Publications by authors named "Rudolf M Huber"

89 Publications

Screening for lung cancer in individuals who never smoked: An IASLC Early Detection and Screening Committee Report.

J Thorac Oncol 2021 Aug 26. Epub 2021 Aug 26.

Division of Respiratory Medicine and Thoracic Oncology, Department of Internal Medicine V, Thoracic Oncology Centre Munich, University of Munich - Campus Innenstadt, Munich, Germany.

Screening with Low-dose computed tomography (LDCT) of high-risk individuals with a smoking history reduces lung cancer mortality. Current screening guidelines and eligibility criteria can miss over 50% of lung cancers, and in some geographical areas, like East Asia, a large proportion of the missed lung cancers are in never-smokers. Although randomized trials demonstrated the benefits of screening for people who smoke, these trials generally excluded never-smokers. Thus, the feasibility and effectiveness of lung cancer screening of individuals never -smoked is uncertain. Several known and suspected risk factors for lung cancers in never-smokers such as exposure to secondhand smoke, occupational carcinogens, radon, air pollution, and pulmonary diseases, such as COPD and interstitial lung diseases and intrinsic factors, such as age are well noted. In this regard, knowledge of risk factors may make possible quantification and prediction of lung cancer risk in never-smokers. It is worth considering if and how never-smokers could be included in population-based screening programs. As the implementation of these programs is challenging in many countries due to multiple factors and the epidemiological differences by global regions, these issues will need to be evaluated in each country taking into account various factors, including accuracy of risk assessment and cost-effectiveness of screening in never-smokers. This report aims to outline current knowledge about risk factors for lung cancer in never-smokers, to propose research strategies for this topic, and initiate a broader discussion about lung cancer screening of never-smokers. Similar considerations can be made in current and ex-smokers, which don't fulfill the current screening inclusion criteria, but otherwise are at increased risk. Although screening of never-smokers may in the future be effectively conducted, current evidence to support widespread implementation of this practice is lacking.
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http://dx.doi.org/10.1016/j.jtho.2021.07.031DOI Listing
August 2021

Correction to: Treatment Sequencing for Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer.

Drugs 2021 Jun;81(9):1131

Division of Respiratory Medicine and Thoracic Oncology, Department of Internal Medicine V and Thoracic Oncology Centre Munich (TOM), Hospital of the University of Munich (LMU), Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Medizinische Klinik, Ziemssenstraße 1, 80336, Munich, Germany.

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http://dx.doi.org/10.1007/s40265-021-01536-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217020PMC
June 2021

New developments in locally advanced nonsmall cell lung cancer.

Eur Respir Rev 2021 Jun 5;30(160). Epub 2021 May 5.

Dept of Radiation Oncology and Palliative Medicine, University of Würzburg, Würzburg, Germany.

Locally advanced nonsmall cell lung cancer, due to its varying prognosis, is grouped according to TNM stage IIIA, IIIB and IIIC. Developments over the last 3 years have been focused on the integration of immunotherapy into the combination treatment of a locally definitive therapy (surgery or radiotherapy) and chemotherapy. For concurrent chemoradiotherapy, consolidation therapy with durvalumab was established. Adjuvant targeted therapy has again gained increasing interest. In order to adapt treatment to the specific stage subgroup and its prognosis, fluorodeoxyglucose positron emission tomography/computed tomography and pathological evaluation of the mediastinum are important. Tumours should be investigated for immunological features and driver mutations. Regarding toxicity, evaluation of pulmonary and cardiac function, as well as symptoms and quality of life, is of increasing importance. To improve the management and prognosis of this heterogeneous entity, clinical trials and registries should take these factors into account.
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http://dx.doi.org/10.1183/16000617.0227-2020DOI Listing
June 2021

Treatment Sequencing for Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer.

Drugs 2021 Jan;81(1):87-100

Division of Respiratory Medicine and Thoracic Oncology, Department of Internal Medicine V and Thoracic Oncology Centre Munich (TOM), Hospital of the University of Munich (LMU), Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Medizinische Klinik, Ziemssenstraße 1, 80336, Munich, Germany.

Non-small-cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases and is the leading cause of cancer-related deaths. Most NSCLC patients are diagnosed with advanced disease and require systemic treatment. Despite emerging advances in chemotherapy and immunotherapy, the prognosis of stage IV patients remains poor. However, the discovery of oncogenic driver mutations including mutations in the epidermal growth factor receptor (EGFR), the anaplastic lymphoma kinase (ALK) and others, characterize a subset of patients with the opportunity of targeted therapies. Fusions between the ALK and echinoderm microtubule-associated protein-like 4 (EML4) are present in ∼ 3-5% of patients with NSCLC. Several first-, second-, and third-generation ALK tyrosine kinase inhibitors (TKIs) have been developed in the last decade and have tremendously changed treatment options and outcomes of ALK-positive NSCLC patients. With increasing treatment options, treatment sequence decisions have become more and more complex. ALK-mutations, fusion variants, or activation of by-pass pathways result in treatment resistance during the course of treatment in nearly all patients. Mutation-guided treatment sequencing can lead to better outcomes, and re-biopsy or liquid-biopsy should be performed whenever possible in case of disease progression in ALK-rearranged patients. In the future, combinational treatment of ALK TKIs with other pathway-inhibitors might further improve patients' treatment options and outcomes. Here, we review the data for currently available ALK TKIs, discuss approaches of treatment sequencing, and give an outlook on emerging developments.
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http://dx.doi.org/10.1007/s40265-020-01445-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154809PMC
January 2021

Role of the erythropoietin receptor in Lung Cancer cells: erythropoietin exhibits angiogenic potential.

J Cancer 2020 21;11(20):6090-6100. Epub 2020 Aug 21.

Department of Internal Medicine V, Division of Respiratory Medicine and Thoracic Oncology, Ludwig-Maximilians University (LMU), Thoracic Oncology Centre Munich. Comprehensive Pneumology Center Munich, Member of the German Center for Lung Research (DZL), Munich, Bavaria, Germany.

Recombinant human erythropoietin (rHuEPO), a hormone regulating the proliferation and differentiation of erythroid cells, is one of the prescription drugs used to treat cancer-associated anemia. However, administration of rHuEPO to cancer patients has been reported to be associated with decreased survival, and the mechanism by which it acts remains controversial. The present study aimed to investigate the expression of the EPO-receptor in lung cancer cell lines and whether rHuEPO treatment affected its growth and migration. Moreover, the angiogenic effects of rHuEPO were also explored . Expression of the EPO-receptor in lung cancer cell lines was measured by Western blotting and enzyme linked immunosorbent assays (ELISAs). Proliferation of the lung cancer cells was monitored in the presence of rHuEPO. Human umbilical vein endothelial cells (HUVECs) were used for tube formation assays , and transwell migration assays were performed to detect migration under rHuEPO treatment. Matrigel plug technology was employed to observe the angiogenic effects in both nude mice and Matrigel-containing lung cancer cell lines H838 or H1975. Microvessel density (MVD) was measured using CD31 Immunohistochemistry (IHC) staining. EPO-receptor (EPO-R) was only detected in the cell lines H838 and H1339 by ELISA. However, the EPO-R protein was detected in all cell lines by Western blotting, which is in contradiction to the ELISA results. Proliferation and migration were not affected by rHuEPO treatment. However, rHuEPO promoted HUVEC tube formation and significantly induced the formation of new blood vessels . Furthermore, rHuEPO did not antagonize the inhibitory effects of Afatinib (epidermal growth factor receptor-tyrosine kinase inhibitor; EGFR-TKI) in simultaneous treatment with rHuEPO. In a 3D cell co-culture model, rHuEPO did not enhance the secretion of vascular endothelial growth factor (VEGF) in lung cancer cells or human lung fibroblast cell line MRC-5. We have shown that the role of EPO goes beyond erythropoiesis, also playing a strong role in angiogenesis by participating in new blood vessel formation in lung cancer models. Thus, rHuEPO may raise the risk of thrombosis and metastasis . Additionally, our results suggest that studies using commercially available EPO-R antibodies should be reexamined; some of these antibodies may not in fact recognize EPO-R.
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http://dx.doi.org/10.7150/jca.36924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477424PMC
August 2020

Response to Checkpoint Inhibition in Non-Small Cell Lung Cancer with Molecular Driver Alterations.

Oncol Res Treat 2020 8;43(6):289-298. Epub 2020 Apr 8.

Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.

Aims: Non-small cell lung cancer (NSCLC) patients with EGFR mutations do not respond well to checkpoint inhibitors. However, little is known about the activity of immunotherapy in NSCLC with other driver mutations. The increasing use of next-generation sequencing (NGS) leads to molecular findings that face the clinician with problems while choosing the best treatment. This study aims at analyzing response of NSCLC with driver mutations to immunotherapy.

Patients And Methods: We retrospectively included 84 NSCLC patients diagnosed and treated at 2 German tertiary-care lung cancer centers using NGS and treatment with immunotherapy. Response to immunotherapy was analyzed in correlation to molecular findings.

Results: 51 patients harbored at least 1 driver mutation. PIK3CA, EGFR, and STK11 mutations did not respond to immunotherapy. KRAS, TP53, and MET exon 14 skipping mutations responded well. One patient with NF-1 mutation showed durable response.

Conclusions: Molecular testing may be of use in guiding treatment decision making in NSCLC.
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http://dx.doi.org/10.1159/000506842DOI Listing
September 2020

Hedgehog Pathway Activation Might Mediate Pemetrexed Resistance in NSCLC Cells.

Anticancer Res 2020 Mar;40(3):1451-1458

Division of Respiratory Medicine and Thoracic Oncology, Department of Internal Medicine V and Thoracic Oncology Centre Munich (TOM), University of Munich (LMU), Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Munich, Germany

Background/aim: Resistance to chemotherapeutic agents is the main cause of reduced survival in non-small cell lung cancer (NSCLC) patients. The Hedgehog (HH) pathway has been shown to be crucial in cell development and survival. Activated in several types of cancer it might be a potent bypass mechanism mediating chemotherapy resistance.

Materials And Methods: HCC827 NSCLC cells were treated with sub-lethal doses of pemetrexed to produce pemetrexed resistance. RT-qPCR was performed to measure gene expression of HH pathway proteins. A cell growth assay was used to measure the impact of the HH-inhibitor Gant61 in naïve and chemoresistant cell lines.

Results: Pemetrexed resistant cells showed significantly increased expression of HH signaling genes (GLI1, GLI2, GLI3, PTCH1, SHH). Supporting these results, pemetrexed resistant cells treated with the HH inhibitor Gant61 showed reduced proliferation compared to naïve cells.

Conclusion: HH pathway may play an important role in mediating pemetrexed resistance in NSCLC cells. Blocking the HH pathway may be a potential option to overcome this resistance.
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http://dx.doi.org/10.21873/anticanres.14087DOI Listing
March 2020

Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial.

J Thorac Oncol 2020 03 19;15(3):404-415. Epub 2019 Nov 19.

University of Colorado Cancer Center, Aurora, Colorado.

Introduction: We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase-positive NSCLC.

Methods: Patients were randomized 1:1 to take either oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (arm B), stratified by central nervous system (CNS) metastases and best response to crizotinib. The primary end point was investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included independent review committee (IRC)-assessed progression-free survival (PFS), intracranial PFS (iPFS), and overall survival (OS). Exploratory analyses included CNS versus ex-CNS target lesion response and correlation of depth of response with PFS and OS.

Results: Among 222 randomized patients (112 and 110 in arms A and B, respectively), 59 (27%) remained on brigatinib at analysis (median follow-up: 19.6 versus 24.3 months). At baseline, 71% and 67% had brain lesions among A and B arms, respectively. Investigator-assessed confirmed objective response rate was 46% versus 56%. Median IRC-assessed PFS was 9.2 months (95% confidence interval: 7.4-12.8) versus 16.7 months (11.6-21.4). Median OS was 29.5 months (18.2-not reached) versus 34.1 months (27.7-not reached). IRC-confirmed intracranial objective response rate in patients with measurable baseline brain lesions was 50% (13 of 26) versus 67% (12 of 18); median duration of intracranial response was 9.4 versus 16.6 months. IRC-assessed iPFS was 12.8 versus 18.4 months. Across arms, median IRC-assessed PFS was 1.9, 5.5, 11.1, 16.7, and 15.6 months for patients with no, 1%-25%, 26%-50%, 51%-75%, and 76%-100% target lesion shrinkage, respectively. No new safety findings were observed with longer follow-up.

Conclusions: Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. Depth of response may be an important end point to capture in future targeted therapy trials.
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http://dx.doi.org/10.1016/j.jtho.2019.11.004DOI Listing
March 2020

Interdisciplinary multimodality management of stage III nonsmall cell lung cancer.

Eur Respir Rev 2019 Jun 8;28(152). Epub 2019 Jul 8.

Division of Respiratory Medicine and Thoracic Oncology, Dept of Medicine, University of Munich - Campus Innenstadt, and Thoracic Oncology Centre Munich, Member of the German Centre of Lung Research, Munich, Germany.

Stage III nonsmall cell lung cancer (NSCLC) comprises about one-third of NSCLC patients and is very heterogeneous with varying and mostly poor prognosis. It is also called "locoregionally or locally advanced disease". Due to its heterogeneity a general schematic management approach is not appropriate. Usually a combination of local therapy (surgery or radiotherapy, depending on functional, technical and oncological operability) with systemic platinum-based doublet chemotherapy and, recently, followed by immune therapy is used. A more aggressive approach of triple agent chemotherapy or two local therapies (surgery and radiotherapy, except for specific indications) has no benefit for overall survival. Until now tumour stage and the general condition of the patient are the most relevant prognostic factors. Characterising the tumour molecularly and immunologically may lead to a more personalised and effective approach. At the moment, after an exact staging and functional evaluation, an interdisciplinary discussion amongst the tumour board is warranted and offers the best management strategy.
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http://dx.doi.org/10.1183/16000617.0024-2019DOI Listing
June 2019

Defining aggressive or early progressing nononcogene-addicted non-small-cell lung cancer: a separate disease entity?

Future Oncol 2019 Apr 13;15(12):1363-1383. Epub 2019 Feb 13.

Boehringer Ingelheim Pharma GmbH & Co, KG, Germany & Institute of Pharmacology, Johannes Gutenberg-University Mainz, Germany.

A substantial proportion of patients with nononcogene-addicted non-small-cell lung cancer (NSCLC) has 'aggressive disease', as reflected in short time to progression or lack of disease control with initial platinum-based chemotherapy. Recently, clinical correlates of aggressive disease behavior during first-line therapy have been shown to predict greater benefit from addition of nintedanib to second-line docetaxel in adenocarcinoma NSCLC. Positive predictive effects of aggressive disease have since been reported with other anti-angiogenic agents (ramucirumab and bevacizumab), while such features may negatively impact on outcomes with nivolumab in nonsquamous NSCLC with low PD-L1 expression. Based on a review of the clinical data, we recommend aggressive nonsquamous NSCLC should be defined by progression within <6-9 months of first-line treatment initiation.
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http://dx.doi.org/10.2217/fon-2018-0948DOI Listing
April 2019

Successful Treatment of a Patient With NSCLC Harboring an EGFR Mutation and a Concomitant Met Exon 14 Skipping Mutation Combining Afatinib and Crizotinib.

Clin Lung Cancer 2019 01 21;20(1):59-62. Epub 2018 Sep 21.

Department of Internal Medicine V, University of Munich (LMU), Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Munich, Germany.

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http://dx.doi.org/10.1016/j.cllc.2018.09.009DOI Listing
January 2019

Characteristics and treatment of new-onset arthritis after checkpoint inhibitor therapy.

RMD Open 2018 17;4(2):e000714. Epub 2018 Aug 17.

Division of Rheumatology and Clinical Immunology, Department of Internal Medicine IV, Ludwig-Maximilians-University Munich, Munich, Germany.

Immune checkpoint inhibitors (ICIs) may cause immune-related adverse events (IRAEs). Characterisation and data on treatment of musculoskeletal IRAEs are scarce. In this cohort study, patients receiving ICI therapy who experienced arthralgia were evaluated for the presence of synovitis. Data on demographics, ICI regime, time of onset, imaging and response to therapy of synovitis were prospectively collected. Arthritis was demonstrated in 14 of 16 patients of whom 7 showed monarthritis, 5 had oligoarthritis and 2 had polyarthritis. Patients with ICI-induced arthritis were predominantly male (57%) and seronegative (69%). Regarding the detection of synovitis in staging imaging, moderate sensitivity for contrast-enhanced CT with PET-CT as reference was observed. Disease burden at baseline was high and was significantly reduced after anti-inflammatory treatment. Nine patients were treated with systemic and eight patients with intra-articular glucocorticoids. Six patients who flared on glucocorticoid treatment on tapering were given methotrexate resulting in long-term remission. Patients with synovitis were more likely to have good tumour response. Patients with ICI-induced arthritis were predominantly male and seronegative showing different patterns of arthritis with high disease burden. Good efficacy and safety was observed for methotrexate, particularly for ICI-induced polyarthritis.
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http://dx.doi.org/10.1136/rmdopen-2018-000714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109812PMC
August 2018

Pretherapeutic Inflammation Predicts Febrile Neutropenia and Reduced Progression-Free Survival after First-Line Chemotherapy in SCLC.

Oncol Res Treat 2018 8;41(9):506-512. Epub 2018 Aug 8.

Background: Despite initial response to chemotherapy, the prognosis of small cell lung cancer (SCLC) patients is limited. Following first-line therapy, the strongest predictor of durable progression-free survival (PFS) is remission quality. Febrile neutropenia (FN) is a frequent complication after chemotherapy, and its prevention could improve treatment density and degree of remission.

Patients And Methods: We retrospectively analyzed 39 SCLC patients treated at a German tertiary care lung cancer center between 2013 and 2016. We extracted data sets from electronic records and analyzed anthropometric data, pretherapeutic blood values, and prognostic scores. Discriminant analysis was performed to predict FN.

Results: PFS after first-line chemotherapy was significantly shorter in patients with FN (p = 0.003). Pretherapeutic albumin (p = 0.019), C-reactive protein (CRP; p < 0.001), lactate dehydrogenase (p = 0.041), neutrophil-to-lymphocyte ratio (p = 0.009), prognostic nutritional index (p = 0.018), and Glasgow prognostic score (p < 0.001) were significantly associated with FN. CRP in combination with absolute neutrophil count is a strong predictor of FN (positive predictive value 79.8%).

Conclusion: SCLC patients with FN after chemotherapy showed significantly reduced PFS. Prevention of FN may improve treatment results. We identified pretherapeutic markers which can predict FN risk. This simple and cost-effective method could serve to identify the need for preventive measures against FN (e.g., prophylactic antibiotic treatment or granulocyte colony stimulating factor administration).
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http://dx.doi.org/10.1159/000488688DOI Listing
September 2019

Less radiation, same quality: contrast-enhanced multi-detector computed tomography investigation of thoracic lymph nodes with one milli-sievert.

Radiol Med 2018 Nov 30;123(11):818-826. Epub 2018 Jun 30.

Department of Radiology, Klinikum der Universität München, LMU - University of Munich, Ziemssenstrasse 1, 80336, Munich, Germany.

Purpose: Mediastinal, hilar, and peripheral pulmonary lymphadenopathy is a hallmark sign of different benign and malignant diseases of the chest. Contrast-enhanced (CE) chest CT is a test frequently applied to examine thoracic lymph node zones. We attempted to find out whether mediastinal, hilar, and peripheral lymph nodes delineate equally in CE chest CT with reduced dose (CE-LDCT, about 1 mSv) when compared with accepted standard CE chest CT (CE-SDCT).

Materials And Methods: In this ethics committee-approved, mono-institutional, retrospective (20 months) matched case-control study, two independent, blinded observers compared measurable lymph node delineation (yes-no) in six different International Association for the Study of Lung Cancer (IASLC) zones (upper mediastinal, aortopulmonary, subcarinal, lower mediastinal, hilar, peripheral) between 62 CE-LDCT cases and 124 CE-SDCT controls (respective tube charge, 100, 120 KVp, computed tomography dose index, 1.66 ± 0.51, 5.36 ± 2.24 mGy, automatic exposure control-modulated 64-row multi-detector chest CT with iterative image reconstruction). Individual matching for gender (53% female), age (53 ± 19 years), body height, weight, anterior-posterior and transverse diameters of chest and lung ruled out pre-test confounders. Lymph node size (cut-off value, 1 cm) was a potential post-test confounder. Two-tailed T test and Chi-square test were significant for p < 0.05.

Results: Measurable lymph nodes delineated equally in cases (261/372 IASLC zones, 70%; 280/372, 75%) and controls (528/744, 71%; 519/744, 70%; no significant differences, power 90%). One observer delineated significantly more peripheral zone lymph nodes in cases (35/62) than in controls (43/124); there were no significant differences otherwise. Lymph node size did not differ significantly; effective dose was 1.0 ± 0.3 mSv in cases and 3.4 ± 1.5 mSv in controls.

Conclusion: CE-LDCT with about 1 mSv demonstrated equal delineation of thoracic lymph nodes when compared with accepted standard CE-SDCT.
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http://dx.doi.org/10.1007/s11547-018-0915-2DOI Listing
November 2018

Uric acid, lung function, physical capacity and exacerbation frequency in patients with COPD: a multi-dimensional approach.

Respir Res 2018 06 4;19(1):110. Epub 2018 Jun 4.

Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Comprehensive Pneumology Center Munich (CPC-M), Ludwig-Maximilians-Universität München, Ziemssenstr. 1, 80336, Munich, Germany.

Background: Recent investigations showed single associations between uric acid levels, functional parameters, exacerbations and mortality in COPD patients. The aim of this study was to describe the role of uric acid within the network of multiple relationships between function, exacerbation and comorbidities.

Methods: We used baseline data from the German COPD cohort COSYCONET which were evaluated by standard multiple regression analyses as well as path analysis to quantify the network of relations between parameters, particularly uric acid.

Results: Data from 1966 patients were analyzed. Uric acid was significantly associated with reduced FEV, reduced 6-MWD, higher burden of exacerbations (GOLD criteria) and cardiovascular comorbidities, in addition to risk factors such as BMI and packyears. These associations remained significant after taking into account their multiple interdependences. Compared to uric acid levels the diagnosis of hyperuricemia and its medication played a minor role.

Conclusion: Within the limits of a cross-sectional approach, our results strongly suggest that uric acid is a biomarker of high impact in COPD and plays a genuine role for relevant outcomes such as physical capacity and exacerbations. These findings suggest that more attention should be paid to uric acid in the evaluation of COPD disease status.
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http://dx.doi.org/10.1186/s12931-018-0815-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987642PMC
June 2018

Exploratory Analysis of Brigatinib Activity in Patients With Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer and Brain Metastases in Two Clinical Trials.

J Clin Oncol 2018 09 16;36(26):2693-2701. Epub 2018 May 16.

D. Ross Camidge, University of Colorado Cancer Center, Aurora, CO; Dong-Wan Kim, Seoul National University Hospital; Myung-Ju Ahn, Samsung Medical Center; Dae Ho Lee, Asan Medical Center, Seoul, South Korea; Marcello Tiseo, University Hospital of Parma, Parma, Italy; Corey J. Langer, University of Pennsylvania, Philadelphia, PA; Alice T. Shaw, Massachusetts General Hospital, Boston; William Reichmann, Jeff Haney, Tim Clackson, and David Kerstein, ARIAD Pharmaceuticals, Cambridge, MA; Rudolf M. Huber, University Hospital of Munich, Munich, Germany; Maximilian J. Hochmair, Otto Wagner Hospital, Vienna, Austria; Lyudmila A. Bazhenova and Kathryn A. Gold, University of California San Diego Moores Cancer Center, La Jolla; Sai-Hong Ignatius Ou, University of California Irvine School of Medicine, Irvine, CA; Howard L. West, Swedish Cancer Institute, Seattle, WA; and Scott N. Gettinger, Yale Cancer Center, New Haven, CT.

Purpose In patients with crizotinib-treated, anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC), initial disease progression often occurs in the CNS. We evaluated brigatinib, a next-generation ALK inhibitor, in patients with ALK-positive NSCLC with brain metastases. Patients and Methods Patients with ALK-positive NSCLC received brigatinib (90 to 240 mg total daily) in a phase I/II trial (phI/II; ClinicalTrials.gov identifier: NCT01449461) and in the subsequent randomized phase II trial ALTA (ALK in Lung Cancer Trial of AP26113; ClinicalTrials.gov identifier: NCT02094573; patients in arm A received 90 mg once daily; patients in arm B received 180 mg once daily with 7-day lead-in at 90 mg). Primary end points (systemic objective response rates [ORRs]) were previously reported. Independent review committees assessed intracranial efficacy in patients with baseline brain metastases. Results Most patients with ALK-positive NSCLC had baseline brain metastases (50 of 79 [63%], phI/II; 80 of 112 [71%] and 73 of 110 [66%] in ALTA arms A and B, respectively), many of whom had no prior brain radiotherapy (23 of 50 [46%], phI/II; 32 of 80 [40%], ALTA arm A; 30 of 73 [41%], arm B). All patients, except four in phI/II, had received crizotinib. Among patients with measurable (≥ 10 mm) brain metastases, confirmed intracranial ORR was 53% (eight of 15; 95% CI, 27% to 79%) in phI/II, 46% (12 of 26; 95% CI, 27% to 67%) in ALTA arm A, and 67% (12 of 18; 95% CI, 41% to 87%) in arm B. Intracranial ORRs were similar in subsets without prior radiation or progression postradiation. Among patients with any baseline brain metastases, median intracranial progression-free survival (iPFS) was 14.6 months (95% CI, 12.7 to 36.8 months), phI/II; 15.6 months (95% CI, 9.0 to 18.3 months), ALTA arm A; 18.4 months (95% CI, 12.8 months to not reached), ALTA arm B. Conclusion Brigatinib yielded substantial intracranial responses and durable iPFS in ALK-positive, crizotinib-treated NSCLC, with highest iPFS in patients receiving 180 mg once daily (with lead-in).
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http://dx.doi.org/10.1200/JCO.2017.77.5841DOI Listing
September 2018

Relationship of spirometric, body plethysmographic, and diffusing capacity parameters to emphysema scores derived from CT scans.

Chron Respir Dis 2019 Jan-Dec;16:1479972318775423. Epub 2018 May 9.

10 Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Comprehensive Pneumology Center Munich (CPC-M), Ludwig-Maximilians-Universität München, Munich, Germany.

Phenotyping of chronic obstructive pulmonary disease (COPD) with computed tomography (CT) is used to distinguish between emphysema- and airway-dominated type. The phenotype is reflected in correlations with lung function measures. Among these, the relative value of body plethysmography has not been quantified. We addressed this question using CT scans retrospectively collected from clinical routine in a large COPD cohort. Three hundred and thirty five patients with baseline data of the German COPD cohort COPD and Systemic Consequences-Comorbidities Network were included. CT scans were primarily evaluated using a qualitative binary emphysema score. The binary score was positive for emphysema in 52.5% of patients, and there were significant differences between the positive/negative groups regarding forced expiratory volume in 1 second (FEV), FEV/forced vital capacity (FVC), intrathoracic gas volume (ITGV), residual volume (RV), specific airway resistance (sRaw), transfer coefficient (KCO), transfer factor for carbon monoxide (TLCO), age, pack-years, and body mass index (BMI). Stepwise discriminant analyses revealed the combination of FEV/FVC, RV, sRaw, and KCO to be significantly related to the binary emphysema score. The additional positive predictive value of body plethysmography, however, was only slightly higher than that of the conventional combination of spirometry and diffusing capacity, which if taken alone also achieved high predictive values, in contrast to body plethysmography. The additional information on the presence of CT-diagnosed emphysema as conferred by body plethysmography appeared to be minor compared to the well-known combination of spirometry and CO diffusing capacity.
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http://dx.doi.org/10.1177/1479972318775423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302978PMC
June 2020

The revised GOLD 2017 COPD categorization in relation to comorbidities.

Respir Med 2018 01 5;134:79-85. Epub 2017 Dec 5.

Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Comprehensive Pneumology Center Munich (CPC-M), Ludwig-Maximilians-Universität München, Ziemssenstr. 1, 80336 Munich, Germany.

Introduction: The COPD classification proposed by the Global Initiative for Obstructive Lung Disease was recently revised, and the A to D grouping is now based on symptoms and exacerbations only. Potential associations with comorbidities have not been assessed so far. Thus the aim of the present study was to determine the relationship between the revised (2017) GOLD groups A-D and major comorbidities.

Methods: We used baseline data from the COPD cohort COSYCONET. Comorbidities were identified from patient self-reports and disease-specific medication: gastrointestinal disorders, asthma, sleep apnea, hyperuricemia, hyperlipidemia, diabetes, osteoporosis, mental disorders, heart failure, hypertension, coronary artery disease. The A-D groups were based on either the COPD Assessment Test or the modified Medical Research Council scale. Exacerbations were also categorized as per GOLD recommendations.

Results: Data from 2228 patients were analyzed. Using GOLD group A as a reference, group D was associated with nearly all comorbidities, followed by group B and C. When groups A-D were dichotomized as AC vs. BD (symptoms) and AB vs. CD (exacerbations), all comorbidities correlated with symptoms and/or exacerbations. This was true for both mMRC- and CAT-based categorizations.

Conclusions: These findings suggest that the recently modified GOLD categorization is clinically relevant beyond being purely an assessment of symptoms and exacerbations. As the A-D groups correlated with the risk of important comorbidities, with some differences in terms of the correlation with symptoms and exacerbations, the findings underline the importance of identifying comorbidities in COPD, particularly in non-responders to therapy who have high symptoms and/or exacerbation rates.
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http://dx.doi.org/10.1016/j.rmed.2017.12.003DOI Listing
January 2018

Heterogeneous pattern of differences in respiratory parameters between elderly with either good or poor FEV.

BMC Pulm Med 2018 Feb 6;18(1):27. Epub 2018 Feb 6.

Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, D-85764, Neuherberg, Germany.

Background: The relationship of spirometric values to other respiratory and functional parameters in advanced age is not well studied. We assessed this relationship in elderly subjects with either good or poor spirometric parameters to reveal whether different domains of lung function show comparable differences between the two groups.

Methods: Among subjects of the population-based KORA-Age cohort (n = 935, 65-90y; 51% male) two groups were selected from either the lower (LED; n = 51) or the upper (UED; n = 72) end of the FEV distribution. All subjects did not have a history of lung disease and were non-smokers at the time of the study. Measurements included spirometry, body plethysmography, diffusing capacity for NO and CO, respiratory pump function and exhaled NO (FeNO). In addition, 6-min walking distance as a functional overall measure, as well as telomere length of blood leukocytes and serum 8-hydroxydeoxyguanosine (8-OHdG) as potential markers of overall biological ageing and stress were determined.

Results: In the majority of parameters, LED subjects showed significantly impaired values compared to UED subjects. Differences in spirometric parameters, airway resistance and respiratory pump function ranged between 10% and more than 90% in terms of predicted values. In contrast, volume-related CO and NO diffusing capacity showed differences between groups of lower than 5%, while telomere length, 8-OHdG and FeNO were similar. This was reflected in the differences in "functional age" as derived from prediction equations.

Conclusions: In elderly subjects without a history of lung disease differences in spirometric parameters were associated with differences in other lung-mechanical parameters including body plethysmography but not with differences in volume-corrected gas exchange measures. Thus, the concept of a general "lung age" as suggested by the widespread use of this term in connection with spirometry should be considered with caution.
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http://dx.doi.org/10.1186/s12890-018-0582-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801692PMC
February 2018

Perception of climate change in patients with chronic lung disease.

PLoS One 2017 18;12(10):e0186632. Epub 2017 Oct 18.

Department of Internal Medicine V, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), University of Munich, Munich, Germany.

Background: Climate change affects human health. The respective consequences are predicted to increase in the future. Patients with chronic lung disease are particularly vulnerable to the involved environmental alterations. However, their subjective perception and reactions to these alterations remain unknown.

Methods: In this pilot study, we surveyed 172 adult patients who underwent pulmonary rehabilitation and 832 adult tourists without lung disease in the alpine region about their perception of being affected by climate change and their potential reaction to specific consequences. The patients' survey also contained the COPD Assessment Test (CAT) to rate the severity of symptoms.

Results: Most of the patients stated asthma (73.8%), COPD (9.3%) or both (11.0%) as underlying disease while 5.8% suffered from other chronic lung diseases. Patients and tourists feel equally affected by current climate change in general, while allergic subjects in both groups feel significantly more affected (p = 0.04). The severity of symptoms assessed by CAT correlates with the degree of feeling affected (p<0.01). The main disturbing consequences for patients are decreased air quality, increasing numbers of ticks and mosquitos and a rising risk for allergy and extreme weather events such as thunderstroms, while tourists are less disturbed by these factors. Increasing number of heat-days is of little concern to both groups.

Conclusion: Overall patients are more sensitive to health-related consequences of climate change. Yet, the hazard of heat-days seems underestimated and awareness should be raised.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186632PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646841PMC
October 2017

Relationship of hyperlipidemia to comorbidities and lung function in COPD: Results of the COSYCONET cohort.

PLoS One 2017 15;12(5):e0177501. Epub 2017 May 15.

Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.

Although hyperlipidemia is common in COPD, its relationship to comorbidities, risk factors and lung function in COPD has not been studied in detail. Using the baseline data of the COSYCONET cohort we addressed this question. Data from 1746 COPD patients (GOLD stage 1-4; mean age 64.6 y, mean FEV1%pred 57%) were evaluated, focusing on the comorbidities hyperlipidemia, diabetes and cardiovascular complex (CVC; including arterial hypertension, cardiac failure, ischemic heart disease). Risk factors comprised age, gender, BMI, and packyears of smoking. The results of linear and logistic regression analyses were implemented into a path analysis model describing the multiple relationships between parameters. Hyperlipidemia (prevalence 42.9%) was associated with lower intrathoracic gas volume (ITGV) and higher forced expiratory volume in 1 second (FEV1) when adjusting for its multiple relationships to risk factors and other comorbidities. These findings were robust in various statistical analyses. The associations between comorbidities and risk factors were in accordance with previous findings, thereby underlining the validity of our data. In conclusion, hyperlipidemia was associated with less hyperinflation and airway obstruction in patients with COPD. This surprising result might be due to different COPD phenotypes in these patients or related to effects of medication.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177501PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432186PMC
September 2017

Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial.

J Clin Oncol 2017 Aug 5;35(22):2490-2498. Epub 2017 May 5.

Dong-Wan Kim, Seoul National University Hospital; Myung-Ju Ahn, Samsung Medical Center; Sang-We Kim, Asan Medical Center, Seoul, South Korea; Marcello Tiseo, University Hospital of Parma, Parma, Italy; Karen L. Reckamp, City of Hope, Duarte, CA; Karin Holmskov Hansen, Odense University Hospital, Odense, Denmark; Rudolf M. Huber, University Hospital of Munich, German Centre for Lung Research, Munich, Germany; Howard L. West, Swedish Cancer Institute, Seattle, WA; Harry J.M. Groen, University of Groningen, University Medical Center Groningen, Groningen; Egbert F. Smit, VU University Medical Center, Amsterdam, the Netherlands; Maximilian J. Hochmair, Otto Wagner Hospital, Vienna, Austria; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Scott N. Gettinger, Yale Cancer Center, New Haven, CT; Corey J. Langer, University of Pennsylvania Abramson Cancer Center, Philadelphia, PA; Luis G. Paz-Ares Rodríguez, Hospital Universitario 12 de Octubre, Madrid, Spain; Edward S. Kim, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC; William Reichmann, Frank G. Haluska, and David Kerstein, ARIAD Pharmaceuticals, Cambridge, MA; and D. Ross Camidge, University of Colorado Cancer Center, Aurora, CO.

Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC. Patients and Methods Patients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1:1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point. Results Of 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review committee-assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events with early onset (median onset: day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥ 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of 14 patients were successfully retreated with brigatinib. Conclusion Brigatinib yielded substantial whole-body and intracranial responses as well as robust progression-free survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.
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http://dx.doi.org/10.1200/JCO.2016.71.5904DOI Listing
August 2017

Assessment of lung function in a large cohort of patients with acromegaly.

Eur J Endocrinol 2017 Jul 21;177(1):15-23. Epub 2017 Apr 21.

Medizinische Klinik und Poliklinik IVKlinikum der Universität München und Lungentumorzentrum München, Germany.

Objective: Acromegaly is associated with increased mortality due to respiratory disease. To date, lung function in patients with acromegaly has only been assessed in small studies, with contradicting results. We assessed lung function parameters in a large cohort of patients with acromegaly.

Design: Lung function of acromegaly patients was prospectively assessed using spirometry, blood gas analysis and body plethysmography. Biochemical indicators of acromegaly were assessed through measurement of growth hormone and IGF-I levels. This study was performed at the endocrinology outpatient clinic of a tertiary referral center in Germany.

Methods: We prospectively tested lung function of 109 acromegaly patients (53 male, 56 female; aged 24-82 years; 80 with active acromegaly) without severe acute or chronic pulmonary disease. We compared lung volume, air flow, airway resistance and blood gases to normative data.

Results: Acromegaly patients had greater lung volumes (maximal vital capacity, intra-thoracic gas volume and residual volume:  < 0.001, total lung capacity:  = 0.006) and showed signs of small airway obstruction (reduced maximum expiratory flow when 75% of the forced vital capacity (FVC) has been exhaled:  < 0.001, lesser peak expiratory flow:  = 0.01). There was no significant difference between active and inactive acromegaly. Female patients had significantly altered lung function in terms of subclinical airway obstruction.

Conclusions: In our cross-sectional analysis of lung function in 109 patients with acromegaly, lung volumes were increased compared to healthy controls. Additionally, female patients showed signs of subclinical airway obstruction. There was no difference between patients with active acromegaly compared with patients biochemically in remission.
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http://dx.doi.org/10.1530/EJE-16-1080DOI Listing
July 2017

Transfer factor for carbon monoxide in patients with COPD and diabetes: results from the German COSYCONET cohort.

Respir Res 2017 01 13;18(1):14. Epub 2017 Jan 13.

Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universität München, Ziemssenstr. 1, 80336, Munich, Germany.

Background: An impairment of CO diffusing capacity has been shown in diabetic patients without lung disease. We analyzed how diffusing capacity in patients with COPD is affected by the concurrent diagnosis of diabetes.

Methods: Data from the initial visit of the German COPD cohort COSYCONET were used for analysis. 2575 patients with complete lung function data were included, among them 358 defined as diabetics with a reported physician diagnosis of diabetes and/or specific medication. Pairwise comparisons between groups and multivariate regression models were used to identify variables predicting the CO transfer factor (TLCO%pred) and the transfer coefficient (KCO%pred).

Results: COPD patients with diabetes differed from those without diabetes regarding lung function, anthropometric, clinical and laboratory parameters. Moreover, gender was an important covariate. After correction for lung function, gender and body mass index (BMI), TLCO%pred did not significantly differ between patients with and without diabetes. The results for the transfer coefficient KCO were similar, demonstrating an important role of the confounding factors RV%pred, TLC%pred, ITGV%pred, FEV%pred, FEV/FVC, age, packyears, creatinine and BMI. There was not even a tendency towards lower values in diabetes.

Conclusion: The analysis of data from a COPD cohort showed no significant differences of CO transport parameters between COPD patients with and without diabetes, if BMI, gender and the reduction in lung volumes were taken into account. This result is in contrast to observations in lung-healthy subjects with diabetes and raises the question which factors, among them potential anti-inflammatory effects of anti-diabetes medication are responsible for this finding.
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http://dx.doi.org/10.1186/s12931-016-0499-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237203PMC
January 2017

Systematic Analysis of Self-Reported Comorbidities in Large Cohort Studies - A Novel Stepwise Approach by Evaluation of Medication.

PLoS One 2016 28;11(10):e0163408. Epub 2016 Oct 28.

Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital LMU Munich, München, Germany.

Objective: In large cohort studies comorbidities are usually self-reported by the patients. This way to collect health information only represents conditions known, memorized and openly reported by the patients. Several studies addressed the relationship between self-reported comorbidities and medical records or pharmacy data, but none of them provided a structured, documented method of evaluation. We thus developed a detailed procedure to compare self-reported comorbidities with information on comorbidities derived from medication inspection. This was applied to the data of the German COPD cohort COSYCONET.

Methods: Approach I was based solely on ICD10-Codes for the diseases and the indications of medications. To overcome the limitations due to potential non-specificity of medications, Approach II was developed using more detailed information, such as ATC-Codes specific for one disease. The relationship between reported comorbidities and medication was expressed by a four-level concordance score.

Results: Approaches I and II demonstrated that the patterns of concordance scores markedly differed between comorbidities in the COSYCONET data. On average, Approach I resulted in more than 50% concordance of all reported diseases to at least one medication. The more specific Approach II showed larger differences in the matching with medications, due to large differences in the disease-specificity of drugs. The highest concordance was achieved for diabetes and three combined cardiovascular disorders, while it was substantial for dyslipidemia and hyperuricemia, and low for asthma.

Conclusion: Both approaches represent feasible strategies to confirm self-reported diagnoses via medication. Approach I covers a broad spectrum of diseases and medications but is limited regarding disease-specificity. Approach II uses the information from medications specific for a single disease and therefore can reach higher concordance scores. The strategies described in a detailed and reproducible manner are generally applicable in large studies and might be useful to extract as much information as possible from the available data.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163408PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085029PMC
June 2017

Pathway Targeted Immunotherapy: Rationale and Evidence of Durable Clinical Responses with a Novel, EGF-directed Agent for Advanced NSCLC.

J Thorac Oncol 2016 11 24;11(11):1954-1961. Epub 2016 Aug 24.

Bioven (Europe) Ltd, London, United Kingdom. Electronic address:

Abnormalities in the epidermal growth factor (EGF) and EGFR pathway promote progression of NSCLC. Immunization with EGF vaccine induces specific, neutralizing anti-EGF antibodies that prevent binding of the ligand to its receptor. This concept of pathway targeted immunotherapy (PTI) was validated in vitro by dose-related suppression of EGFR, Akt, and Erk1/2 phosphorylation in cell lines with different mutations. A randomized phase II trial showed improved overall survival (OS) in subgroups with advanced NSCLC showing a clear immunologic response. By per-protocol analysis of the ensuing phase IIb trial, patients receiving EGF PTI survived 3 months longer than controls (12.43 versus 9.43 months; hazard ratio = 0.77 [95% confidence interval, 0.61-0.98]). These data were confirmed in a larger trial showing an OS benefit over control of >3 months. The variable most strongly correlated with efficacy was circulating EGF at enrolment. Patients with serum EGF levels >250 pg/mL benefited most from treatment with EGF PTI. Of 188 patients tested, 94 were above this biomarker threshold. The OS benefit from active versus control treatment was 6.7 months. More than 15% of patients had responses for >5 years. Long-term survivors are seen in all EGF PTI trials. Treatment is well-tolerated, induces high anti-EGF antibody titers, reduces levels of circulating serum EGF, achieves durable responses, and significantly prolongs OS. A threshold of 250 pg/mL has been set to enrich the study population in the ongoing pivotal trial. This biomarker-guided study in an enriched population of patients with both squamous and nonsquamous stage IV NSCLC aims to replicate the favorable efficacy/tolerability balance of earlier studies.
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http://dx.doi.org/10.1016/j.jtho.2016.08.132DOI Listing
November 2016

The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC.

J Thorac Oncol 2017 02 8;12(2):194-207. Epub 2016 Oct 8.

Department of Medicine, University of Chicago Medical Center, Chicago, Illinois.

Over the past few years, there have been considerable advances in the treatments available to patients with metastatic or locally advanced NSCLC, particularly those who have progressed during first-line treatment. Some of the treatment options available to patients are discussed here, with a focus on checkpoint inhibitor immunotherapies (nivolumab and pembrolizumab) and antiangiogenic agents (bevacizumab, ramucirumab, and nintedanib). It is hypothesized that combining immunotherapy with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. In this review, we explore the theory and potential of this novel treatment option for patients with advanced NSCLC. We discuss the growing body of evidence that proangiogenic factors can modulate the immune response (both by reducing T-cell infiltration into the tumor microenvironment and through systemic effects on immune-regulatory cell function), and we examine the preclinical evidence for combining these treatments. Potential challenges are also considered, and we review the preliminary evidence of clinical efficacy and safety with this novel combination in a variety of solid tumor types.
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http://dx.doi.org/10.1016/j.jtho.2016.10.003DOI Listing
February 2017
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