Treatment decisions, clinical outcomes, and pharmacoeconomics in the treatment of patients with EGFR mutated stage III/IV NSCLC in Germany: an observational study

Background: We evaluated treatment decisions and outcomes in a cohort of predominately Caucasian patients with EGFR mutation-positive (EGFR Mut+) non-small-cell lung cancer (NSCLC). Methods: REASON (NCT00997230) was a non-interventional study in German patients with stage IIIB/IV NSCLC. Secondary endpoints for EGFR Mut + NSCLC included progression-free survival (PFS), overall survival (OS), adverse event (AE) management, and pharmacoeconomic outcomes. Results: Among 334 patients with EGFR Mut + NSCLC, tyrosine kinase inhibitors (TKIs) were the most common first-line therapy (56.6%, 53.0% gefitinib). Among patients who received TKIs/gefitinib before first disease progression, PFS was longer compared with those who did not receive a TKI (median 10.1/10.0 vs. 7.0 months; HR 0.67/0.69; log-rank p = 0.012/p = 0.022). OS was longer for those patients who ever received a TKI/gefitinib during their complete therapy course compared with those who never received a TKI (median 18.4/18.1 vs. 13.6 months; HR 0.53/0.55; p = 0.003/p = 0.005). Total mean first-line treatment healthcare costs per person were higher for those receiving TKIs (€46,443) compared with those who received chemotherapy (€27,182). Mean outpatient and inpatient costs were highest with chemotherapy. Rash, diarrhea, and dry skin were the most commonly reported AEs for patients receiving gefitinib. Conclusions: In REASON, TKI therapy was the most common first- and second-line treatment for EGFR Mut + NSCLC, associated with increased drug costs compared with chemotherapy. Patients who received gefitinib or a TKI ever during their complete therapy course had prolonged PFS and OS compared with patients who did not receive a TKI. Trial registration: The trial was registered on October, 2009 with ClinicalTrials.gov : https://clinicaltrials.gov/ct2/show/NCT00997230?term=NCT00997230&rank=

Antitumor and antiangiogenic activity of cediranib in a preclinical model of renal cell carcinoma

Cediranib is a highly potent and selective vascular endothelial growth factor (VEGF) signaling inhibitor with activity against all three VEGF receptors (VEGFRs) that inhibits angiogenesis and growth of human tumor xenografts in vivo. The present study evaluated the antitumor and antiangiogenic activity of cediranib in the clinically relevant, murine renal cell carcinoma (RENCA) model and its biological response using VEGF and sVEGFR-2 as biomarkers. Mice were treated with cediranib (5 mg/kg/d p.o.) or vehicle for 2, 8 or 12 days and tumor volumes, microvessel density (MVD) and VEGF and sVEGFR-2 plasma concentrations were determined. Cediranib treatment (8 and 12 days) led to a significant reduction in tumor size (42-50%) and a highly significant reduction in MVD (30-55%) versus controls. After 12 days' treatment, VEGF plasma concentration increased significantly in both cediranib-treated and control animals and this increase correlated with tumor size; the cediranib group showed a more pronounced increase in VEGF but a reduced tumor volume compared with control animals. Plasma concentrations of VEGF reached a plateau in the cediranib group after 17-21 days' treatment. sVEGFR-2 concentrations significantly decreased over 12 days in controls, whereas they remained stable in cediranib-treated mice. sVEGFR-2 did not correlate with tumor volume in controls; mice treated with cediranib had lower relative VEGFR-2 plasma concentrations and tumor burdens. In conclusion, cediranib showed potent antitumor and antiangiogenic efficacy in the RENCA model. sVEGFR-2 plasma concentrations can act as a surrogate marker for antitumor activity of VEGFR signaling inhibitors

Additional file 1: Table S1. of Treatment decisions, clinical outcomes, and pharmacoeconomics in the treatment of patients with EGFR mutated stage III/IV NSCLC in Germany: an observational study

Treatment costs according to type of first-line treatment received by patients with EGFR Mut + NSCLC. (DOCX 15 kb

Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors

AZD2171 is a highly potent oral selective inhibitor of vascular endothelial growth factor (VEGF) signaling. This phase I study was designed to evaluate the safety and tolerability of increasing doses of AZD2171, with additional assessments of pharmacokinetics, pharmacodynamics, and efficacy.; In part A, 36 patients with solid tumors and liver metastases refractory to standard therapies received once-daily oral AZD2171 (0.5 to 60 mg). Doses were escalated in successive cohorts until the maximum-tolerated dose was identified. In part B, patients with (n = 36) or without (n = 11) liver metastases were randomly assigned to receive once-daily AZD2171 (20, 30, or 45 mg). In both parts, treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed.; Eighty-three patients received AZD2171, which was generally well tolerated at doses of 45 mg/d or less; the most frequently reported dose-related adverse events were diarrhea, dysphonia, and hypertension. The most common DLT was hypertension (n = 7), which occurred at AZD2171 doses of 20 mg and higher. After a single dose, maximum plasma (peak) drug concentration after single-dose administration (Cmax) was achieved 1 to 8 hours postdosing with an arithmetic mean half-life associated with terminal slope of a semilogarithmic concentration-time curve (t1/2 lamda(z)) of 22 hours. Pharmacodynamic assessments demonstrated time-, dose-, and exposure-related decreases in initial area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC60) using dynamic contrast-enhanced magnetic resonance imaging, as well as dose- and time-dependent reductions in soluble VEGF receptor 2 levels. Preliminary evidence of efficacy included two confirmed partial responses and 22 patients with stable disease; effects on tumor size appeared to be dose related.; Once-daily oral AZD2171 at doses of 45 mg or less was generally well tolerated and was associated with encouraging antitumor activity in patients with a broad range of advanced solid tumors