For the OPTIMAL trial protocol see http://www.shsfkyy.com/upload/html/20110627154244134.pdf
ArticlesErlotinib 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
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
References (21)
- et al.
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial
Lancet Oncol
(2010) - et al.
Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study
Lancet Oncol
(2010) - et al.
Epidermal growth factor receptor mutations and their correlation with gefitinib therapy in patients with non-small cell lung cancer: a meta-analysis based on updated individual patient data from six medical centers in mainland China
J Thorac Oncol
(2007) - et al.
Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008
Int J Cancer
(2010) - et al.
Erlotinib in previously treated non-small-cell lung cancer
N Engl J Med
(2005) - et al.
Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study
Clin Cancer Res
(2006) - et al.
Phase II clinical trial of chemotherapy-naive patients > or = 70 years of age treated with erlotinib for advanced non-small-cell lung cancer
J Clin Oncol
(2007) - et al.
Cancer statistics, 2010
CA Cancer J Clin
(2010) - et al.
Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma
N Engl J Med
(2009) - et al.
Screening for epidermal growth factor receptor mutations in lung cancer
N Engl J Med
(2009)
Cited by (3679)
Hydrogel-based drug delivery systems for synergistic chemo/hyperthermia therapy of cancer: A comprehensive review
2024, Journal of Drug Delivery Science and TechnologyTrial Design and Optimal Determination of CNS Activity of Small Molecule Targeted Therapy in NSCLC
2024, Clinical Lung CancerDistinct Progression and Efficacy of First-Line Osimertinib Treatment According to Mutation Subtypes in Metastatic NSCLC Harboring EGFR Mutations
2024, JTO Clinical and Research ReportsThe impact of comorbidities, neutrophil-to-lymphocyte ratio, and drug toxicities on quality of life in lung cancer patients receiving EGFR-TKI therapy
2024, Journal of the Formosan Medical Association
- ‡
Joint lead authors