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

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

doi:10.1016/s1470-2045(11)70393-x

Cited by 5,489Lung Cancer Treatments and MutationsLung Cancer Diagnosis and TreatmentLung Cancer Research Studies

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

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Rosell, Rafael, Carcereny, Enric, Gervais, Radj, Vergnenegre, Alain, Massuti, Bartomeu, Felip, Enriqueta, Palmero, Ramon, Garcia-Gomez, Ramon +49 more·2012·The Lancet Oncology

DOI 10.1016/s1470-2045(11)70393-x

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Abstract

Background 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.Methods 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/m(2) on day 1 plus docetaxel (75 mg/m(2) on day 1) or gemcitabine (1250 mg/m(2) on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m(2) or AUC 5 with gemcitabine 1000 mg/m(2)) 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.Findings 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.Interpretation 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.Funding Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.

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First-generation EGFR TKIs gefitinib and erlotinib have shown improved efficacy and tolerability compared with chemotherapy in phase III trials.
“have shown improved efficacy and tolerability compared with chemotherapy in numerous phase III trials”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [32]
Reduced sensitivity to gefitinib or erlotinib in NSCLC was linked to EGFR-specific activating mutations.
“Afterwards, studies revealed that the reduced sensitivity to gefitinib or erlotinib in NSCLC was linked to EGFR-specific activating mutations.112–116”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [116]
Third-generation EGFR-TKIs (WZ4002, CO-1686, AZD9291 and HM61713) irreversibly block T790M mutant EGFR and have demonstrated tumour responses in >50% of patients with the EGFR T790M mutation.
“The third-generation EGFR-TKIs include the WZ4002, CO-1686, AZD9291 and HM61713 inhibitors, which have demonstrated tumour responses in >50% of patients with the EGFR T790M mutation.8–12”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [9]
Eight randomised controlled phase III trials have demonstrated that first-generation or second-generation EGFR-TKIs represent the best first-line treatment option in patients with advanced NSCLC whose tumours harbour EGFR mutations, when compared with chemotherapy, because they significantly improved the RR and PFS.
“Eight randomised controlled phase III trials (table 1) have demonstrated that first-generation or second-generation EGFR-TKIs represent the best first-line treatment option in patients with advanced NSCLC whose tumours harbour EGFR mutations, when compared with chemotherapy, because they significantly improved the RR and progression-free survival (PFS).4–11”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [9]
Patients with EGFR-mutant NSCLC usually respond to first-generation TKIs but most progress after about 9-14 months.
“Unfortunately, whilst patients with EGFRm+ tumors typically show good initial responses to first generation TKIs, most patients who respond to therapy ultimately develop disease progression after about 9-14 months of treatment (7-11).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [10]

In first-line targeted therapy trials for oncogene-addicted NSCLC, objective response rates typically range from 50% to 83%, complete responses are rare, and some patients show de novo resistance.
“Across clinical trials of first-line targeted therapy for oncogene-addicted subgroups of NSCLC, rates of objective response [G] typically range between 50% and 83% and complete responses [G] are rare; in addition, some patients exhibit de novo resistance16–26, 28–32, 35.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [18]
Duration of response, progression-free survival, and overall survival are even more variable across these trials.
“Even more variable are duration of response to targeted therapy, progression-free survival and overall survival16–26, 28–32, 35.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [18]
The magnitude of progression-free survival improvement in this study is similar to that in studies of EGFR-mutation-positive tumors treated with first-line EGFR tyrosine kinase inhibitors.
“The magnitude of the improvement in progression-free survival observed in the current study is similar to that observed in studies of EGFR-mutation-positive tumors treated with firstline EGFR tyrosine kinase inhibitors.[24][25][26]”
From First-Line Crizotinib versus Chemotherapy in ALK -Positive Lung Cancer (2014) · cites this paper as [25]
EGFR exon 19 deletions and EGFR exon 21 L858R are exquisitely sensitive to approved EGFR TKIs such as erlotinib, gefitinib, and afatinib.
“EGFR exon 19 deletions and EGFR exon 21 L858R represent the vast majority of EGFR activating mutations, and are exquisitely sensitive to approved EGFR TKIs such as erlotinib, gefitinib, and afatinib”
From Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC (2018) · cites this paper as [2]
Acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors develops after a median of 9 to 13 months.
“acquired resistance develops after a median of 9 to 13 months [2][3][4]”
From Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [3]
Targeted therapies are approved for patients with classical EGFR mutations and a small number of other mutations.
“Targeted therapies are approved for patients with ‘classical’ mutations and a small number of other mutations4–6.”
From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [4]
Patients with classical EGFR mutations show marked improvements in clinical outcomes when treated with first-, second- or third-generation tyrosine kinase inhibitors (TKIs).
“Patients with classical EGFR mutations (L858R or exon 19 deletions (Ex19del)) show marked improvements in clinical outcomes when treated with first-, second- or third-generation tyrosine kinase inhibitors (TKIs)4–6,11.”
From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [4]
The current diagnostic approach of testing only for common exon 19 and 21 mutations, as done in EURTAC or OPTIMAL, might miss identifying a number of patients who could have some benefit from EGFR TKI treatment.
“One potential limitation of the current diagnostic approach of testing only for common exon 19 and 21 mutations, as was done in the EURTAC or OPTIMAL studies, 4,5 is that such an approach might miss identifying a number of patients who could have some benefit from EGFR TKI treatment.”
From Examining Treatment Outcomes with Erlotinib in Patients with Advanced Non–Small Cell Lung Cancer Whose Tumors Harbor Uncommon EGFR Mutations (2016) · cites this paper as [5]
The cohort's OS from diagnosis was strikingly longer than the 19-28 month median OS reported for first- or second-generation EGFR TKIs.
“a strikingly long survival compared to median OS of 19–28 months with first- or second-generation EGFR TKIs[17–19].”
From Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR -Mutant NSCLC (2018) · cites this paper as [19]
Randomized trials show that EGFR TKIs improve response rate and progression-free survival compared with chemotherapy as initial systemic therapy for advanced EGFR-mutant NSCLC.
“Several randomized clinical trials have demonstrated that EGFR TKIs are more effective, as measured by response rate (RR) and progression free survival (PFS), than chemotherapy when used as initial systemic treatment for advanced EGFR mutant NSCLC (1, 4–9).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [4]
EGFR tyrosine kinase inhibitors are effective clinical treatments for advanced non-small cell lung cancer with EGFR mutations.
“Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective clinical therapies for EGFR mutant advanced non small cell lung cancer (NSCLC) patients (1–4).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [4]
The extension of approval of Erlotinib for patients harboring EGFR mutations was obtained after two large phase III trials conducted in Asia and Europe provided definitive demonstration of superiority of an EGFR TKI over standard first-line chemotherapy in molecularly selected patients.
“The extension of approval of Erlotinib for patients harboring EGFR mutations, in addition to the previous indication for unselected patients with NSCLC after at least one chemotherapeutic line, was obtained after the publication of two large phase III trials conducted in Asia [65] and Europe [66], providing the definitive demonstration of superiority of an EGFR TKI over standard first-line”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [66]
Disease progresses in most patients after 9 to 13 months of first-line EGFR-TKI therapy.
“Despite high tumor response rates with first-line EGFR-TKIs, disease progresses in a majority of patients after 9 to 13 months of treatment.5–12”
From Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer (2017) · cites this paper as [8]
Disease progresses in most patients after 9 to 13 months of first-line EGFR-TKI therapy.
“Despite high tumor response rates with first-line EGFR-TKIs, disease progresses in a majority of patients after 9 to 13 months of treatment.5–12”
From Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer (2017) · cites this paper as [7]
Acquired resistance to conventional EGFR-TKIs develops after a median of 10 to 12 months and is most commonly mediated by an acquired T790M mutation.
“Resistance to conventional EGFR-TKIs develops after a median of 10 to 12 months and is most commonly mediated by an acquired mutation, T790M1-5.”
From Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non–Small-Cell Lung Cancer (2016) · cites this paper as [3]
Several studies have consistently shown that EGFR TKIs (gefitinib, erlotinib, afatinib) produce higher response rates, longer PFS and improved quality of life compared with platinum-based doublet chemotherapy in PS 0-2 patients whose tumours have an activating EGFR mutation.
“Several studies have consistently demonstrated that the EGFR TKIs (gefitinib, erlotinib and afatinib) produce higher RRs, longer PFS and improve QoL compared with standard platinum-based doublet chemotherapy in patients with good PS (PS 0-2), whose tumour harbours an activating (sensitising) EGFR mutation [105-112].”
From Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2016) · cites this paper as [112]
In one small study comparing first-line erlotinib with chemotherapy, there was a PFS benefit with erlotinib (9.7 v 5.2 months; HR, 0.37; 95% CI, 0.25 to 0.54; P < .001).
“In one small study, there was a PFS benefit with erlotinib (9.7 v 5.2 months; HR, 0.37; 95% CI, 0.25 to 0.54; P < .001); OS had not been reached by the time of publication.29”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [29]
Since the publication of the ASCO 2009 guideline and the ASCO EGFR provisional clinical opinion, results from seven trials of first-line EGFR TKIs for patients with EGFR mutations have been published.
“Since the publication of the ASCO 2009 guideline and the ASCO EGFR provisional clinical opinion,59 results from seven trials of first-line EGFR TKIs for patients with EGFR mutations have been published.11,13,29,31,34,36,40”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [29]
Lung cancers harboring EGFR mutations are highly responsive to single-agent EGFR inhibitors with RECIST response rates of ~55%-75%.
“It is now well established that lung cancers harboring these EGFR mutations are highly responsive to single-agent EGFR inhibitors with RECIST response rates of ~55%–75% (Mok et al., 2009; Rosell et al., 2012; Sequist et al., 2013b).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Rosell et al., 2012

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Authors: Rosell, R., Carcereny, E., Gervais, R., Vergnenegre, A., Massuti, B., Felip, E., Palmero, R., Garcia-Gomez, R., Pallares, C., Sanchez, J. M., Porta, R., Cobo, M., Garrido, P., Longo, F., Moran, T., Insa, A., De Marinis, F., Corre, R., Bover, I., Illiano, A., Dansin, E., de Castro, J., Milella, M., Reguart, N., Altavilla, G., Jimenez, U., Provencio, M., Moreno, M. A., Terrasa, J., Muñoz-Langa, J., Valdivia, J., Isla, D., Domine, M., Molinier, O., Mazieres, J., Baize, N., Garcia-Campelo, R., Robinet, G., Rodriguez-Abreu, D., Lopez-Vivanco, G., Gebbia, V., Ferrera-Delgado, L., Bombaron, P., Bernabe, R., Bearz, A., Artal, A., Cortesi, E., Rolfo, C., Sanchez-Ronco, M., Drozdowskyj, A., Queralt, C., de Aguirre, I., Ramirez, J. L., Sanchez, J. J., Molina, M. A., Taron, M., & Paz-Ares, L.
Affiliations: Institut Català d'Oncologia (ES)
Centre François Baclesse (FR)
Vall d'Hebron Hospital Universitari (ES)
Hospital Universitario Ramón y Cajal (ES)
Policlinico Umberto I (IT)
Hospital Clínico Universitario de Valencia (ES)
Hôpital Pontchaillou (FR)
Hospital Son Llatzer (ES)
Azienda Ospedaliera Universitaria Policlinico "G. Martino" (IT)
Hospital Universitario Puerta de Hierro Majadahonda (ES)
Hospital Universitario Son Dureta (ES)
Hospital Universitario Virgen de las Nieves (ES)
Hospital Clínico Universitario Lozano Blesa (ES)
Centre Hospitalier du Mans (FR)
Centre Hospitalier Universitaire d'Angers (FR)
La Maddalena (IT)
Hospital Universitario Nuestra Señora de Candelaria (ES)
Centre Hospitalier de Mulhouse (FR)
Centro di Riferimento Oncologico (IT)
Hospital Universitario Miguel Servet (ES)
Sapienza University of Rome (IT)
Clinica Rotger (ES)
Pivotal (Spain) (ES)
Hospital Universitario Virgen del Rocío (ES)
Corresponding author: Rosell, Rafael
ORCID: Rosell, Rafael
Carcereny, Enric
Gervais, Radj
Felip, Enriqueta
Cobo, Manuel
Garrido, Pilar
Longo, Flavia
Insa, Amelia
Corre, Romain
Altavilla, Giuseppe
Provencio, Mariano
Valdivia, Javier
Isla, Dolores
Molinier, Olivier
Gebbia, Vittorio
Bearz, Alessandra
Artal, Angel
Cortesi, Enrico
Rolfo, Christian
Queralt, Cristina
Paz-Ares, Luis
Venue: The Lancet Oncology
Publisher: Elsevier BV
Published: 2012-03
Volume: 13
Issue: 3
Pages: 239-246
ISSN: 1470-2045 (ISSN-L)
DOI: 10.1016/s1470-2045(11)70393-x
OpenAlex: W2111662961
Cited by: 5,489
References: 9
Citations by year: 2026: 92 · 2025: 169 · 2024: 216 · 2023: 269 · 2022: 367 · 2021: 422 · 2020: 441 · 2019: 440 · 2018: 498 · 2017: 534 · 2016: 509 · 2015: 537 · 2014: 448 · 2013: 401 · 2012: 138
FWCI: 392.78
Type: journal article
Language: en
Open access: green
hdl.handle.net
Licence: other-oa
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: The Lancet Oncology (publishedVersion)
PubMed (publishedVersion)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, other-oa)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords: erlotinib, EGFR-mutant non-small cell lung cancer, first-line therapy, exon 19 deletion, L858R mutation, cisplatin, docetaxel, gemcitabine, carboplatin, progression-free survival, targeted therapy, European patients, drug safety, adverse events, treatment discontinuation, EGFR tyrosine kinase inhibitors
MeSH terms: Erlotinib Hydrochloride, Docetaxel, Gemcitabine, Administration, Oral, Aged, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Cisplatin, Deoxycytidine, Drug Administration Schedule, Europe, Exons, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Prospective Studies, Quinazolines, Time Factors, Chi-Square Distribution, Proportional Hazards Models, Carboplatin, Treatment Outcome, Disease-Free Survival, Patient Selection, Taxoids, Protein Kinase Inhibitors, Kaplan-Meier Estimate, Precision Medicine, Molecular Targeted Therapy, ErbB Receptors

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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

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