Modulation of Fexofenadine Pharmacokinetics by Osimertinib in Patients With Advanced EGFR-Mutated Non-Small Cell Lung Cancer.

Osimertinib is a potent, third-generation, irreversible, central nervous system active epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. It is approved for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, and for patients with T790M-positive advanced NSCLC whose disease has progressed on or after EGFR-TKI therapy. This study investigated the pharmacokinetics (PK) of fexofenadine (P-glycoprotein substrate) following single- and multiple-dose osimertinib in patients with advanced NSCLC who have progressed on prior EGFR-TKI therapy. This open-label, phase 1 study (NCT02908750) comprised the PK phase and continued access phase. The former comprised 2 distinct periods with a 3- to 7-day washout: treatment period 1 (n = 24, fexofenadine 120 mg, day 1) and treatment period 2 (fexofenadine 120 mg + osimertinib 80 mg single dose on days 1 and 39 and osimertinib 80 mg once daily from days 4 to 41). Patients could continue osimertinib 80 mg once daily based on investigator's discretion in the continued access phase. Fexofenadine area under the plasma concentration-time curve and maximum concentration increased by 56% (90% confidence interval [CI], 35.4-78.6) and 76% (90%CI, 49.3-108.3) following coadministration with osimertinib single dose, and by 27% (90%CI, 11.2-45.8) and 25% (90%CI, 5.6-48.1) when given with osimertinib at steady state, respectively. Following osimertinib coadministration, median fexofenadine time to maximum concentration increased by approximately 30 minutes compared with time to maximum concentration following fexofenadine alone. No new osimertinib safety findings were observed. The increase in fexofenadine exposure following osimertinib coadministration shows osimertinib as a weak P-glycoprotein inhibitor.

Validation of the Mandarin Chinese version of the Leicester Cough Questionnaire in non-small cell lung cancer patients after surgery.

BACKGROUND: There are no validated and reliable cough-specific instruments to assess health-related quality of life with respect to postoperative cough in non-small cell lung cancer (NSCLC) patients. We used the Leicester Cough Questionnaire in Mandarin-Chinese (LCQ-MC) and investigated the validity, reliability, and repeatability of this instrument. METHODS: A total of 130 NSCLC patients (average age 58.75 ± 9.43 years, 65 men, 65 women) completed the LCQ-MC, cough Visual Analogue Scale (VAS), Cough Symptom Score (CSS), Hospital Anxiety and Depression Scale (HADS), and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). Forty patients completed the LCQ-MC again one week later. Concurrent validity, internal consistency, and repeatability were assessed. RESULTS: Analyses of concurrent validity showed significant correlations between the LCQ-MC and the cough VAS (r = -0.488 to -0.660) and CSS (r = -0.495 to -0.601). The corresponding domains of the LCQ-MC and the SF-36 exhibited moderate correlations (r = 0.421-0.432). However, there was no significant correlation between the LCQ-MC and the HADS (P > 0.05). Internal consistency was acceptable (Cronbach's α of 0.74-0.90). Test-retest reliability was high (intraclass correlation coefficients of 0.89-0.95). CONCLUSION: The LCQ-MC is a reliable, valid instrument for assessing postoperative cough in NSCLC patients.

[Clinical characteristics and outcomes of lung cancer patients 
with EGFR mutations in exons 19 and 21].

BACKGROUND AND OBJECTIVE: Studies on the epidermal growth factor receptor (EGFR) signaling pathways and the therapeutic effects of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have recently proven that targeted therapy has a major role in the treatment of lung cancer. However, the therapeutic effects of EGFR-TKIs on lung cancers with different EGFR mutation subtypes remain unclear. And if there is a significant difference in the effects of EGFR-TKIs, the mechanisms for the difference remain unclear. The aim of this study was to investigate the clinical importance of EGFR mutations in exons 19 and 21 of lung cancer patients and to compare the outcomes of these patients. METHODS: The study recruited 113 patients who had non-small cell lung cancer (NSCLC) with EGFR mutations. EGFR mutations were detected for 47 patients using Real-time PCR or DNA sequencinag. The mutations of the remaining patients were determined using xTag-EGFR liquid chip technology. All stages I-III patients underwent radical resection followed by 4 cycles of postoperative chemotherapy. Patients with pleural metastases underwent pleural biopsy, pleurodesis, and chemotherapy only. Patients with distant metastases underwent biopsy and chemotherapy only. Collected clinical data were analyzed using SPSS 19.0 software. RESULTS: EGFR exon mutations 19 and 21 were found in 56 and 57 patients, respectively. The mean age of patients with exon 19 mutations was lower than the age of the patients with exon 21 mutations (57.02±11.31 years vs 62.25±7.76 years, respectively; P<0.05). The primary tumors of patients with exon 19 mutations were more likely occur in the right lung. There were no significant differences in gender, smoking status, histopathology, level of differentiation, and stage of disease (P>0.05) between the patients with exon 19 and 21 mutations; and survival analysis of 91 (80.5%) patients with complete clinical data found no differences in overall survival. Stratification analysis found out that patients with exon 19 mutations had longer overall survival associated with age>61 years, male gender, ever smoking, and stage IV disease; although the differences were not significant. CONCLUSIONS: Compared to the lung cancer patients with EGFR exon 21 mutations, the patients with EGFR exon 19 mutations were younger, and their primary tumors were more likely to occur in the right lung. There were no significant differences between the lung cancer patients with exon 19 and 21 mutations for overall survival, gender, smoking status, histopathology, level of differentiation, and disease stage.

Epidermal growth factor receptor mutation subtypes and geographical distribution among Indian non-small cell lung cancer patients.

BACKGROUND: The Medical Oncology Department at Tata Memorial Hospital, the single largest tertiary cancer care center in Asia, receives in-house registered and referral patient samples from all parts of the country. Our recent studies establish 23% EGFR mutation frequency among Indian population. Here, we extend our study and report further analysis of distribution of different types of EGFR mutations in 1018 non small cell lung cancer patient, and its co-relation with clinical parameters and geographical variations across the country. MATERIAL AND METHODS: This study is a retrospective analysis on all the patients who were referred for EFGR testing as a routine service over a 1.5 year period. This was part of standard care. EGFR kinase domain mutations in exon 18-21 were probed by TaqMan probe-based assays in 1018 NSCLC patients. RESULTS AND DISCUSSION: While EGFR exon 19 mutations, the most frequent EGFR mutation, were found be higher among non smokers females, we find surprisingly higher incidence of exon 21 mutations among EGFR mutation positive male smokers of Indian ethnicity. Furthermore, as Indian population is known to be composed of a gradient admixture of Ancestral North Indian (with genetic influence from Middle Easterners, Central Asians, and Europeans harboring variant EGFR mutation frequency) and Ancestral South Indians, as a paradox our study indicates comparable EGFR mutation frequency across different geographical locations within India CONCLUSION: Geographically there is uniform distribution in the EGFR mutation frequency within India. Further more, while exon 19 mutations are predominant among non smokers, higher incidence of exon 21 mutations exists among EGFR mutation positive male smokers of Indian ethnicity.

Thiazolidinediones enhance vascular endothelial growth factor expression and induce cell growth inhibition in non-small-cell lung cancer cells.

BACKGROUND: It is known that thiazolidinediones are involved in regulating the expression of various genes, including the vascular endothelial growth factor (VEGF) gene via peroxisome proliferator-activated receptor gamma (PPARgamma); VEGF is a prognostic biomarker for non-small-cell lung cancer (NSCLC). METHODS: In this study, we investigated the effects of troglitazone and ciglitazone on the mRNA expression of VEGF and its receptors in human NSCLC cell lines, RERF-LC-AI, SK-MES-1, PC-14, and A549. These mRNA expressions were evaluated by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. We also studied the effect of Je-11, a VEGF inhibitor, on the growth of these cells. RESULTS: In NSCLC cells, thiazolidinediones increased the mRNA expression of VEGF and neuropilin-1, but not that of other receptors such as fms-like tyrosine kinase and kinase insert domain receptor-1. Furthermore, the PPARgamma antagonist GW9662 completely reversed this thiazolidinedione-induced increase in VEGF expression. Furthermore, the addition of VEGF inhibitors into the culture medium resulted in the reversal of thiazolidinedione-induced growth inhibition. CONCLUSIONS: Our results indicated that thiazolidinediones enhance VEGF and neuropilin-1 expression and induce the inhibition of cell growth. We propose the existence of a pathway for arresting cell growth that involves the interaction of thiazolidinedione-induced VEGF and neuropilin-1 in NSCLC.

Targeted therapies for non-small cell lung cancer.

Despite recent advances in current chemotherapy, the prognosis for locally advanced and metastatic nonsmall-cell cancer remains poor, and new approaches are required. An increased understanding of the biology of lung cancer has identified pathways mediated by receptor tyrosine kinases as an important target. The epidermal growth factor receptor (EGFR) is frequently expressed on the surface of the lung cancer cell. EGFR can be targeted by inhibitors of receptor tyrosine kinase activity such as erlotinib and gefitinib and by antibodies specific for the extracellular domain. Subset analysis of responders to the receptor tyrosine kinase inhibitors suggests that clinical benefit may correlate with the presence of EGFR mutations. Other drugs in earlier clinical development include those directed against HER-2, VEGF, farnesyl transferase, COX-2 and retinoid receptor.