Journal Article

Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial

Provencio, Mariano, Milella, Michele, Isla, Dolores, Molinier, Olivier, Bernabe, Reyes, Molina, Miguel Angel, Drozdowskyj, Ana, Altavilla, Giuseppe, Robinet, Gilles, Lopez-Vivanco, Guillermo, Bombaron, Pierre, De Marinis, Filippo, Ferrera-Delgado, Lioba, Bearz, Alessandra, Sanchez, Jose Miguel, Palmero, Ramon, Porta, Rut, Garrido, Pilar, Massuti, Bartomeu, Felip, Enriqueta, Jimenez, Ulpiano, Corre, Romain, Rosell, Rafael, Cortesi, Enrico, Sanchez, Jose Javier, Queralt, Cristina, Illiano, Alfonso, Mazieres, Julien, Terrasa, Josefa, Gervais, Radj, Longo, Flavia, Dansin, Eric, Gebbia, Vittorio, Rodriguez-Abreu, Delvys, Baize, Nathalie, Pallares, Cinta, Muñoz-Langa, Jose, Taron, Miquel, Vergnenegre, Alain, Garcia-Gomez, Ramon, de Castro, Javier, Artal, Angel, Paz-Ares, Luis, Bover, Isabel, Garcia-Campelo, Rosario, Ramirez, Jose Luis, de Aguirre, Itziar, Rolfo, Christian, Carcereny, Enric, Cobo, Manuel, Valdivia, Javier, Reguart, Noemi, Domine, Manuel, Moran, Teresa, Insa, Amelia, Sanchez-Ronco, Maria, Moreno, Miguel Angel

2012

Overview

Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (>18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m2 on day 1 plus docetaxel (75 mg/m2 on day 1) or gemcitabine (1250 mg/m2 on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m2 or AUC 5 with gemcitabine 1000 mg/m2) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5–5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25–0·54; p<0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.

• Publisher: Elsevier Ltd
• Subject: Adjuvants / Administration, Oral / Aged / Anemia / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Carboplatin / Carboplatin - administration & dosage / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - enzymology / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - mortality / Carcinoma, Non-Small-Cell Lung - pathology / Chemotherapy / Chi-Square Distribution / Cisplatin / Cisplatin - administration & dosage / Clinical trials / Data processing / Deoxycytidine - administration & dosage / Deoxycytidine - analogs & derivatives / Disease-Free Survival / Drug Administration Schedule / Drugs / Epidermal growth factor receptors / Erlotinib Hydrochloride / Europe / Exanthema / Exons / Female / gemcitabine / Gene deletion / Hematology, Oncology and Palliative Medicine / Hospitals / Humans / Intravenous administration / Kaplan-Meier Estimate / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - enzymology / Lung Neoplasms - genetics / Lung Neoplasms - mortality / Lung Neoplasms - pathology / Male / Metastases / Middle Aged / Molecular Targeted Therapy / Mutation / Neutropenia / Oncology / Patient Selection / Precision Medicine / Proportional Hazards Models / Prospective Studies / Protein Kinase Inhibitors - administration & dosage / Protein Kinase Inhibitors - adverse effects / Protein Kinase Inhibitors - therapeutic use / Quinazolines - administration & dosage / Quinazolines - adverse effects / Quinazolines - therapeutic use / Receptor, Epidermal Growth Factor - antagonists & inhibitors / Receptor, Epidermal Growth Factor - genetics / Survival / Taxoids - administration & dosage / Time Factors / Toxicity / Treatment Outcome