Rationale of a relaunch of gefitinib in Caucasian non-small cell lung cancer patients.
ABSTRACT In 2002 results of two-phase II studies with the new epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib showed not only promising efficacy in second and third line non-small cell lung cancer (NSCLC) therapies but also an excellent tolerability. Since then, thousands of patients have been treated in one of the largest expanded access programs ever performed and the successful application in daily routine led to a preliminary approval of the drug by the U.S. Food and Drug Administration in 2003. In the light of the negative results of a subsequent phase III trial comparing gefitinib with best supportive care, the approval was withdrawn. In 2009 gefitinib was relaunched for Caucasian patients in the US and Europe based on new data and on the re-interpretation of previous studies. The approval is now recommended exclusively for patients with an activating EGFR mutation. For the first time in lung cancer, molecular work-up is of clinical relevance and will change the diagnostic and therapeutic algorithms. The present review summarizes these data, presents the rationale for this development and proposes a diagnostic work-up.
Article: Pyrosequencing, a method approved to detect the two major EGFR mutations for anti EGFR therapy in NSCLC.[show abstract] [hide abstract]
ABSTRACT: Epidermal Growth Factor Receptor (EGFR) mutations, especially in-frame deletions in exon 19 (ΔLRE) and a point mutation in exon 21 (L858R) predict gefitinib sensitivity in patients with non-small cell lung cancer. Several methods are currently described for their detection but the gold standard for tissue samples remains direct DNA sequencing, which requires samples containing at least 50% of tumor cells. We designed a pyrosequencing assay based on nested PCR for the characterization of theses mutations on formalin-fixed and paraffin-embedded tumor tissue. This method is highly specific and permits precise characterization of all the exon 19 deletions. Its sensitivity is higher than that of "BigDye terminator" sequencing and enabled detection of 3 additional mutations in the 58 NSCLC tested. The concordance between the two methods was very good (97.4%). In the prospective analysis of 213 samples, 7 (3.3%) samples were not analyzed and EGFR mutations were detected in 18 (8.7%) patients. However, we observed a deficit of mutation detection when the samples were very poor in tumor cells. pyrosequencing is then a highly accurate method for detecting ΔLRE and L858R EGFR mutations in patients with NSCLC when the samples contain at least 20% of tumor cells.Journal of Experimental & Clinical Cancer Research 01/2011; 30:57. · 2.15 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Tumor angiogenesis has been identified to play a critical role in tumor growth and tumor progression, and is regulated by a balance of angiogenic and anti-angiogenic cytokines. Among them VEGF (vascular endothelial growth factor) and its signaling through its receptors are of crucial relevance. Inhibition of VEGF signaling by monoclonal antibodies or small molecules (kinase inhibitors) has already been successfully established for the treatment of different cancer entities and multiple new drugs are being tested in clinical trials. However not all patients are likely to respond to these therapies, but to date there are no reliable biomarkers available to predict therapy response. Many studies integrated biomarker programs in their study protocols, thus several potential biomarkers have been identified which are currently under clinical investigation in prospective randomized studies. This review intends to give an overview of the described potential biomarkers as well as different imaging techniques such as ultrasound and magnetic resonance imaging that can indicate benefit, resistance and toxicity to anti-angiogenic therapies.International Journal of Molecular Sciences 01/2011; 12(10):7077-99. · 2.60 Impact Factor