Elsevier

The Lancet Oncology

Volume 16, Issue 8, August 2015, Pages 990-998
The Lancet Oncology

Articles
Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial

https://doi.org/10.1016/S1470-2045(15)00121-7Get rights and content

Summary

Background

Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefined. We aimed to assess the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to first-line gefitinib.

Methods

The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacific region. Eligible patients were aged at least 18 years with histologically confirmed, chemotherapy-naive, stage IIIB–IV EGFR-mutation-positive advanced NSCLC with previous disease control with first-line gefitinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1:1) by central block randomisation to oral gefitinib 250 mg or placebo once daily in tablet form; randomisation did not include stratification factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 on the first day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179.

Findings

Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to the placebo group. At the time of data cutoff (May 5, 2014), 98 (74%) patients had disease progression in the gefitinib group compared with 107 (81%) in the placebo group (hazard ratio 0·86, 95% CI 0·65–1·13; p=0·27; median progression-free survival 5·4 months in both groups [95% CI 4·5–5·7 in the gefitinib group and 4·6–5·5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefitinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefitinib group and five [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefitinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events.

Interpretation

Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting.

Funding

AstraZeneca.

Introduction

EGFR tyrosine-kinase inhibitors (TKIs) are standard first-line treatments for patients with non-small-cell lung cancer (NSCLC) with tumours harbouring activating EGFR mutations, whereas platinum-based doublet chemotherapy is standard first-line treatment for patients whose tumours do not harbour mutations.1, 2 Findings from several randomised studies have confirmed improved proportions of patients achieving objective responses and better progression-free survival in patients with EGFR-mutation-positive NSCLC tumours treated with first-line EGFR TKIs as compared with those with EGFR-mutation-negative NSCLC tumours.3, 4, 5, 6, 7, 8, 9, 10 However, almost all patients eventually develop acquired resistance,11 and optimum management strategies for patients with acquired resistance to first-line EGFR TKIs are undefined.12 Outside clinical trials, treatment options include systemic chemotherapy alone or continuation of EGFR TKIs in combination with chemotherapy at the time of disease progression.12

Acquired resistance to EGFR TKIs is defined by the Jackman criteria,11 which adopt the Response Evaluation Criteria in Solid Tumors (RECIST) for radiological progression.13 However, the mechanism of resistance is complex and heterogeneous, and might not be identified by radiological imaging alone.14, 15 The most common cause of acquired resistance to EGFR TKIs is the presence of a mutation in the EGFR gene at exon 20—the T790M mutation.16 However, many other causes exist, including MET amplification or a PI3K mutation17 and transformation into small-cell lung cancer.18 Therefore, radiological progression does not always imply that all metastatic sites share the same cause of resistance, and some tumour sites could potentially be sensitive to EGFR TKIs at the time of RECIST progression.19 This potential tumour heterogeneity suggests that continuation of EGFR TKIs in combination with chemotherapy might be beneficial—a hypothesis supported by findings from a retrospective study.20 Goldberg and colleagues20 reported that 48% of patients with tumours resistant to EGFR TKI treatment who were subsequently treated with a combination of chemotherapy and erlotinib achieved a tumour response versus 18% of patients treated with chemotherapy alone.

In this study, we aimed to establish whether patients who developed acquired resistance to first-line gefitinib as per RECIST would benefit from continuation of EGFR TKI treatment in addition to platinum-based doublet chemotherapy.

Section snippets

Study design and participants

The aim of this prospective, randomised phase 3 study (IMPRESS) was to compare continuation of gefitinib (AstraZeneca, Macclesfield, UK) in combination with cisplatin plus pemetrexed versus placebo plus cisplatin plus pemetrexed in patients with EGFR-mutation-positive advanced NSCLC with progression after first-line gefitinib. Patients were enrolled at 71 centres in 11 countries in Europe (France, Germany, Hungary, Italy, Russia, and Spain) and the Asia-Pacific region (China, Hong Kong, Japan,

Results

Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to the placebo group (figure 1). 264 patients received treatment (132 in each group). The appendix lists study recruitment sites, principal investigators, and numbers of patients enrolled. Patient sociodemographic and clinicopathological characteristics were generally well balanced between treatment groups (table 1). 206 (78%) of 265 patients were from the Asia-Pacific region. Use

Discussion

IMPRESS—to our knowledge, the first randomised study to investigate optimum treatment strategies for patients with acquired resistance to first-line EGFR TKIs—did not show a significant improvement in progression-free survival with continuation of gefitinib in addition to platinum-based doublet chemotherapy versus chemotherapy alone. Independent masked central review (data not shown) confirmed this result. Furthermore, no statistical differences were noted between treatment groups for objective

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