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      Neoadjuvant anti-programmed Death-1 immunotherapy by Pembrolizumab in resectable nodal positive stage II/IIIa non-small-cell lung cancer (NSCLC): the NEOMUN trial

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          Abstract

          Background

          Immunotherapies targeting the PD1/PD-L1 pathway have had a large impact on the treatment of advanced NSCLC. Concerning multimodality tumor therapy, only few trials until today have been performed investigating neoadjuvant treatment with anti PD-1 immunotherapy prior to curative intent surgery. Aim of the NEOMUN investigator initiated trial (EudraCT-Number: 2017–000105-20; ClinicalTrials.gov Identifier: NCT03197467) is to assess feasibility and safety of pre-surgical anti PD-1 treatment in order to improve long term survival.

          Methods

          The study is designed as an open-label, single arm, prospective, monocenter, phase II study including 30 patients with NSCLC stage II/IIIA suitable for curative intent surgery. Investigational drug is Pembrolizumab. After 2 cycles of immunotherapy (à 200 mg q3w i.v.), tumor resection with lobectomy or bilobectomy will be performed. Primary objectives are to assess the feasibility and safety of a neoadjuvant immunotherapy and to assess antitumor activity of Pembrolizumab with regard to clinical and pathological tumor response. Secondary objective is disease free and overall survival. Exploratory objective is to analyze potential predictive biomarkers and to evaluate the therapeutic efficacy of Pembrolizumab by extended immune cell and cytokine analysis of tumor tissue.

          The study protocol was approved by the local ethics committee and the federal authority. Start of patient enrollment is scheduled for June 2018.

          Discussion

          The NEOMUN trial will be one of the first clinical trials investigating a multimodal treatment strategy including neoadjuvant immunotherapy using Pembrolizumab as an investigational drug. Assessing the safety and therapeutic potential of neoadjuvant immunotherapy in connection with lung surgery will be of great interest for thoracic surgeons.

          Trial registration

          Prospectively, the NEOMUN study has been registered on www.clinicaltrials.gov; NCT03197467 (first post: June 23rd, 2017).

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          Most cited references16

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          Non-small-cell lung cancer.

          In the decade since the last Lancet Seminar on lung cancer there have been advances in many aspects of the classification, diagnosis, and treatment of non-small-cell lung cancer (NSCLC). An international panel of experts has been brought together to focus on changes in the epidemiology and pathological classification of NSCLC, the role of CT screening and other techniques that could allow earlier diagnosis and more effective treatment of the disease, and the recently introduced seventh edition of the TNM classification and its relation to other prognostic factors such as biological markers. We also describe advances in treatment that have seen the introduction of a new generation of chemotherapy agents, a proven advantage to adjuvant chemotherapy after complete resection for specific stage groups, new techniques for the planning and administration of radiotherapy, and new surgical approaches to assess and reduce the risks of surgical treatment. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Trends in stage distribution for patients with non-small cell lung cancer: a National Cancer Database survey.

            We examined the recent changes in stage distribution in newly diagnosed patients with non-small cell lung cancer (NSCLC) using a national database to assess the impact of recent advances in imaging modalities. We searched the National Cancer Database for patients with NSCLC diagnosed between the calendar years 1998 and 2006 for which staging information was available. Among the 877,518 patients diagnosed with NSCLC during the study period, staging information was available for 813,302 patients (92.6%). We observed a change in stage distribution between the years 2000 and 2001, with a decrease in stage I, from 27.5 to 24.8%, and a corresponding increase in stage IV, from 35.4 to 38.8%. No significant changes in stage distribution were noted after 2002. Our study showed a recent and significant stage migration in patients with NSCLC. It is likely that increased acceptance and widespread use of (18)fluorodeoxyglucose-positron emission tomography scan and routine brain imaging could account for these changes.
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              Long-term results of the international adjuvant lung cancer trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer.

              PURPOSE Based on 5-year or shorter-term follow-up data in recent randomized trials, adjuvant cisplatin-based chemotherapy is now generally recommended after complete surgical resection for patients with non-small-cell lung cancer (NSCLC). We evaluated the results of the International Adjuvant Lung Cancer Trial study with three additional years of follow-up. PATIENTS AND METHODS Patients with completely resected NSCLC were randomly assigned to three or four cycles of cisplatin-based chemotherapy or to observation. Cox models were used to evaluate treatment effect according to follow-up duration. Results The trial included 1,867 patients with a median follow-up of 7.5 years. Results showed a beneficial effect of adjuvant chemotherapy on overall survival (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.02; P = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there was a significant difference between the results of overall survival before and after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P = .006 for interaction. Similar results were observed for disease-free survival. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06). CONCLUSION These results confirm the significant efficacy of adjuvant chemotherapy at 5 years. The difference in results beyond 5 years of follow-up underscores the need for the long-term follow-up of other adjuvant lung cancer trials and for a better identification of patients deriving long-term benefit from adjuvant chemotherapy.
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                Author and article information

                Contributors
                florian.eichhorn@med.uni-heidelberg.de
                laura.klotz@med.uni-heidelberg.de
                helge.bischoff@med.uni-heidelberg.de
                michael.thomas@med.uni-heidelberg.de
                Felix.Lasitschka@med.uni-heidelberg.de
                Hauke.Winter@med.uni-heidelberg.de
                hans.hoffmann@tum.de
                +496221 396 1101 , martin.eichhorn@med.uni-heidelberg.de
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                2 May 2019
                2 May 2019
                2019
                : 19
                : 413
                Affiliations
                [1 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Department of Thoracic Surgery, , Thoraxklinik, Heidelberg University, ; Roentgenstraße 1, 69126 Heidelberg, Germany
                [2 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Institute of Pathology, Heidelberg University, ; Heidelberg, Germany
                [3 ]ISNI 0000000123222966, GRID grid.6936.a, Divison of Thoracic Surgery, , Technical University of Munich, ; Munich, Germany
                [4 ]Translational Lung Research Center (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany
                [5 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Department of Thoracic Oncology, , Thoraxklinik, Heidelberg University, ; Heidelberg, Germany
                Article
                5624
                10.1186/s12885-019-5624-2
                6498462
                31046714
                4d028142-6312-4d84-8d03-024af0e7c05b
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 23 July 2018
                : 18 April 2019
                Funding
                Funded by: Oncology Merck Investigator Studies Program (MISP), MSD SHARP & DOHME GMBH, Germany
                Award ID: MISP 52887
                Award Recipient :
                Categories
                Study Protocol
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                nsclc,neoadjuvant immunotherapy,checkpoint inhibitor,thoracic surgery,pembrolizumab

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