Τίτλος:
Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Background The tyrosine kinase inhibitor erlotinib improves the outcomes of patients with advanced non-small-cell lung carcinoma (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. The coexistence of the T790M resistance mutation with another EGFR mutation in treatment-naive patients has been associated with a shorter progression-free survival to EGFR inhibition than in the absence of the T790M mutation. To test this hypothesis clinically, we developed a proof-of-concept study, in which patients with EGFR-mutant NSCLC were treated with the combination of erlotinib and bevacizumab, stratified by the presence of the pretreatment T790M mutation. Methods BELIEF was an international, multicentre, single-arm, phase 2 trial done at 29 centres in eight European countries. Eligible patients were aged 18 years or older and had treatment-naive, pathologically confirmed stage IIIB or stage IV lung adenocarcinoma with a confirmed, activating EGFR mutation (exon 19 deletion or L858R mutation). Patients received oral erlotinib 150 mg per day and intravenous bevacizumab 15 mg/kg every 21 days and were tested centrally for the pretreatment T790M resistance mutation with a peptide nucleic acid probe-based real-time PCR. The primary endpoint was progression-free survival. The primary efficacy analysis was done in the intention-to-treat population and was stratified into two parallel substudies according to the centrally confirmed pretreatment T790M mutation status of enrolled patients (T790M positive or negative). The safety analysis was done in all patients that have received at least one dose of trial treatment. This trial was registered with ClinicalTrials.gov, number NCT01562028. Findings Between June 11, 2012, and Oct 28, 2014, 109 patients were enrolled and included in the efficacy analysis. 37 patients were T790M mutation positive and 72 negative. The overall median progression-free survival was 13·2 months (95% CI 10·3–15·5), with a 12 month progression-free survival of 55% (95% CI 45–64). The primary endpoint was met only in substudy one (T790M-positive patients). In the T790M-positive group, median progression-free survival was 16·0 months (12·7 to not estimable), with a 12 month progression-free survival of 68% (50–81), whereas in the T790M-negative group, median progression-free survival was 10·5 months (9·4–14·2), with a 12 month progression-free survival of 48% (36–59). Of 106 patients included in the safety analysis, five had grade 4 adverse events (one acute coronary syndrome, one biliary tract infection, one other neoplasms, and two colonic perforations) and one died due to sepsis. Interpretation The BELIEF trial provides further evidence of benefit for the combined use of erlotinib and bevacizumab in patients with NSCLC harbouring activating EGFR mutations. Funding European Thoracic Oncology Platform, Roche. © 2017 Elsevier Ltd
Συγγραφείς:
Rosell, R.
Dafni, U.
Felip, E.
Curioni-Fontecedro, A.
Gautschi, O.
Peters, S.
Massutí, B.
Palmero, R.
Aix, S.P.
Carcereny, E.
Früh, M.
Pless, M.
Popat, S.
Kotsakis, A.
Cuffe, S.
Bidoli, P.
Favaretto, A.
Froesch, P.
Reguart, N.
Puente, J.
Coate, L.
Barlesi, F.
Rauch, D.
Thomas, M.
Camps, C.
Gómez-Codina, J.
Majem, M.
Porta, R.
Shah, R.
Hanrahan, E.
Kammler, R.
Ruepp, B.
Rabaglio, M.
Kassapian, M.
Karachaliou, N.
Tam, R.
Shames, D.S.
Molina-Vila, M.A.
Stahel, R.A.
BELIEF collaborative group
Περιοδικό:
The Lancet Respiratory Medicine
Εκδότης:
The Lancet Publishing Group
Λέξεις-κλειδιά:
bevacizumab; BRCA1 protein; epidermal growth factor; erlotinib; antineoplastic agent; bevacizumab; EGFR protein, human; epidermal growth factor receptor; erlotinib, abdominal pain; acute coronary syndrome; acute diarrhea; adult; alopecia; anorexia; aphonia; Article; backache; biliary tract infection; bone pain; clinical evaluation; cohort analysis; colon perforation; comparative study; conjunctivitis; constipation; controlled study; coughing; disease course; dizziness; drug efficacy; dry skin; dysgeusia; dyspnea; epistaxis; evaluation and follow up; fatigue; female; food and drug administration; gene deletion; gene mutation; headache; health care planning; human; hypertension; lung adenocarcinoma; lung infection; major clinical study; male; middle aged; multicenter study; multivariate analysis; nausea; non small cell lung cancer; oral mucositis; outcome assessment; pain; phase 2 clinical trial; pleura effusion; priority journal; progression free survival; proteinuria; pruritus; randomized controlled trial; rash; real time polymerase chain reaction; sepsis; thromboembolism; urinary tract infection; validation process; vomiting; young adult; aged; clinical trial; disease free survival; genetics; intention to treat analysis; international cooperation; lung tumor; mutation; non small cell lung cancer; proof of concept; response evaluation criteria in solid tumors, Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Erlotinib Hydrochloride; Female; Humans; Intention to Treat Analysis; International Cooperation; Lung Neoplasms; Male; Middle Aged; Mutation; Proof of Concept Study; Receptor, Epidermal Growth Factor; Response Evaluation Criteria in Solid Tumors
DOI:
10.1016/S2213-2600(17)30129-7
