Elsevier

The Lancet

Volume 373, Issue 9674, 2–8 May 2009, Pages 1525-1531
The Lancet

Articles
Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial

https://doi.org/10.1016/S0140-6736(09)60569-9Get rights and content

Summary

Background

Use of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced non-small-cell lung cancer. We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer.

Methods

In a multinational, multicentre, open-label, phase III trial, chemotherapy-naive patients (≥18 years) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy. Chemotherapy was cisplatin 80 mg/m2 intravenous infusion on day 1, and vinorelbine 25 mg/m2 intravenous infusion on days 1 and 8 of every 3-week cycle) for up to six cycles. Cetuximab—at a starting dose of 400 mg/m2 intravenous infusion over 2 h on day 1, and from day 8 onwards at 250 mg/m2 over 1 h per week—was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred. The primary endpoint was overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00148798.

Findings

Between October, 2004, and January, 2006, 1125 patients were randomly assigned to chemotherapy plus cetuximab (n=557) or chemotherapy alone (n=568). Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median 11·3 months vs 10·1 months; hazard ratio for death 0·871 [95% CI 0·762–0·996]; p=0·044). The main cetuximab-related adverse event was acne-like rash (57 [10%] of 548, grade 3).

Interpretation

Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer.

Funding

Merck KGaA.

Introduction

Patients with advanced non-small-cell lung cancer are treated with a combination of a platinum drug (cisplatin or carboplatin) and a non-platinum drug (eg, vinorelbine), which results in a slight increase in survival and relief of cancer-related symptoms.1 Cisplatin-based two-drug combinations are slightly better than carboplatin-based combinations in patients with good performance status and adequate organ function.2 Strategies to further improve survival of patients with advanced non-small-cell lung cancer include the addition of targeted drugs to cytotoxic chemotherapy,3 and chemotherapy that is customised according to biomarkers.4

Epidermal growth factor receptor (EGFR) is a promising therapeutic target in non-small-cell lung cancer.5 The EGFR-directed tyrosine kinase inhibitors erlotinib and gefitinib are established treatment options for patients with advanced disease who have been pretreated with platinum-based combinations6, 7 but their addition to first-line chemotherapy does not improve outcome.8, 9, 10, 11 Cetuximab (Erbitux, developed by Merck KGaA, Darmstadt, Germany, under licence from Imclone Systems, Branchburg, NJ, USA), an anti-EGFR immunoglobulin G1 monoclonal antibody, has shown activity when given in combination with cisplatin in preclinical studies.12, 13 The results of a randomised phase II trial in 86 patients with advanced EGFR-expressing non-small-cell lung cancer suggested an increased response rate and improved survival in patients given cisplatin and vinorelbine plus cetuximab compared with those given the same chemotherapy alone.14 We therefore did the phase III FLEX (First-Line ErbituX in lung cancer) trial with the aim of showing a prolonged overall survival time with chemotherapy plus cetuximab compared with chemotherapy alone as first-line treatment in patients with EGFR-expressing advanced non-small-cell lung cancer.

Section snippets

Study design

We randomly assigned chemotherapy-naive patients with EGFR-expressing advanced non-small-cell lung cancer centrally using an interactive voice response system (IVRS) in a ratio of 1:1 to chemotherapy plus cetuximab or chemotherapy alone in a multinational, open-label, phase III trial done in 155 centres. The clinical research organisation generated the random allocation schedule using a computer; physicians and study monitors did not have access to the code. Randomisation was stratified by the

Results

Figure 1 shows the trial profile. Between October, 2004, and January, 2006, 1125 patients (intention-to-treat population) were assigned to chemotherapy plus cetuximab or just chemotherapy. Table 1 shows that the baseline characteristics of the randomly assigned patients were well balanced between the groups.

Median number of chemotherapy cycles given to patients was four (range 0–6 for chemotherapy plus cetuximab, and 1–7 for chemotherapy alone) and median duration of chemotherapy was 14 weeks

Discussion

The FLEX trial showed that overall survival is prolonged with the EGFR targeted antibody cetuximab added to chemotherapy in patients with advanced non-small-cell lung cancer across all histological subtypes. Results of this study are consistent with those from other randomised phase II trials14, 15, 16 and the BMS-099 phase III trial.17, 18 The BMS-099 trial17, 18 was not powered to detect a significant difference in overall survival. However, a reduction in the risk of death of the same

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