Elsevier

The Lancet Oncology

Volume 12, Issue 8, August 2011, Pages 735-742
The Lancet Oncology

Articles
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study

https://doi.org/10.1016/S1470-2045(11)70184-XGet rights and content

Summary

Background

Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor (TKI) therapy in non-small-cell lung cancer (NSCLC). The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus standard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC.

Methods

We undertook an open-label, randomised, phase 3 trial at 22 centres in China. Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received either oral erlotinib (150 mg/day) until disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin. Patients were randomly assigned (1:1) with a minimisation procedure and were stratified according to EGFR mutation type, histological subtype (adenocarcinoma vs non-adenocarcinoma), and smoking status. The primary outcome was progression-free survival, analysed in patients with confirmed disease who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT00874419, and has completed enrolment; patients are still in follow-up.

Findings

83 patients were randomly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin; 82 in the erlotinib group and 72 in the chemotherapy group were included in analysis of the primary endpoint. Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy (13.1 [95% CI 10.58–16.53] vs 4.6 [4.21–5.42] months; hazard ratio 0.16, 95% CI 0.10–0.26; p<0.0001). Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib (including neutropenia in 30 [42%] of 72 patients and thrombocytopenia in 29 [40%] patients on chemotherapy vs no patients with either event on erlotinib); the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations (three [4%] of 83 patients) and skin rash (two [2%] patients). Chemotherapy was also associated with increased treatment-related serious adverse events (ten [14%] of 72 patients [decreased platelet count, n=8; decreased neutrophil count, n=1; hepatic dysfunction, n=1] vs two [2%] of 83 patients [both hepatic dysfunction]).

Interpretation

Compared with standard chemotherapy, erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability. These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC.

Funding

F Hoffmann-La Roche Ltd (China); Science and Technology Commission of Shanghai Municipality.

Introduction

Lung cancer, of which non-small-cell lung cancer (NSCLC) is the most common form, remains the leading cause of cancer-related mortality worldwide, with many patients presenting with advanced disease at initial diagnosis.1 Recent advances in chemotherapy and targeted therapy have provided us with new treatment options for this disease. One such example is the orally administered targeted agent erlotinib, which inhibits the tyrosine kinase domain of EGFR and was approved for use in the second-line setting on the basis of the positive results of the phase 3 BR.21 trial,2 in which erlotinib showed an improvement in overall survival versus best supportive care. Erlotinib has also shown clinical benefit in first-line advanced NSCLC, achieving tumour response rates of 10–20% and a median survival of between 10.9 and 12.9 months in phase 2 studies.3, 4 However, despite important new additions to the therapeutic armamentarium for NSCLC, 5-year survival for patients with this disease is still disappointingly low at less than 20%.5

Increasingly, NSCLC research has focused on efforts to identify biomarkers that are able to predict an increase in clinical benefit from new agents in selected patient subgroups, thereby allowing clinicians to make informed treatment decisions about the most appropriate initial treatment option for an individual patient. The most promising of these markers to date is EGFR mutation status; recent data suggest that patients with tumours that harbour activating mutations in EGFR (ie, exon 19 deletions or exon 21 L858R point mutations) achieve a substantially increased benefit from treatment with EGFR tyrosine kinase inhibitor (TKI) therapy compared with patients whose tumours lack such mutations.6, 7, 8, 9, 10, 11 Notably, EGFR mutations occur with greater frequency in Asian patients compared with white patients, with typical mutation rates of around 30% and 8%, respectively.7, 12, 13 Almost one in three Asian patients could therefore possess a biomarker to predict exceptional response to EGFR TKI therapy. Implementation of accurate EGFR mutation testing is a key factor in use of biomarker-based treatment strategies in clinical practice, although patient selection on the basis of clinical characteristics to achieve enrichment for activating EGFR mutations has thus far proved unsatisfactory.6, 14

The OPTIMAL study was initiated to compare the efficacy and tolerability of first-line erlotinib as monotherapy versus the standard chemotherapy regimen in China (four cycles of gemcitabine plus carboplatin) in patients with advanced or metastatic NSCLC whose tumours carried activating mutations in EGFR.

Section snippets

Study design and patients

This phase 3, open-label, randomised study was undertaken at 22 centres in China. Eligible patients were more than 18 years of age and had histologically confirmed advanced or recurrent stage IIIB or IV NSCLC (Union for International Cancer Control classification version 6) with a confirmed activating mutation of EGFR—ie, an exon 19 deletion or an exon 21 L858R point mutation. They also had measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST version 1.0), an

Results

Figure 1 shows the trial profile. 549 patients were screened for EGFR mutations and 165 were randomly assigned to treatment groups between Aug 24, 2008, and July 17, 2009. Of these patients, 154 had measurable disease and received at least one dose of study drug (82 erlotinib, 72 chemotherapy; figure 1). Both treatment groups were generally well matched with respect to baseline characteristics (table 1). Median duration of treatment was 55.5 weeks (range 3.1–93.0) for erlotinib and 10.4 weeks

Discussion

To our knowledge, OPTIMAL is the first prospective head-to-head phase 3 study to examine the efficacy and safety of first-line erlotinib versus platinum doublet chemotherapy in patients with advanced NSCLC whose tumours harbour activating mutations in EGFR (exons 19 or 21; panel). Platinum doublet chemotherapy consisting of a platinum agent plus a third-generation cytotoxic agent such as gemcitabine, paclitaxel, or docetaxel is the standard first-line treatment for advanced NSCLC15 and

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