Elsevier

European Journal of Cancer

Volume 47, Issue 15, October 2011, Pages 2331-2340
European Journal of Cancer

A double-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03)

https://doi.org/10.1016/j.ejca.2011.06.045Get rights and content

Abstract

Background

EORTC study 08021/ILCP 01/03 evaluated the role of consolidation gefitinib, an oral tyrosine kinase inhibitor (TKI), administered in patients with advanced non-small cell lung cancer (NSCLC), not progressing following standard 1st-line chemotherapy.

Methods

Patients with advanced NSCLC, not-progressing after four cycles of platinum-based chemotherapy, were randomised to receive either gefitinib 250 mg/d or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival (OS). Secondary end-points were progression-free survival (PFS) and toxicity. The study was powered to detect a 28% increase in OS from a median of 11–14.1 months (HR = 0.78) and planned to randomise 598 patients to observe 514 deaths.

Results

After inclusion of 173 patients, the trial was prematurely closed due to low accrual. Baseline characteristics for gefitinib (n = 86) and placebo (n = 87) arms were well balanced. After a median follow up of 41 months, the difference in median OS in the gefitinib and placebo arms was not statistically significant (10.9 and 9.4 months, HR 0.83 [95% confidence interval (95% CI) 0.60–1.15]; p = 0.2). The difference in median PFS significantly favoured gefitinib (4.1 and 2.9 months, HR = 0.61, [95% CI 0.45, 0.83]), p = 0.0015). Adverse events reported in more than 10% of patients were rash (47% with gefitinib versus 13% with placebo) and diarrhoea (34% with gefitinib versus13% with placebo).

Conclusions

Despite its premature closure, this trial confirms previous evidence that consolidation gefitinib is safe and improves PFS. However, no difference in OS was observed in this study (NCT00091156).

Introduction

Lung cancer is the most common cancer and the leading cause of cancer-related deaths in the United States of America.1 In Europe, lung cancer accounted for 12% of approximately 3.2 million new cancer cases and 19.7% of cancer-related deaths.2 More than 85% of lung cancer cases are classified as non-small cell lung cancer (NSCLC). The distressingly low cure rate for NSCLC, approximately 15% 5-year survival, can be attributed to the high rate of unresectable disease at presentation and the inability of systemic therapy to cure metastatic disease. It has become clear that for the latter group of patients, treatment with platinum-based chemotherapy confers a median survival benefit of 6–8 weeks when compared to the best supportive care alone or no chemotherapy.3 In second line, the administration of single agent docetaxel and pemetrexed in selected patients has resulted in an improved outcome by increasing their 1 year survival by 10%.4, 5, 6 However, many patients do not receive this salvage chemotherapy as they present with poor performance status (PS) and co-morbid conditions.7, 8 With the efficacy of chemotherapy plateauing, we need alternative treatment approaches to attain further improvements in outcome, such as the use of targeted agents and consolidation treatments.

As in many other solid tumours, NSCLC is often associated with the overexpression of the Epidermal Growth Factor Receptor (EGFR), which’s activity is tightly regulated by the presence and identity of a ligand, its heterodimer composition, and the availability of phosphotyrosine-binding proteins.9 Upon activation, EGFR activates two major pathways in solid tumours, the PI3K/AKT/mTOR pathway, and the RAS/RAF/MEK/MAPK pathway. These signalling pathways are important in tumour cell growth, local invasion, angiogenesis, protein translation and cell metabolism. Blocking of the EGFR pathway can be obtained either by a chimeric monoclonal antibody against the extracellular domain of EGFR e.g. cetuximab, or by orally active, reversible HER-1/EGFR TKIs, e.g. erlotinib and gefitinib. Four large randomised phase III studies of platinum based doublet chemotherapy regimens in combination with a TKI failed to show a survival benefit over the doublet chemotherapy alone as first line treatment in advanced NSCLC.10, 11, 12, 13 This was thought to be due to a presumed antagonism between TKI’s and chemotherapy by blocking cells in the G1 phase of the cell cycle, and by their interference with platinum uptake into tumour cells, possibly by decreasing expression of membrane uptake transporters.14, 15 The PFS and OS curves of both INTACT-studies showed a crossing of the experimental over the placebo arm in favour of the former. In a landmark subgroup analysis of patients with adenocarcinoma who received more than 90 d of chemotherapy, a statistically significant improvement of OS was furthermore observed. As the oral TKI in both trials could be continued after the end of chemotherapy in non-progressing patients, both these findings could be considered the result of this, consolidation therapy.11

This hypothesis is further strengthened by the results of a placebo-controlled study in which single agent salvage erlotinib was shown to improve outcome in unselected NSCLC patients previously treated with platinum-based chemotherapy.16

Maintenance or consolidation chemotherapy aims at the prolongation of chemotherapy response with the administration of additional drugs at the end of a defined number of initial chemotherapy cycles.17 Recent trials of maintenance chemotherapy given immediately after first-line treatment regimens have shown improvement in PFS and OS.8

These observations were the rationale to study the role of consolidation gefitinib in a placebo-controlled fashion, following first line palliative chemotherapy in non-progressive patients with advanced NSCLC.

Section snippets

Methods

EORTC 08021/ILCP 01/03 was a double blind placebo-controlled randomised phase 3 trial designed to study the effect of gefitinib consolidation therapy on outcome in patients non-progressing after receiving first line platinum doublet chemotherapy. Patients with histologically or cytologically confirmed stage IIIB or IV NSCLC (according to the UICC 6th staging system), who were; not amenable to local therapy, non-progressing after prior platinum based chemotherapy (2–6 cycles), and without

Results

Starting in May 2004, 24 institutions included 173 patients of whom 86 received gefitinib and 87 placebos. The study underwent two major scientific amendments. In May 2006, after accrual of 100 patients, an attempt was made to include patients with the highest chance of responding and, therefore, the possibility of a smaller sample size. At the time selection was based on high EGFR staining by IHC. In December 2007, after accrual of 166 patients, an unplanned interim analysis for futility was

Discussion

EORTC 08021/ILCP 01/03 shows that a consolidation treatment with gefitinib following first line platinum-based chemotherapy in patients with advanced NSCLC results in a highly significant improvement in PFS. This improvement was observed in all clinical subgroups of patients, except in patients with PS 2 at randomisation. Although there was no significant improvement of the primary end-point OS, the observed HR trend was in favour of consolidation gefitinib. As the study was stopped early, it

Role of the funding source

This study was supported by educational grants from AstraZeneca to the EORTC and ILCP, Grants number 5U10 CA11488-32 through 5U10 CA011488-38 from the National Cancer Institute (Bethesda, Maryland, USA) and by Fonds Cancer (FOCA) from Belgium. Its content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Cancer Institute. The funding sources had no influence on data acquisition, quality control, data analysis, interpretation,

Clinical trials

This study was registered in ClinicalTrials.gov with number NCT00091156 and presented at the 46th ASCO Annual Meeting (Chicago, June, 2010) and the 35th ESMO meeting (Milan, October 2010).

Conflict of interest statement

None declared.

Acknowledgements

The authors would like to thank Dr. Sabine Margerit, who replaced Dr. J.J. Welch as the EORTC HQ lung group clinical research physician for her contributions to the study. The authors are grateful to the investigators, their data managers and study nurses for their enduring commitment to the conduct of this trial and to the patients for their confidence.

The following institutions (with their respective accrual) participated in this study: EGYPT: National Cancer Instititute, Cairo (54); BELGIUM:

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