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