Elsevier

The Lancet Oncology

Volume 14, Issue 13, December 2013, Pages 1326-1336
The Lancet Oncology

Articles
Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial

https://doi.org/10.1016/S1470-2045(13)70473-XGet rights and content

Summary

Background

Available preclinical and phase 2 clinical data suggest that the addition of cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR), to chemotherapy might improve outcome in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to assess whether the addition of cetuximab to chemotherapy improved progression-free survival in patients with recurrent or progressive NSCLC after platinum-based therapy.

Methods

In this unmasked, open-label randomised phase 3 trial we enrolled patients with metastatic, unresectable, or locally advanced NSCLC from 121 sites in Canada and the USA. Eligible patients were those aged 18 years or older who had experienced progressive disease during or after one previous platinum-based regimen. Initially, patients were randomly assigned to receive either pemetrexed (500 mg/m2) or docetaxel (75 mg/m2) and then randomly assigned within each group to receive their chemotherapy with or without cetuximab (400 mg/m2 at first dose and 250 mg/m2 weekly thereafter) until disease progression or unacceptable toxicity. However, after a change in the standard of care, investigators chose whether to treat with pemetrexed or docetaxel on a patient-by-patient basis. The primary analysis was changed to compare progression-free survival with cetuximab plus pemetrexed versus pemetrexed, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00095199.

Findings

Between Jan 10, 2005, and Feb 10, 2010, we enrolled 939 patients; data for one patient was accidentally discarded. Of the remaining 938 patients, 605 received pemetrexed (301 patients with cetuximab and 304 alone) and 333 received docetaxel (167 in combination with cetuximab and 166 alone). Median progression-free survival with cetuximab plus pemetrexed was 2·9 months (95% CI 2·7–3·2) versus 2·8 months (2·5–3·3) with pemetrexed (HR 1·03, 95% CI 0·87–1·21; p=0·76). The most common grade 3–4 adverse events with cetuximab plus pemetrexed were fatigue (33 [11%] of 292 patients), acneiform rash (31 [11%]), dyspnoea (29 [10%]), and decreased neutrophil count (28 [10%]), and with pemetrexed alone were dyspnoea (35 [12%] of 289 patients), decreased neutrophil count (26 [9%]), and fatigue (23 [8%]). A significantly higher proportion of patients in the cetuximab plus pemetrexed group (119 [41%] of 292 patients) experienced at least one serious adverse event than those patients in the pemetrexed group (85 [29%] of 289 patients; p=0·0054). Nine (3%) of 292 treated patients in the cetuximab and pemetrexed group died of adverse events compared with five (2%) of 289 treated patients in the pemetrexed alone group.

Interpretation

The use of cetuximab is not recommended in combination with chemotherapy in patients previously treated with platinum-based therapy.

Funding

Eli Lilly and Company and ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Company.

Introduction

Most patients receiving front-line cytotoxic therapy for advanced non-small-cell lung cancer (NSCLC) experience progressive disease.1 Due to limited life expectancy, goals of second-line treatment are prolonged survival with symptom palliation, and enhanced quality of life. A review of phase 3 clinical trials2 done between 1991 and 2006 involving second-line and beyond systemic chemotherapy in this patient population identified that the median proportion of patients achieving an objective response across trials was 6·8%, and median overall survival was 6·6 months. It is clear that improvements are needed in this setting.

Several single agents are approved for use in advanced, second-line NSCLC, including pemetrexed, docetaxel, and erlotinib.3, 4, 5, 6 In a phase 3 trial comparing pemetrexed with docetaxel in patients with recurrent stage III or IV NSCLC treated with one previous chemotherapy regimen pemetrexed resulted in clinically equivalent efficacy outcomes, with significantly fewer side-effects.5 Pemetrexed has since been shown to be more efficacious in patients with non-squamous histology.7

Cetuximab is a monoclonal antibody directed against epidermal growth factor receptor (EGFR), and is approved by the US Food and Drug Administration (FDA) for use in colorectal and head and neck cancers. Preclinical studies in lung cancer cell lines and xenografts have assessed the effect of cetuximab, and shown tumour growth inhibition in EGFR-positive lung cancer cell lines when combined with taxanes and platinum.8 At the time of protocol development, some phase 2 clinical data were available. A single-arm phase 2 study of cetuximab plus docetaxel in second-line NSCLC showed that the combination had promising safety and efficacy (20% of patients achieved an objective response, median time to progression was 104 days, and median overall survival was 7·5 months).9 A randomised phase 2 study of cetuximab with cisplatin plus vinorelbine compared with cisplatin plus vinorelbine as first-line therapy for patients with advanced NSCLC showed a greater proportion of patients achieving objective responses when treated with cetuximab (35% [15 of 43] vs 28% [12 of 43]).10 In patients who become refractory to front-line chemotherapy, no new treatment has shown significant survival benefit in unselected patient populations for the past decade outside of single-agent therapy. Therefore, our objective was to test the addition of cetuximab to standard chemotherapy in a randomised phase 3 trial.

Section snippets

Participants

This open-label, parallel-group, randomised phase 3 study was done at 121 sites in the USA and Canada (appendix). Patients aged 18 years or older with metastatic, unresectable, or locally advanced NSCLC who experienced progressive disease during or after one previous platinum-based regimen were eligible. Key eligibility criteria included baseline Karnofsky performance status of 60–100 at entry, measurable disease, and tissue availability for EGFR determination by immunohistochemistry. Exclusion

Results

Figure 1 shows the trial profile and the appendix lists the study sites. The number of discontinued patients is analysed from the intention-to-treat population. All data for one patient were accidently discarded at the research site. Hence, the intention-to-treat population contained 938 patients (515 before the amendment of May, 2007), of whom 605 were in the pemetrexed group. Table 1 shows baseline characteristics of the pemetrexed group. The characteristics of the docetaxel and combined

Discussion

Our findings show that the addition of cetuximab to pemetrexed did not improve progression-free survival, nor were there improvements in any of the other assessed efficacy or quality-of-life measures, including overall survival. More and worse adverse events were recorded with cetuximab plus pemetrexed, mainly due to skin-related toxic effects, gastrointestinal symptoms (diarrhoea or stomatitis), and hypomagnesaemia. Likewise, there was no improvement in outcome when patients were assessed by

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