ArticlesSafety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study
Introduction
Advanced non-small-cell lung cancer (NSCLC) is one of the most common types of cancer, with 1·35 million newly diagnosed cases and 1·18 million deaths worldwide every year.1 Bevacizumab is the first and only approved anti-vascular endothelial growth factor (anti-VEGF) therapy for first-line treatment of non-squamous NSCLC. The drug is also licensed by the European Medicines Agency and the US Food and Drug Administration (FDA) for treatment of colorectal cancer, breast cancer, and renal-cell cancer, and by the FDA for treatment of glioblastoma multiforme.
First-line bevacizumab-based therapy followed by single-agent bevacizumab until disease progression improves clinical outcomes compared with chemotherapy alone in patients with advanced non-squamous NSCLC, as shown in two phase 3 trials (E4599 and BO17704 [AVAiL]).2, 3 In E4599, the hazard ratios (HRs) for progression-free survival (PFS) and overall survival were 0·66 (95% CI 0·57–0·77; p<0·001) and 0·79 (0·67–0·92; p=0·003), respectively, for bevacizumab-based therapy versus chemotherapy alone.2 Furthermore, in a preplanned analysis of E4599, bevacizumab-based therapy improved median overall survival in patients with adenocarcinoma histology to 14·2 months versus 10·3 months with chemotherapy alone (HR 0·69, 0·58–0·83).4 In the AVAiL trial, PFS was significantly improved with bevacizumab-based therapy versus chemotherapy plus placebo (bevacizumab 7·5 mg/kg: HR 0·75, 0·62–0·91, p=0·003; 15 mg/kg: HR 0·82, 0·68–0·98, p=0·03).3 Although median overall survival in AVAiL was longer than 13 months in all treatment groups, overall survival did not differ between the bevacizumab groups and the chemotherapy plus placebo group (bevacizumab 7·5 mg/kg: HR 0·93, 0·78–1·11, p=0·420; 15 mg/kg: HR 1·03, 0·86–1·23, p=0·761).5
Results of phase 2 and phase 3 clinical trials have shown a manageable adverse-event profile for bevacizumab in non-squamous NSCLC. In a phase 2 trial, pulmonary bleeding seemed to be more common in patients with squamous-cell carcinoma than in those with non-squamous disease.6 The subsequent exclusion of patients with squamous-cell histology from clinical trials of bevacizumab in NSCLC reduced the incidence of grade 3 or higher pulmonary bleeding, which occurred in 1·9% of bevacizumab-treated patients in E4599, and in 1·5% and 0·9% of patients receiving bevacizumab 7·5 mg/kg and 15 mg/kg, respectively, in AVAiL. In E4599 and AVAiL, the incidence of hypertension, proteinuria, and bleeding were higher in the bevacizumab groups than in the control groups.2, 3
Although phase 3 trials remain the gold standard for assessment of new treatments, such trials are done in strictly defined patient populations. Phase 4 studies offer the opportunity to assess treatments in a broad patient population, mirroring clinical practice in the community setting. SAiL (Safety of Avastin in Lung) was a phase 4 study undertaken in a large patient population, with the aim of assessing the safety and efficacy of first-line bevacizumab combined with several standard chemotherapy regimens in patients with advanced or recurrent non-squamous NSCLC. We report final safety and efficacy data for first-line bevacizumab-based therapy in patients with non-squamous NSCLC.
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Patients
Participants in this open-label, multicentre, single group, phase 4 study were recruited from 40 countries across six continents. Eligible patients had histologically or cytologically documented inoperable, locally advanced (stage IIIB with supraclavicular lymph node metastases or malignant pleural or pericardial effusion), metastatic (stage IV), or recurrent non-squamous NSCLC; an ECOG performance status of 0–2; and adequate haematological, hepatic, and renal function. Patients with mixed,
Results
Patients were recruited between August, 2006, and June, 2008. At the final data cutoff (July 24, 2009), an ITT population of 2212 patients was assessed. Table 1 shows demographic and baseline characteristics for the ITT population. 1624 (73%) patients were receiving concomitant drugs at baseline. 699 (32%) patients were receiving antihypertensive treatment: 248 (11%) patients were taking angiotensin-converting enzyme inhibitors; 240 (11%) received β blockers; 183 (8%) received diuretic drugs;
Discussion
The primary objective of SAiL was to assess the safety of first-line bevacizumab in a broad population of patients with metastatic non-squamous NSCLC. The study findings confirm the well-established and manageable safety profile of bevacizumab, add to the efficacy evidence supporting the use of bevacizumab in first-line treatment, and establish the relevance of findings from randomised phase 3 studies to treatment with bevacizumab in a clinical-practice setting.
Safety data from SAiL build on
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