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Background: [18F]fluorodeoxyglucose (FDG)-PET is being evaluated as a tool for the early detection of response to various targeted agents in solid tumors. The aim of this study was to evaluate the predictive value of PET response after 2 days of erlotinib in unselected pretreated patients with stage IV NSCLC., Patients and Methods: FDG-PET/CT scans were conducted at baseline and after 2 days of erlotinib, with a CT evaluation performed at baseline and after 45-60 days of therapy. PET responses were evaluated by quantitative changes on SUVmax tumor/non-tumor ratio and classified according to EORTC criteria. PET responses were compared with RECIST responses and related to progression-free (PFS) and overall (OS) survival. Erlotinib effects on glucose uptake were also studied in a panel of NSCLC cell lines., Results: Fifty-three patients were enrolled. At 2 days of erlotinib, 20 (38 %) patients showed partial metabolic response (PMR), 25 (47 %) had stable metabolic disease (SMD) and 8 (15 %) had progressive metabolic disease (PMD). All patients with PMD had confirmed RECIST progression at 45-60 days. Patients with early PMR and SMD had significantly longer PFS (p < 0.001 and p = 0.001, respectively) and OS (p = 0.001 for both) than PMD patients., Conclusions: FDG-PET assessment after 2 days of erlotinib could be useful to identify early resistant patients and to predict survival in unselected NSCLC pretreated population.

Objectives: An association between skin toxicity and outcome has been reported for NSCLC patients treated with erlotinib. Several explanations have been suggested, including pharmacokinetic and pharmacogenomic variability. The purposes of this study were to characterize erlotinib pharmacokinetic and to correlate drug serum and urine levels to toxicity and outcomes in advanced NSCLC patients., Methods: Patients with stage IV NSCLC consecutively treated with erlotinib in second- or third-line were enrolled. Biological samples (blood, urine and tumor specimens) were collected. Erlotinib levels in serum and urine samples of all patients after 7 (T1) and 30 (T2) days of treatment were quantified by LC-MS/MS analysis, along with urinary 6β-hydroxycortisol/cortisol ratio, as marker of metabolic phenotype of the CYP3A4/5 enzyme., Results: 56 patients were recruited and for 46 all samples were available. At T1 erlotinib levels were 3.90 [2.13] μmol/l and 0.37 [2.90]μmol/mol creat in serum and urinary samples, respectively; at T2 drug concentrations were significantly lower (2.02 [4.05] μmol/l and 0.23 [4.47] μmol/mol creat, respectively). Patients with grade 3 skin toxicity showed serum T1 drug levels significantly higher than those with grade 0-2 (6.84 [2.28] vs. 3.08 [1.97] μmol/l, respectively, p=0.004) and had longer progression-free and overall survival. An inverse correlation between erlotinib serum levels and urinary 6β-hydroxycortisol/cortisol ratio was observed in patients with grade 3 skin toxicity., Conclusions: These findings suggest that the pharmacokinetics and metabolism of erlotinib are related to skin toxicity and may support further studies where erlotinib dosing is tailored according to pharmacokinetic parameters., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The identification of activating EGFR gene mutations and the availability of effective target therapies such as gefitinib and erlotinib have radically changed the therapeutic approach and prognosis for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, despite an initial response to EGFR tyrosine kinase inhibitors (TKIs), acquired resistance inevitably develops and the way to overcome it is an open challenge. We report the first case, to our knowledge, of a patient affected by metastatic EGFR-mutated NSCLC with T790M-driven acquired TKI resistance who obtained a significant response to afatinib. Considering the improvement achieved in all disease sites but those in the brain, this case puts a strain on afatinib's activity on brain metastases.

Introduction: Epidermal growth factor receptor (EGFR) gene intron 1 contains a polymorphic single sequence dinucleotide repeat (CA)n whose length has been found to inversely correlate with transcriptional activity. This study was designed to assess the role of (CA)n polymorphism in predicting the outcome of gefitinib treatment in advanced non-small cell lung cancer (NSCLC)., Methods: Blood and tumor tissue from 58 patients with advanced NSCLC submitted to gefitinib were collected. EGFR intron 1 gene polymorphism, along with EGFR gene mutation, gene copy number and immunohistochemistry expression were determined. Moreover, a panel of lung cancer cell lines characterized for EGFR intron 1 polymorphism was also studied., Results: EGFR intron 1 polymorphism showed a statistically significant correlation with the gefitinib response (response rate 25 versus 0%, for patients with a (CA)16 and with a (CA)else genotype, respectively; p = 0.044). Patients with a (CA)16 genotype had a longer survival compared with those with a (CA)else genotype (11.4 versus 4.8 months, respectively; p = 0.037). In addition, cell lines lacking the (CA)16 allele showed a statistically significant higher IC50 compared with cell lines bearing at least one (CA)16 allele (p = 0.003)., Conclusions: This study supports a potential role of EGFR intron 1 polymorphism in predicting the outcome of gefitinib treatment in advanced NSCLC.

Purpose: To evaluate the role of pretreatment and posttreatment expression in buccal mucosa cells of signal transduction proteins activated by epidermal growth factor receptor, including phosphorylated epidermal growth factor receptor (p-EGFR), phosphorylated mitogen-activated protein kinase (p-MAPK), and phosphorylated AKT (p-AKT), in predicting gefitinib activity in advanced non-small cell lung cancer patients. Expression of the same proteins was also assessed on corresponding tissue samples for comparison. Moreover, EGFR gene mutations and copy number were analyzed., Experimental Design: Protein expression was evaluated by standard immunocytochemistry in buccal smears, obtained by scraping immediately before and after 2 weeks of gefitinib treatment, and in the available archival tumor specimens. EGFR gene mutations were evaluated by direct sequencing and gene copy number was determined by fluorescence in situ hybridization. Data were correlated with gefitinib toxicity and objective response., Results: Fifty-eight patients with pretreated advanced non-small cell lung cancer were enrolled and nine of these patients (15%) showed an objective response to gefitinib (including two complete responses). Toxicity (P = 0.025) and baseline p-AKT expression in buccal mucosa cells (P = 0.061) showed a potential predictive role. On the contrary, the probability of achieving an objective response was not affected by pretreatment expression of EGFR, p-EGFR, and p-MAPK, either in buccal mucosa or in tumor tissue. Responders showed a nonstatistically significant trend toward a more pronounced reduction in the expression of p-EGFR, p-MAPK, and p-AKT after gefitinib treatment. Among responders, five of six (83%) tumors showed EGFR gene mutation, whereas none of the tumors from patients with stable or progressive disease did (P < 0.001)., Conclusions: Epithelial cells obtained from buccal mucosa may be used to assess the pharmacodynamic effect of EGFR-targeted agents, and pretreatment p-AKT expression may be a possible predictive biomarker of in vivo gefitinib activity.