Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models

Abstract

Our objective was the preclinical assessment of the pharmacokinetics, monotherapy and combined antitumor activity of the epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor erlotinib in athymic nude mice bearing non-small cell lung cancer (NSCLC) xenograft models. Immunohistochemistry determined the HER1/EGFR status of the NSCLC tumor models. Pharmacokinetic studies assessed plasma drug concentrations of erlotinib in tumor- and non-tumor-bearing athymic nude mice. These were followed by maximum tolerated dose (MTD) studies for erlotinib and each chemotherapy. Erlotinib was then assessed alone and in combination with these chemotherapies in the NSCLC xenograft models. Complete necropsies were performed on most of the animals in each study to further assess antitumor or toxic effects. Erlotinib monotherapy dose-dependently inhibited tumor growth in the H460a tumor model, correlating with circulating levels of drug. There was antitumor activity at the MTD with each agent tested in both the H460a and A549 tumor models (erlotinib 100 mg/kg: 71 and 93% tumor growth inhibition; gemcitabine 120 mg/kg: 93 and 75% tumor growth inhibition; cisplatin 6 mg/kg: 81 and 88% tumor growth inhibition). When each compound was given at a fraction of the MTD, tumor growth inhibition was suboptimal. Combinations of gemcitabine or cisplatin with erlotinib were assessed at 25% of the MTD to determine efficacy. In both NSCLC models, doses of gemcitabine (30 mg/kg) or cisplatin (1.5 mg/kg) with erlotinib (25 mg/kg) at 25% of the MTD were well tolerated. For the slow growing A549 tumor, there was significant tumor growth inhibition in the gemcitabine/erlotinib and cisplatin/erlotinib combinations (above 100 and 98%, respectively), with partial regressions. For the faster growing H460a tumor, there was significant but less remarkable tumor growth inhibition in these same combinations (86 and 53% respectively). These results show that in NSCLC xenograft tumors with similar levels of EGFR expression, the antitumor activity of erlotinib is robust both as monotherapy and in combination with chemotherapies.

EGFR-targeting drugs in combination with cytotoxic agents: from bench to bedside, a contrasted reality

“…Erlotinib, combined with chemotherapy, has also been studied in preclinical models of lung, pancreas, and head and neck cancer. When administered in combination with cisplatin and gemcitabine, erlotinib more effectively induced xenograft growth arrest, and this combination was more effective than either the chemotherapeutic agents or erlotinib alone (Higgins et al, 2004). Similar observations were previously reported regarding experimental chemosensitisation by EGFR blockade using mAbs, particularly C225.…”

Concomitant inhibition of epidermal growth factor and vascular endothelial growth factor receptor tyrosine kinases reduces growth and metastasis of human salivary adenoid cystic carcinoma in an orthotopic nude mouse model

“…Paclitaxel was obtained from Sigma Chemical Co. (St. Louis, MO) and administered at 200 Ag/wk, a dosing regimen that was selected on the basis of results of previous studies at our institution (14). Cisplatin was purchased from American Pharmaceutical Partners, Inc. (Schaumburg, IL) and was administered at 1.5 mg/kg/wk, a dose regimen that was previously reported in the literature (15). Propidium iodide and tetrazolium [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] were both purchased from Sigma Chemical.…”

Erlotinib in the treatment of advanced non-small cell lung cancer: an update for clinicians

“…EGFR TKIs combined with chemotherapy for advanced NSCLC in first-line setting Erlotinib improves the cytotoxic effects of chemotherapy in preclinical models [Higgins et al 2004]. So, it was proposed that combination of erlotinib and chemotherapy could further improve outcome of chemotherapy in patients with advanced NSCLC.…”