID 4000)

      14:30 - 15:45  |  Author(s): W. Eberhardt

      • Abstract

      Background:
      First-line treatment with afatinib prolongs overall survival in patients with metastatic non-small-cell lung cancer (NSCLC) harboring EGFR exon 19 deletion mutations. Conversely, somatic KRAS mutations are negative predictors for benefit from EGFR-targeting agents. Rapid availability of these biomarker results is mandatory to prevent delayed or inferior treatments. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is well-established for lung cancer diagnosis and staging. Next generation sequencing (NGS) via targeted resequencing allows simultaneous interrogation for multiple mutations, but has its limitations based on the amount of tumor tissue required and assay times. RT-PCR using Light-Cycler technology (LC-RTPCR) is a rapid and sensitive assay to detect somatic mutations in various tissues from NSCLC patients. The study’s aim was to analyze if LC-RTPCR is feasible for rapid EGFRdelEx19 and KRAS Exon 2 mutation detection in EBUS-TBNA samples and to compare results with results obtained via standard NGS mutation analyses.

      Methods:
      48 surplus EBUS-TBNA samples (38 lymph nodes, 10 primary tumor) from 47 patients with pulmonary adenocarcinoma were analyzed. Two samples were collected per lymph node. One was used for routine cytology, the other was freshly frozen (ff). DNA from ff-biopsies was extracted using Genomic DNA buffer set (QIAgen, Germany). Mutation analysis by LC-RTPCR was conducted as previously described. NGS was performed on MiSeq (Illumina) via targeted resequencing using a customized multiplex-PCR panel covering 36 exons from 11 genes. Mutations were annotated with a minimum frequency of 2%. Processing time was approximately 4 days for NGS and 2 hours for LC-RTPCR analyses.

      Results:
      NGS of EBUS-TBNA samples was technically feasible for both markers in 22 (46%) samples, for EGFR testing in 32 (67%) samples, and for KRAS in 23 (48%) samples. EGFRdelEx19 mutations were detected in four (8.3% of intention-to-screen), and KRAS Exon 2 mutations in 15 cases (31%) cases. LC-RTPCR was technically feasible in all cases. All mutations detected by NGS were also detected by LC-RTPCR. LC-RTPCR detected three additional KRAS Exon 2 mutations and three additional EGFRdelEx19 mutations. NGS detected additional mutations in 4 cases (2 EGFR Exon 21, 1 KRAS Codon 61, 1 PIK3CA).

      Conclusion:
      LC-RTPCR is a rapid, highly sensitive method to detect mutations of immediate therapeutic relevance, such as EGFRdelEx19 and KRAS Exon 2 mutations, in limited EBUS-TBNA specimens from metastatic NSCLC patients. It is of value as rapid and sensitive initial assay in a two-step diagnostic process for first-line treatment decision, incorporating broader biomarker panels as second step.

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    SC25 - The Role of Surgeons in Multimodality Clinical Trials (ID 349)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Surgery
    • Presentations: 1
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      SC25.04 - The Importance of Cooperation: The Essen Experience (ID 6708)

      11:00 - 12:30  |  Author(s): W. Eberhardt

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    SH04 - WCLC 2016 Scientific Highlights - Screening, Radiology, Staging, Pulmonology (ID 486)

    • Event: WCLC 2016
    • Type: Scientific Highlights
    • Track: Radiology/Staging/Screening
    • Presentations: 1
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      SH04.02 - Radiology/Staging (ID 7127)

      07:30 - 08:30  |  Author(s): W. Eberhardt

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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