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Reck M.,Hospital Grosshansdorf
Expert Opinion on Investigational Drugs | Year: 2010

Importance of the field: For patients with advanced non-small cell lung cancer (NSCLC), chemotherapy offers modest benefits and outcomes are poor. Angiogenesis, the formation of new blood vessels from the pre-existing vasculature, is a fundamental process for tumor growth and development. Tumor vasculature is therefore emerging as an important target for cancer therapy. Areas covered in this review: This expert review will briefly discuss several antiangiogenic agents approved for the treatment of NSCLC, including many more currently being investigated in clinical trials, such as neutralizing antibodies of pro-angiogenic factors and inhibitors of their tyrosine kinase receptors. This review will also provide an overview of BIBF 1120, a novel, potent, triple angiokinase inhibitor that simultaneously acts on three receptor families involved in blood vessel formation: vascular endothelial growth factor receptors, platelet-derived growth factor receptors and fibroblast growth factor receptors. What the reader will gain: Expert opinion on the promising results obtained in Phase I studies demonstrating that BIBF 1120 is well tolerated in patients with advanced solid tumors will be provided. Further experience from a Phase II monotherapy trial also indicates promising efficacy and a favorable safety profile in patients with relapsed advanced NSCLC. Take home message: Based on these data, the BIBF 1120 Phase III clinical development program is currently underway and will be discussed in further detail. © 2010 Informa UK Ltd.

Reck M.,Hospital Grosshansdorf | Bondarenko I.,Clinical Facility | Luft A.,Leningrad Regional Clinical Hospital | Serwatowski P.,Specjalistyczny Szpital im | And 5 more authors.
Annals of Oncology | Year: 2013

Ipilimumab, an anti-CTLA4 monoclonal antibody, demonstrated survival benefit in melanoma with immune-related (ir) adverse events (irAEs) managed by the protocol-defined guidelines. This phase 2 study evaluated ipilimumab + paclitaxel (Taxol)/carboplatin in extensive-disease-small-cell lung cancer (ED-SCLC). Design: Patients (n = 130) with chemotherapy-naïve ED-SCLC were randomized 1: 1: 1 to receive paclitaxel (175 mg/m2)/carboplatin (area under the curve = 6) with either placebo (control) or ipilimumab 10 mg/kg in two alternative regimens, concurrent ipilimumab (ipilimumab + paclitaxel/carboplatin followed by placebo + paclitaxel/carboplatin) or phased ipilimumab (placebo + paclitaxel/carboplatin followed by ipilimumab + paclitaxel/carboplatin). Treatment was administered every3 weeks for a maximum of 18 weeks (induction), followed by maintenance ipilimumab or placebo every 12 weeks. End points included progression-free survival (PFS), irPFS, best overall response rate (BORR); irBORR,overall survival (OS), and safety. Results: Phased ipilimumab, but not concurrent ipilimumab, improved irPFS versus control [HR (hazard ratio) = 0.64;P = 0.03]. No improvement in PFS (HR = 0.93; P = 0.37) or OS (HR = 0.75; P = 0.13) occurred. Phased ipilimumab,concurrent ipilimumab and control, respectively, were associated with median irPFS of 6.4, 5.7 and 5.3 months;median PFS of 5.2, 3.9 and 5.2 months; median OS of 12.9, 9.1 and 9.9 months. Overall rates of grade 3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and control, respectively. Conclusion: These results suggest further investigation of ipilimumab in ED-SCLC. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Most patients with NSCLC are diagnosed at an advanced stage and have a poor prognosis, with a 5-year survival rate of <5%. Despite the introduction of new chemotherapeutic agents and molecularly targeted drugs, outcomes remain poor, emphasising the need for new treatment approaches. Inducing or potentiating immune responses via immunotherapeutic manipulation is a viable treatment approach for lung cancer. Antigen-specific, tumour-cell, and dendritic cell-based vaccines have all been evaluated in lung cancer, and some have shown promising clinical activity in phase II trials. These include liposomal BLP25 vaccine (L-BLP25), which targets mucin 1, and melanoma-associated antigen 3 (MAGE-A3) antigen-specific cancer immunotherapeutic (ASCI), which targets MAGE-A3, a peptide expressed almost exclusively on tumour cells. MAGE-A3 ASCI is being evaluated in the adjuvant setting in a phase III trial of patients with early-stage NSCLC, while a phase III trial of L-BLP25 is enrolling patients with unresectable stage III NSCLC. T-cell modulating agents (e.g. antibodies against programmed death 1 and cytotoxic T-lymphocyte-associated antigen-4 [CTLA-4]) are also being investigated. For example, in patients with NSCLC treated with paclitaxel and carboplatin, the phased administration of ipilimumab (an antibody against CTLA-4) resulted in substantial improvements in immune-related progression-free survival compared with chemotherapy alone (5.7 versus 4.6 months; P = 0.05). Immunotherapy in lung cancer is starting to deliver promising results in clinical trials. However, further research will be required to establish the optimal timing of therapy (i.e. in the adjuvant or metastatic settings). In addition, it will be important to determine if immunotherapies are most effective when used alone or in combination with other agents. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Reck M.,Hospital Grosshansdorf
Targeted Oncology | Year: 2010

Dysregulation of angiogenesis in solid tumors enables tumor growth and metastasis. Receptors that mediate angiogenesis, and their ligands, have been identified; among these, vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase play a central role. In non-small cell lung cancer (NSCLC), clinical benefit has been shown with bevacizumab, which blocks VEGF binding to its receptors. In addition, small-molecule tyrosine kinase inhibitors are currently in clinical practice or development in several indications. The potential clinical benefit of antiangiogenic agents is accompanied by the need to understand their safety profiles, seek suitable combination regimens and identify patients able to tolerate one treatment over another. This is particularly relevant in cancers for which patients often present with advanced disease and suffer co-morbidities, requiring an agent that is both efficacious and well tolerated over long-term continuous treatment. Using literature from peer-reviewed journals, this review considers different antiangiogenic agents and their safety profiles, focusing on the potential impact of these data on the treatment of patients with NSCLC. © Springer-Verlag 2010.

Reck M.,Hospital Grosshansdorf
Expert Review of Anticancer Therapy | Year: 2010

Most patients with non-small-cell lung cancer (NSCLC) present with advanced disease and have poor long-term prognosis. Gefitinib, a targeted therapy that prevents ATP binding in the tyrosine kinase domain of the EGF receptor, has been subject to comprehensive clinical development. A Phase III trial has demonstrated that gefitinib is superior to carboplatin/paclitaxel in terms of progression-free survival and objective response rate, as first-line treatment for pulmonary adenocarcinoma among never-smokers or former light smokers in East Asia (the IRESSA™ Pan-Asia Study), with the presence of an EGFR mutation being a strong predictor of the effect of gefitinib compared with carboplatin/paclitaxel. In this article, these results are discussed in the context of other recently reported studies of EGFR mutation-positive patients in both Asian and non-Asian countries. Furthermore, the clinical implications and future challenges for gefitinib are highlighted. © 2010 Expert Reviews Ltd.

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