ArticlesErlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study
Introduction
Lung cancer is a leading cause of death worldwide; it is the primary cause of cancer deaths in men and the secondary cause in women.1 Most patients with lung cancer have non-small-cell lung cancer (NSCLC) and a clinically significant proportion of patients have activating mutations of EGFR.2 In this subgroup of patients, EGFR tyrosine-kinase inhibitors have consistently led to better outcomes than has standard chemotherapy.3, 4, 5, 6 Erlotinib and gefitinib have been shown to prolong progression-free survival compared with chemotherapy in several phase 3 trials.7, 8, 9, 10 Unfortunately, most patients with NSCLC with activating EGFR mutations who are given EGFR tyrosine-kinase inhibitors eventually develop resistance and relapse within about 1 year of initiation of treatment.5, 7, 8, 9, 10, 11 To improve outcomes, the foundation treatment of EGFR tyrosine-kinase inhibitors should be built on through investigation of biologically synergistic combinations.
The anti-angiogenic monoclonal antibody bevacizumab targets the VEGF signalling pathway and has been shown to provide additional efficacy when used in combination with first-line platinum-based chemotherapy in several trials in non-squamous NSCLC.12, 13, 14 The combination of erlotinib and bevacizumab has the potential to prolong progression-free survival in unselected populations of patients with NSCLC.15, 16 In a subgroup analysis of EGFR mutation-positive participants in the phase 3 BeTa study of second-line treatment of NSCLC (12 patients treated with erlotinib and bevacizumab and 18 with erlotinib alone), median progression-free survival with erlotinib plus bevacizumab in patients with EGFR mutation-positive disease was substantially higher than with erlotinib alone (17·1 months vs 9·7 months).16, 17 However, this analysis was post-hoc and EGFR mutation status was not a prespecified stratification factor in this trial. Because of this limitation, we undertook this phase 2 trial to examine the combination of erlotinib and bevacizumab in patients with EGFR mutation-positive NSCLC.
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Study design and patients
JO25567 was a randomised, open-label, multicentre, phase 2 study in patients with stage IIIB/IV (according to the 7th edition of the General Rule for Clinical and Pathological Record of Lung Cancer18) or recurrent NSCLC with activating EGFR mutations. Patients were enrolled from 30 centres across Japan.
Eligible patients had histologically or cytologically (excluding sputum cytology) confirmed stage IIIB/IV or postoperative recurrent non-squamous NSCLC with activating EGFR mutation (either exon
Results
Between Feb 21, 2011, and March 5, 2012, 154 patients were enrolled, of whom 77 were randomly assigned to receive erlotinib plus bevacizumab and 77 to erlotinib alone. Two patients withdrew before treatment started and were excluded (one had multiple thrombosis and the other had increased pleural effusion). Thus, data from 152 patients (75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group) were included in the analysis population (figure 1). The cutoff date
Discussion
In this study, the addition of bevacizumab to erlotinib significantly prolonged progression-free survival in patients with NSCLC with activating EGFR mutation-positive disease compared with erlotinib alone. To our knowledge, this is the first randomised study to show a clinically significant treatment effect of combining an EGFR tyrosine-kinase inhibitor with another biological drug in patients with activating EGFR mutation-positive NSCLC (panel). We noted clear separation of the Kaplan-Meier
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