Großhansdorf, Germany
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Reck M.,Airway Research Center North | Paz-Ares L.,University of Seville
Seminars in Oncology | Year: 2015

Despite the availability of radiotherapy, cytotoxic agents, and targeted agents, a high unmet medical need remains for novel therapies that improve treatment outcomes in patients with lung cancer who are ineligible for surgical resection. Building upon the early promise shown with general immunostimulatory agents, immuno-oncology is at the forefront of research in this field, with several novel agents currently under investigation. In particular, agents targeting immune checkpoints, such as the cytotoxic T-lymphocyte antigen-4 (CTLA-4) receptor and programmed death-1 (PD-1) receptor, have shown in early clinical trials potential for improving tumor responses and survival in patients with non-small cell lung cancer (NSCLC). Here, we examine the rationale for targeting immune checkpoints in lung cancer and review the clinical data from studies with immune checkpoint inhibitors currently in development. The challenges associated with optimizing treatment with these agents in lung cancer also are discussed. © 2015 Elsevier Inc.


Thatcher N.,The Christie Hospital | Hirsch F.R.,Aurora University | Luft A.V.,Leningrad Regional Clinical Hospital | Szczesna A.,Regional Lung Disease Hospital | And 17 more authors.
The Lancet Oncology | Year: 2015

Background: Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. Methods: We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash-a class effect of EGFR antibodies-that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. Findings: Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4-12·6]) vs 9·9 months [8·9-11·1]; stratified hazard ratio 0·84 [95% CI 0·74-0·96; p=0·01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3-4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [<1%]). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations. Interpretation: Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Funding: Eli Lilly and Company. © 2015 Elsevier Ltd.


Martinez F.J.,New York Medical College | Martinez F.J.,University of Michigan | Calverley P.M.A.,University of Liverpool | Goehring U.-M.,Takeda Development Center Europe Ltd | And 4 more authors.
The Lancet | Year: 2015

Summary Background Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease. Its effect in patients using fixed combinations of inhaled corticosteroids and longacting β2 agonists is unknown. We postulated that roflumilast would reduce exacerbations in patients with severe chronic obstructive pulmonary disease at risk for exacerbations, even in combination with inhaled corticosteroid and longacting β2 agonist treatment. Methods For this 1-year double-blind, placebo-controlled, parallel group, multicentre, phase 3-4 trial, the Roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy (REACT) study, we enrolled patients with severe chronic obstructive pulmonary disease from 203 centres (outpatient clinics, hospitals, specialised pulmonologists, and family doctors) in 21 countries. Eligible patients were 40 years of age or older with a smoking history of at least 20 pack-years and a diagnosis of chronic obstructive pulmonary disease with severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year. We used a computerised central randomisation system to randomly assign patients in a 1:1 ratio to the two treatment groups: roflumilast 500 μg or placebo given orally once daily together with a fixed inhaled corticosteroid and longacting β2 agonist combination. Background tiotropium treatment was allowed. All patients and investigators were masked to group assignment. The primary outcome was the rate of moderate to severe chronic obstructive pulmonary disease exacerbations per patient per year, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329029. Findings Between April 3, 2011, and May 27, 2014, we enrolled 1945 eligible participants and randomly assigned 973 to the roflumilast group and 972 to the placebo group. The rate of moderate-to-severe chronic obstructive pulmonary disease exacerbations was 13·2% lower in the roflumilast group than in the placebo group according to a Poisson regression analysis (roflumilast 0·805 vs placebo 0·927; rate ratio [RR] 0·868 [95% CI 0·753-1·002], p=0·0529), and 14·2% lower according to a predefined sensitivity analysis using negative binomial regression (0·823 vs 0·959; 0·858 [0·740-0·995], p=0·0424). Adverse events were reported by 648 (67%) of 968 patients receiving roflumilast and by 572 (59%) of 967 patients in the placebo group; adverse event-associated patient withdrawal from the study was also more common in the roflumilast group (104/968 [11%]) than in the placebo group (52/967 [5%]). The most frequently reported serious adverse events were chronic obstructive pulmonary disease exacerbations and pneumonia, and 17 (1·8%) deaths occurred in the roflumilast group compared with 18 (1·9%) in the placebo group. Interpretation Our findings suggest that roflumilast reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting β2 agonist therapy, even in combination with tiotropium. Funding Takeda. © 2015 Elsevier Ltd.


Reck M.,Airway Research Center North | Heigener D.F.,Airway Research Center North | Mok T.,Chinese University of Hong Kong | Soria J.-C.,Institute Gustave Roussy Villejuif | And 3 more authors.
The Lancet | Year: 2013

Non-small-cell lung cancer is one of the leading causes of deaths from cancer worldwide. Therefore, improvements in diagnostics and treatments are urgently needed. In this review, we will discuss the evolution of lung cancer staging towards more non-invasive, endoscopy-based, and image-based methods, and the development of stage-adapted treatment. A special focus will be placed on the role of novel surgical approaches and modern radiotherapy strategies for early stages of disease, the effect of multimodal treatment in locally advanced disease, and ongoing developments in the treatment of patients with metastatic disease. In particular, we will include an emphasis on targeted therapies, which are based on the assumption that a treatable driver mutation or gene rearrangement is present within the tumour. Finally, the position of lung cancer treatment on the pathway to personalised therapy will be discussed. © 2013 Elsevier Ltd.


Horn L.,Vanderbilt University | Reck M.,Airway Research Center North | Spigel D.R.,Sarah Cannon Research Institute
Oncologist | Year: 2016

Small cell lung cancer (SCLC), which accounts for 10%–15% of lung cancer cases, is an aggressive disease characterized by rapid growth and early widespread metastasis. Although up to 80% of patients respond to first-line chemotherapy, most eventually relapse, and there are no approved agents beyond the second line. Despite the high incidence of mutations in SCLC, to date no targeted therapy has shown a benefit for this patient population, and systemic treatment has not changed significantly during the past 3 decades. Given that extensive-stage SCLC has a 5-year survival rate of only 1%–2%, novel therapies are desperately needed. Recent evidence shows that the immune system is capable of generating antitumor responses against various tumors, including lung cancer, suggesting that immunotherapy may be a viable therapeutic approach to the treatment of patients with SCLC. Of the immunotherapies being investigated for patients with SCLC, antibodies that target the programmed cell death protein-1 (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte antigen-4 (ipilimumab) immune checkpoint pathways are perhaps the most promising. Because these immune checkpoint pathways, which under normal circumstances function to protect healthy tissues from damage during inflammatory responses and maintain self-tolerance, can help tumor cells evade elimination by the immune system, they represent potential therapeutic targets.This review discusses the rationale for immunotherapy and the early clinical results of immunotherapeutic agents being investigated in SCLC. © AlphaMed Press 2016.


Wedzicha J.A.,Imperial College London | Calverley P.M.,University of Liverpool | Rabe K.F.,University of Kiel | Rabe K.F.,Airway Research Center North
International Journal of COPD | Year: 2016

COPD is a progressive condition involving chronic inflammation and parenchymal destruction with resulting airflow limitation. COPD is associated with worsening airflow limita- tion over time and increased frequency of COPD exacerbations, leading to increased mortality and morbidity. The effects of COPD extend beyond the lungs, as multiple comorbidities may occur with COPD, including cardiovascular disease, diabetes mellitus, osteoporosis, depres- sion, and pneumonia. COPD exacerbations are associated with a rapid worsening of baseline symptoms that requires prompt management and may necessitate hospitalization in the case of a severe episode. Patients with COPD exacerbations require urgent management of symptoms to prevent further worsening, and preventative steps may be taken to help reduce the number and frequency of future exacerbations. Roflumilast is a potent and selective inhibitor of the enzyme phosphodiesterase-4 that targets the systemic inflammation associated with COPD. Roflumilast has a variety of anti-inflammatory effects including decreasing inflammatory mediators and the expression of cell surface markers and inhibition of apoptosis. Several clinical trials evaluating roflumilast in the treatment of COPD have demonstrated significant improvements from baseline versus placebo in lung function, including increases in mean pre- and postbronchodilator forced expiratory volume in 1 second and forced vital capacity. Data suggest that roflumilast reduces moderate to severe exacerbations with the benefit most well established in patients with severe disease. Given this evidence, roflumilast, as part of a combination regimen with long-acting bronchodilators, appears to be a reasonable treatment option for patients with severe to very severe COPD associated with chronic bronchitis and a history of exacerbations. © 2016 Wedzicha et al.


Reinmuth N.,Member of the German Center for Lung Research | Reck M.,Airway Research Center North
Oncology Research and Treatment | Year: 2016

Immune evasion is recognized as a key strategy for cancer survival and progression. Hence, various approaches to restore antitumor immune responses are currently being investigated. In particular, agents targeting immune checkpoints, such as the cytotoxic T-lymphocyte-associated antigen-4 receptor and programmed death-1 receptor, have shown potential for improving tumor responses and survival in lung cancer patients. With the first immunomodulating agents having been approved for treatment of selected lung cancer patients, there are high expectations that treatment outcomes may be improved with the incorporation of immunotherapies into the various treatment cascades. © 2016 S. Karger GmbH, Freiburg.


Heigener D.,Airway Research Center North | Reck M.,Airway Research Center North
Expert Review of Anticancer Therapy | Year: 2014

Immune evasion is recognized as a key strategy for cancer survival and progression. With increased understanding of immune escape mechanisms, the development of immunotherapies to restore anti-tumor immune responses has flourished. Immuno-oncology (I-O) agents targeting checkpoints in the immune regulation cascade currently form the mainstay of approaches of cancer immunotherapy. Since initial success in melanoma, evidence for the notable effects of the I-O modality has been expanding, with numerous clinical studies underway or completed in a variety of solid tumors, including non-small cell lung cancer. This review highlights the rationale and potential role of immunotherapy in non-small cell lung cancer management, with a focus on immune checkpoint inhibitors. We also discuss the potential for I-O-based combination therapy. © 2015 Informa UK Ltd.


Evidence-based guidelines are important for primary prevention of allergic diseases, i.e. atopic dermatitis, allergic rhinoconjunctivitis, and allergic asthma. Scientific publications were searched for the period 2008 - 2013 in the electronic databases and of originally 3,284 hits, 165 studies (15 systematic reviews, 1 meta-analysis, 31 RCTs, 65 cohort-, 12 case-control, and 41 cross sectional studies) were reviewed. The revision of this guideline in 2014 resulted in (1) a conformation of existing recommendations, (2) substantial revisions, and (3) new recommendations. The recommendation on breast feeding over 4 months was confirmed. If breast feeding is not possible, hypoallergenic formulas for babies with a family history of atopic disease is the recommended alternative feeding strategy. Neonates without a family history of atopy can receive a cow's milk formula. Actually there is no scientific evidence for a prolonged introduction of solid food with respect to allergy prevention. Therefore the guideline for allergy prevention suggests introducing solid food with the beginning of the 5th month. The advice to avoid environmental tobacco smoke and the suggestion to vaccinate children according to current recommendations were grossly unchanged, as well as the avoidance of overweight, fish consumption (during pregnancy/ breast feeding and as solid food in the first year), reduction of the exposure to indoor and outdoor air pollutants. The recommendation regarding pet keeping were alleviated and specified: While dogs in a household are not associated with an increased allergy risk, families at risk for atopic disease should not acquire a cat. Newly introduced was the information, that children born via Caesarean section showed up to be at increased risk for the development of asthma later in life. © 2015 Dustri-Verlag Dr. Karl Feistle.


Reck M.,Airway Research Center North
Expert Review of Anticancer Therapy | Year: 2015

Antiangiogenic agents are effective standard-of-care options in several malignancies, but are generally associated with only modest improvements in survival, as well as leading to additional toxicities. Furthermore, almost all patients develop acquired resistance to therapy, possibly due to the activation of alternative proangiogenic pathways. Here we discuss: the rationale for developing nintedanib, an agent that simultaneously inhibits signaling pathways activated by platelet-derived growth factor, FGF, as well as VEGF; how its distinctive inhibitory and pharmacokinetic profile could underlie promising efficacy and tolerability observed in Phase II trials in patients with relapsed/refractory non-small cell lung cancer, advanced ovarian cancer and metastatic colorectal cancer; the ongoing Phase III program that is assessing nintedanib in these areas of major unmet medical need; and recent progress in the development of biomarkers that may predict response to nintedanib. © 2015 Informa UK, Ltd.

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