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A Phase II Pharmacodynamic Study of Erlotinib in Patients with Advanced Non–Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy

2008; American Association for Cancer Research; Volume: 14; Issue: 12 Linguagem: Inglês

10.1158/1078-0432.ccr-07-5186

1557-3265

Enriqueta Felip, Federico Rojo, Martin Reck, Astrid Heller, Barbara Klughammer, Gemma Laguillo Sala, S. Cedrés, Sergio Peralta, Heiko Maacke, Dorothee Foernzler, Marta Parera, Joachim Möcks, Cristina Saura, U. Gatzemeier, José Baselga,

Cancer therapeutics and mechanisms

Abstract Purpose: To examine potential markers of clinical benefit and the effects of erlotinib on the epidermal growth factor receptor (EGFR) signaling pathway in advanced non–small cell lung cancer patients refractory to platinum-based chemotherapy. Experimental Design: Patients were given erlotinib (150 mg/d). Tumor biopsies were done immediately before treatment and in a subgroup of patients after 6 weeks' treatment. Results: Of 73 evaluable patients, 7 (10%) had partial response and 28 (38%) had stable disease. In 53 patients with baseline tumor samples, no relationship was observed between pretreatment levels of EGFR, phosphorylated (p)-EGFR, p-AKT, p-mitogen-activated protein kinase (MAPK), or p27 and clinical benefit (i.e., response, or stable disease ≥12 weeks). Tumors from 15 of 57 patients had high EGFR gene copy number, assessed using fluorescence in situ hybridization (FISH positive), 10 of whom had clinical benefit, compared with 5 of 42 FISH-negative patients. FISH-positive patients had longer median progression-free [137 versus 43 days, P = 0.002; hazard ratio (HR), 0.37] and overall (226 versus 106 days, P = 0.267; HR, 0.70) survival than FISH-negative patients. In paired biopsy samples from 14 patients, p-EGFR (P = 0.002), p-MAPK (P = 0.001), and Ki-67 (P = 0.025) levels were significantly reduced after 6 weeks' treatment. Apoptosis was significantly increased in patients with clinical benefit (P = 0.029), and may be a marker of clinical benefit. Conclusion: In this study, EGFR FISH-positive status was associated with improved outcome after erlotinib therapy. Erlotinib led to reduced levels of p-EGFR, p-MAPK, and Ki-67, and stimulated apoptosis in tumor samples from patients with clinical benefit.