Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study

Summary

Background

Results of two phase 3 trials have shown first-line bevacizumab in combination with chemotherapy improves clinical outcomes in patients with advanced or recurrent non-squamous non-small-cell lung cancer (NSCLC). The SAiL (MO19390) study was undertaken to assess the safety and efficacy of first-line bevacizumab combined with standard chemotherapy regimens in clinical practice.

Methods

Between August, 2006, and June, 2008, patients with untreated locally advanced, metastatic, or recurrent non-squamous NSCLC were recruited to this open-label, single group, phase 4 study from centres in 40 countries. Eligible patients had histologically or cytologically documented inoperable, locally advanced, metastatic, or recurrent disease (stage IIIB–IV); an Eastern Cooperative Oncology Group performance status of 0–2; and adequate haematological, hepatic, and renal function. Patients received bevacizumab (7·5 or 15 mg/kg every 3 weeks) plus standard chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety; analysis was by intention to treat (ITT). This study is registered with ClinicalTrials.gov, number NCT00451906.

Findings

At the final data cutoff (July 24, 2009), an ITT population of 2212 patients was assessed. The incidence of clinically significant (grade ≥3) adverse events of special interest was generally low; thromboembolism occurred in 172 (8%) patients, hypertension in 125 (6%), bleeding in 80 (4%), proteinuria in 67 (3%), and pulmonary haemorrhage in 15 (1%). 57 (3%) patients died because of these adverse events, with thromboembolism (26 patients, 1%) and bleeding (17, 1%) as the most common causes. The most common grade 3 or higher serious adverse events deemed by investigators to be associated with bevacizumab were pulmonary embolism (28 patients; 1%) and epistaxis, neutropenia, febrile neutropenia, and deep vein thrombosis (all of which occurred in 13 patients [1%]). Bevacizumab was temporarily interrupted after 28 (2%) of 1347 bleeding events and 72 (7%) of 1025 hypertension events, and permanently discontinued after 110 (8%) bleeding events and 40 (4%) hypertension events. No new safety signals were reported.

Interpretation

Our results confirm the manageable safety profile of first-line bevacizumab in combination with various standard chemotherapy regimens for treatment of advanced non-squamous NSCLC.

Funding

F Hoffmann-La Roche Ltd.

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.