ArticlesDocetaxel 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
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
References (31)
- et al.
Second-line treatment of advanced non-small cell lung cancer
J Thorac Oncol
(2008) - et al.
Relationship between response and survival in more than 50,000 patients with advanced non-small cell lung cancer treated with systemic chemotherapy in 143 phase III trials
J Thorac Oncol
(2007) - et al.
Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer
J Thorac Oncol
(2011) - et al.
Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer
Ann Oncol
(2008) - et al.
EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study
Lancet Oncol
(2012) - et al.
Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial
Lancet
(2012) - et al.
Gefitinib versus docetaxel in previously treated non-small-cell-lung cancer (INTEREST): a randomised phase III trial
Lancet
(2008) - et al.
Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial
Lancet Oncol
(2012) - et al.
Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial
Lancet
(2009) - et al.
Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial
Lancet Oncol
(2012)
Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study
Lancet Oncol
A retrospective subgroup analysis of EGFR immunohistochemistry (IHC) expression by histo-score correlated to outcomes from the BMS099 1st line phase III NSCLC trial of cetuximab (cet) plus carboplatin/taxane
Eur J Cancer
Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens
J Clin Oncol
Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy
J Clin Oncol
Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy
J Clin Oncol
Cited by (61)
Association of Early Palliative Care With Chemotherapy Intensity in Patients With Advanced Stage Lung Cancer: A National Cohort Study
2019, Journal of Thoracic OncologyCitation Excerpt :These randomized controlled trials showed increased risk of treatment-related death, especially in patients older than 65 years old. Cetuximab was also considered high intensity given its adverse safety profile and equivalent progression-free survival compared to safer alternatives.36,37 Receipt of erlotinib before January 1, 2011, was considered intensive therapy as it was not likely guided by mutation testing and there was no evidence of benefit in wild-type EGFR patients.
Lung Adenocarcinoma: Second-Line Treatment
2018, Pulmonary Adenocarcinoma: Approaches to TreatmentHealth Care Management: Cancer Prediction and Diagnosis Using Artificial Intelligence (AI)
2023, Lecture Notes in Mechanical Engineering