Abstract A43: EGFR-targeted therapy in African Americans with advanced non-small cell lung cancer: A prospective clinical, pharmacogenetic, and pharmacokinetic study.

Context: Focused evaluation of the efficacy and pharmacokinetics of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and the potential influence of pharmacogenetics and tumor genetics, has not been previously performed in African American patients with Non-Small Cell lung cancer (NSCLC). Objective: To evaluate disease control rate (DCR) in African American patients with NSCLC produced by erlotinib, the effect of its titration to rash occurrence, and to characterize pharmacokinetics of parent drug and metabolite, tumor genetics, and pharmacogenetics of erlotinib metabolizing enzymes and transporter genes. Design, Setting and Patients: 55 African Americans with NSCLC on a 2-stage-minimax randomized phase II study. Intervention: Patients received erlotinib 150 mg daily or a dose based on body weight with subsequent escalations to 200 mg to achieve skin rash. Main Outcome Measures: The primary endpoint was DCR (CR+PR+SD) at 3 months. Time to progression and 1-year survival were also evaluated. Results: 12 of 52 evaluable patients had disease control at 3 months; 6 per arm. Absence of skin rash on therapy was associated with early PD (10/11), exposures for erlotinib and OSI-420 were lower compared to previous reports, and pharmacogenetic factors were consistent with high erlotinib clearance in most patients. Tumor genetics showed one EGFR exon 19 mutation, a novel EGFR exon 20 missense mutation, EGFR amplification in 17/47 samples, 8 KRAS mutations and 5 EML4-ALK translocations. Conclusions: Results from this trial support the serial linkage of cytochrome P450 pharmacogenetics, erlotinib pharmacokinetics, rash, and response. Factors consistent with high erlotinib metabolism are predominantly present in African Americans. However, the dose-to-rash strategy failed to increase clinical benefit within the dose-range tested, and a relatively high incidence of tumor genetics associated with erlotinib resistance was found. As with other ethnicities, assessment of tumor genetics is recommended. The high clearance data suggests that the concept of standard erlotinib dosing in African American patients should be reconsidered Citation Format: Mitch Phelps, Thomas Stinchcombe, James S. Blachly, Weiqiang Zhao, Larry J. Schaaf, Sherri L. Starrett, Gregory Otterson, William Hicks, Mark Socinski, Miguel Villalona-Calero. EGFR-targeted therapy in African Americans with advanced non-small cell lung cancer: A prospective clinical, pharmacogenetic, and pharmacokinetic study. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A43.