Approval Summary for Erlotinib for Treatment of Patients with Locally Advanced or Metastatic Non–Small Cell Lung Cancer after Failure of at Least One Prior Chemotherapy Regimen

Abstract

Purpose: To describe the Food and Drug Administration (FDA) review and approval of erlotinib (Tarceva, OSI Pharmaceuticals, Melville, NY) for treatment of patients with locally advanced or metastatic non^small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. Experimental Design: The FDA reviewed raw data in electronic format from a randomized controlled clinical trial comparing erlotinib with placebo in patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. Results: Patients were randomized in a 2:1 ratio (erlotinib, n = 488 and placebo, n = 243). Erlotinib was superior to placebo for survival, progression-free survival, and tumor response rate. Exploratory analyses indicate that epidermal growth factor receptor status may be an important predictor of the erlotinib survival effect. Rash (75% versus 17%) and diarrhea (54% versus 18%) in the erlotnib and placebo group respectively were the most common adverse events. Severe rash occurred in 9% and severe diarrhea in 6% of erlotinib-treated patients and each resulted in study discontinuation in 1% of patients. Dose reductions were required for 10% of patients with rash and 4% of patients with diarrhea. Conclusions: On November18, 2004, the FDA granted erlotinib regular approval for treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. The applicant has committed to conduct post-marketing clinical trials to assess further the effect of epidermal growth factor receptor expression, measured with immunohistochemical staining, on erlotinib treatment effect.Lung cancer is the leading cause of cancer death in both men and women in the United States (1). Initial therapy for advanced non -small lung cancer (NSCLC) is systemic chemotherapy with a two-drug combination regimen that often includes a platinum. Docetaxel and pemetrexed are approved by the Food and Drug Administration (FDA) for use as the second-line chemotherapy. Recently, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib was granted FDA-accelerated approval under subpart H for treatment of advanced NSCLC after failure of both platinum-based and docetaxel chemotherapy, based on a response rate of f10% in single-arm clinical trials. Erlotinib (T arceva, OSI Pharmaceuticals, Melville, NY) inhibits EGFR tyrosine kinase autophosphorylation by inhibition of the intracellular domain. Studies in cell lines and enzyme assays have both shown that erlotinib inhibits EGFR at concentrations significantly lower than those needed to inhibit c-src and v-abl. Whereas erlotinib was more selective for EGFR tyrosine kinase than it was for several other tyrosine kinases tested, several other tyrosine kinases in the same family as EGFR were not tested. Although erlotinib seems rather selective for EGFR, insufficient data exist to make a definitive decision regarding selectivity (2 -4). Chemistry and ToxicologyErlotinib hydrochloride is a quin...

Clinical Significance of Smoking Cessation in Subjects With Cancer: A 30-Year Review

“…[17][18][19][25][26][27] Every candidate for treatment with erlotinib should be strongly advised to quit smoking to achieve a higher survival rate.…”

“…Erlotinib is an oral epidermal growth factor receptor inhibitor that is currently approved in second-line and third-line treatment for non-small-cell lung cancer. 19,25 In clinical trials using erlotinib, subjects were characterized according to their smoking status as never-smokers, ex-smokers, or current smokers. All subgroups of smokers benefited from erlotinib therapy compared with placebo, but the magnitude of benefit varied with smoking status.…”

“…Median survival in the erlotinib arm was 12.3 months in never-smokers, 5.5 months in ex-smokers, and 6.12 months in current smokers (P ϭ .006). [17][18][19]25,26 These differences have been attributed to several factors, including differences in the natural history and histological type of lung cancer and pharmacokinetics of erlotinib between smokers and never-smokers. The more serious adverse events observed in ex-smokers and never-smokers receiving the erlotinib treatment are suggestive of differences in erlotinib exposure across various smoking status groups.…”

Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition inin vitroandin vivopharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice

“…It has been reported previously that food can significantly increase the bioavailability of erlotinib. In humans, the bioavailability increased from f60% to f90% when erlotinib was taken with food (42). For this reason, in our experiments, mice were fasted for 4 h before the treatment with erlotinib.…”

A chemical biology approach identifies a beta-2 adrenergic receptor agonist that causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway

“…For example, inhibitors of receptor tyrosine kinases, Ras, Raf-1 and Mek-1 have all been identified and are at various stages of development (English and Cobb, 2002;Hao and Rowinsky, 2002). Some, like the epidermal growth factor receptor (EGFR) kinase inhibitors, Iressa and Tarceva, were recently approved by the Food and Drug Administration for the treatment of patients with lung cancer (Johnson et al, 2005).…”