Elsevier

The Lancet Oncology

Volume 11, Issue 6, June 2010, Pages 521-529
The Lancet Oncology

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Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study

https://doi.org/10.1016/S1470-2045(10)70112-1Get rights and content

Summary

Background

First-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) is usually limited to four to six cycles. Maintenance therapy can delay progression and prolong survival. The oral epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib has proven efficacy and tolerability in second-line NSCLC. We designed the phase 3, placebo-controlled Sequential Tarceva in Unresectable NSCLC (SATURN; BO18192) study to assess use of erlotinib as maintenance therapy in patients with non-progressive disease following first-line platinum-doublet chemotherapy.

Methods

Between December, 2005, and May, 2008, 1949 patients were included in the run-in phase (four cycles of platinum-based chemotherapy). At the end of the run-in phase, 889 patients who did not have progressive disease were entered into the main study, and were randomly allocated using a 1:1 adaptive randomisation method through a third-party interactive voice response system to receive erlotinib (150 mg/day; n=438) or placebo (n=451) until progression or unacceptable toxicity. Patients were stratified by EGFR immunohistochemistry status, stage, Eastern Cooperative Oncology Group performance status, chemotherapy regimen, smoking history, and region. Co-primary endpoints were progression-free survival (PFS) in all analysable patients irrespective of EGFR status, and PFS in patients whose tumours had EGFR protein overexpression, as determined by immunohistochemistry. This study is registered with www.ClinicalTrials.gov, number NCT00556712.

Findings

884 patients were analysable for PFS; 437 in the erlotinib group and 447 in the placebo group. After a median follow-up of 11·4 months for the erlotinib group and 11·5 months for the placebo group, median PFS was significantly longer with erlotinib than with placebo: 12·3 weeks for patients in the erlotinib group versus 11·1 weeks for those in the placebo group (HR 0·71, 95% CI 0·62–0·82; p<0·0001). PFS was also significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib (n=307) compared with EGFR-positive patients given placebo (n=311; median PFS 12·3 weeks in the erlotinib group vs 11·1 weeks in the placebo group; HR 0·69, 0·58–0·82; p<0·0001). The most common grade 3 or higher adverse events were rash (37 [9%] of 443 patients in the erlotinib group vs none of 445 in the placebo group) and diarrhoea (seven [2%] of 443 patients vs none of 445). Serious adverse events were reported in 47 patients (11%) on erlotinib compared with 34 patients (8%) on placebo. The most common serious adverse event was pneumonia (seven cases [2%] with erlotinib and four [<1%] with placebo).

Interpretation

Maintenance therapy with erlotinib for patients with NSCLC is well tolerated and significantly prolongs PFS compared with placebo. First-line maintenance with erlotinib could be considered in patients who do not progress after four cycles of chemotherapy.

Funding

F Hoffmann-La Roche Ltd.

Introduction

Non-small-cell lung cancer (NSCLC) accounts for most cases of lung cancer, and is often diagnosed at an advanced stage when treatment options are limited. First-line treatment of advanced NSCLC is based on the backbone of platinum-doublet chemotherapy, with a median overall survival of 8–11 months.1

Although around 70 to 80% of patients who receive first-line chemotherapy will experience clinical benefit in terms of response or stable disease,2, 3, 4, 5 subsequent disease progression is often rapid, with most patients experiencing progressive disease within 2–3 months of their final chemotherapy cycle.3, 6, 7 Several trials have investigated prolonged-duration platinum-based chemotherapy in the first-line setting, but longer treatment periods had modest or no incremental overall survival benefit and increased toxicity.8, 9, 10, 11, 12, 13

Second-line treatments are indicated after disease progression, but studies suggest that around 30–50% of patients do not receive second-line therapy.3, 6, 7, 8, 9, 10, 11, 14, 15, 16, 17 Rapid progression, declining performance status, and increased symptom burden can render patients unsuitable to receive further treatment.7 This means that a large proportion of patients might lose the opportunity to receive effective therapy after first-line treatment. The effect of active maintenance therapy on disease progression when introduced immediately after first-line platinum-doublet chemotherapy has therefore been investigated for patients with advanced NSCLC.17 A precedent already exists for this approach, with first-line biological agents such as bevacizumab and cetuximab being continued until disease progression.2, 15, 18 Recent trials of maintenance chemotherapy given immediately after first-line treatment regimens have shown improvements in progression-free survival (PFS)6, 7 and overall survival.6

The oral epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) erlotinib is an established second-line treatment for advanced NSCLC.19, 20 Significant improvements in overall survival, time to symptom deterioration, and quality of life (QoL) were noted with erlotinib versus placebo in patients who had received at least one previous line of therapy,21, 22 with similar efficacy to second-line chemotherapy.23 Erlotinib has shown efficacy in a broad patient population, regardless of age, sex, ethnic origin, or histology, with benefits in both adenocarcinoma and squamous-cell carcinoma.21 A first-line trial of erlotinib with concurrent chemotherapy showed a significantly increased (p=0·045) duration of response among patients receiving erlotinib in combination with chemotherapy followed by maintenance erlotinib (compared with placebo in combination and maintenance).24 This proven efficacy, combined with oral administration and acceptable tolerability, make erlotinib a strong candidate for investigation in the maintenance setting.

We designed the phase 3, placebo-controlled Sequential Tarceva in Unresectable NSCLC (SATURN; BO18192) study to investigate the effect of erlotinib as maintenance therapy on PFS in patients with non-progressive disease following first-line platinum-doublet chemotherapy. We assessed PFS in the overall population and in patients with tumours that over-express EGFR.

Section snippets

Patients

The SATURN study was done at 110 sites in 26 countries. Patients entering the chemotherapy run-in phase of the study had to be aged 18 years or over, with histologically documented, measurable (according to Response Evaluation Criteria In Solid Tumours [RECIST] 1.025), unresectable or metastatic NSCLC. The main exclusion criteria were previous exposure to anti-EGFR agents; uncontrolled, symptomatic brain metastases; and any other malignancies within the previous 5 years (excluding carcinoma in

Results

The study design and trial profile are shown in figure 1. Between December, 2005, and May, 2008, 1949 patients were screened and received first-line platinum doublet chemotherapy. The specific regimen used was at the discretion of individual investigators and reflective of normal clinical practice, with the exception that bevacizumab and pemetrexed were not permitted. Details of regimens were not recorded for the pre-randomisation population; however, the most common regimens recorded among the

Discussion

The SATURN trial is, to our knowledge, the first study to show that a targeted therapy, given as maintenance immediately after a standard first-line platinum-based chemotherapy regimen, can significantly improve the outcome of metastatic NSCLC. PFS was significantly improved with erlotinib in the overall population, irrespective of EGFR status, and in patients with EGFR immunohistochemistry-positive tumours; an improvement in PFS with erlotinib versus placebo was noted in all patient subgroups,

References (27)

  • MA Socinski et al.

    Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer

    J Clin Oncol

    (2002)
  • C von Plessen et al.

    Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer

    Br J Cancer

    (2006)
  • JO Park et al.

    Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer

    J Clin Oncol

    (2007)
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