Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: a meta-analysis from six phase III randomized controlled trials

CRD summary

The review concluded that epidermal growth factor receptor tyrosine kinase inhibitor achieved statistically longer progression-free survival, greater overall response rate and numerically longer overall survival than platinum-based doublet chemotherapy in patients with advanced non-small-cell lung cancer with activated epidermal growth factor receptor mutations. Given the substantial heterogeneity the authors' conclusion should be interpreted with caution.

Authors' objectives

To determine the efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy compared with platinum-based doublet chemotherapy for first-line treatment in advanced non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation.

Searching

PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and Chinese Biomedical Literature Database were searched from inception to June 2011. There were no restrictions for publication status and language. Search terms were reported. American Society of Clinical Oncology, European Society of Medical Oncology and International Association for the Study of Lung Cancer conference proceedings were searched manually from 2000 to 2011. Reference lists from relevant articles were checked.

Study selection

Randomised controlled trials of participants (>18 years) with pathologically proven NSCLC with EGFR mutation-positive and clinical disease stage IIIB-IV that had not previously been treated were eligible for inclusion in the review if the trial compared EGFR-TKI with platinum-based doublet chemotherapy. Studies needed at least 10 participants per study arm. Phase I and phase II trials and trials in which second- or third-line treatment or sequential or maintained therapy were assessed were excluded.

The primary outcome in the review was progression-free survival (as defined by Therasse et al., 2000). Secondary outcomes included overall survival and overall response rate. Progression-free survival was the primary endpoint in all included trials except one that used overall survival as the primary outcome.

EGFR-TKI regimens used included gefitinib (250mg/day) and erlotinib (150mg/day). Chemotherapy regimens used included paclitaxel and carboplatin, gemcitabine and cisplatin, docetaxel and cisplatin, docetaxel and carboplatin, and gemcitabine and carboplatin. All trials compared the EGFR-TKI schedule with the standard platinum-based doublet chemotherapy schedule. Where reported, 59% to 79% of participants were female, 86% to 100% had adenocarcinoma and 57.9% to 100% had never smoked. Trials were conducted in Asia (China, Hong Kong, Japan, Taiwan, Singapore, Philippines, Thailand) and Europe (Spain, France, Italy).

Two reviewers independently selected trials for inclusion in the review. Disagreements were resolved by consensus involving a third reviewer.

Assessment of study quality

Study quality was assessed with criteria for randomisation, blinding of patients and clinicians, concealment of treatment allocation, reporting of withdrawals and drop-outs and use of intention-to-treat analysis.

The authors did not state how many reviewers performed the validity assessment.

Data extraction

Two reviewers independently extracted data for the main outcomes of interest: hazard ratios (HRs) for progression-free survival and overall survival and relative risks (RRs) for overall response rate.

Methods of synthesis

Pooled hazard ratios and relative risks, with associated 95% CIs, were calculated using a random-effects model. Subgroup analyses were performed by type of EGFR-TKI (gefitinib or erlotinib). Statistical heterogeneity was investigated using the Ι² statistic. Publication bias was assessed using Begg and Egger's test.

Results of the review

Six phase III RCTs were included in the review (1,031 participants, range 42 to 271, reported in table 1). No placebo-controlled double-blinded trials were included.

Progression-free survival (six RCTs, 1,006 patients): A significant difference in progression-free survival was found in favour of patients who received EGFR-TKI as first-line therapy compared with patients who received chemotherapy (HR 0.37, 95% CI 0.27 to 0.52; Ι²=76.4%). Subgroup analysis by type of EGFR-TKI demonstrated similar results for gefitinib versus chemotherapy (HR 0.43, 95% CI 0.32 to 0.58; Ι²=57.8%; four RCTs) and erlotinib (HR 0.26, 95% CI 0.10 to 0.67; Ι²=88.4%; two RCTs).

Overall survival (five RCTs, 852 patients): No significant between-group difference was found for overall survival (HR 0.94, 95% CI 0.77 to 1.15; Ι²=0%). Similar results were found when type of EGFR-TKI was considered.

Overall response rate (six RCTs, 1,021 patients): A significant improvement in overall response rate was found in patients receiving EGFR-TKI as first-line therapy compared with patients who received chemotherapy (RR 5.68, 95% CI 3.17 to 10.18; Ι²=74.3%). Intention-to-treat analysis was performed. Subgroup analysis by type of EGFR-TKI demonstrated similar results for gefitinib versus chemotherapy (RR 3.82, 95% CI 2.28 to 6.39; Ι²=54.6%; four RCTs) and erlotinib (RR 11.99, 95% CI 6.80 to 21.15; Ι²=0%; two RCTs).

No evidence of publication bias was found.

Authors' conclusions

EGFR-TKI achieved statistically longer progression-free survival, greater overall response rate and numerically longer overall survival than platinum-based doublet chemotherapy in patients with advanced NSCLC with activated EGFR mutations. EGFR-TKI should be used as first-line treatment in previously untreated NSCLC patients with activated EGFR mutation.

CRD commentary

The review was supported by clear inclusion criteria. Several sources were searched without limitations on publication status or language. No evidence of publication bias was found but this should be treated cautiously as there were only six included trials. Appropriate steps were taken to minimise error and bias during study selection and data extraction. The quality of the included trials was assessed using relevant criteria but individual trial results were not reported. It was not clear how many reviewers were involved in the quality assessment.

Estimates were pooled using standard meta-analytic techniques and heterogeneity was investigated. The authors highlighted possible difficulties with identifying differences between the treatment groups in overall survival due to treatment cross-over.

The reliability of the authors' conclusion is unclear given the substantial heterogeneity found in the analyses.

Implications of the review for practice and research

Practice: The authors stated that EGFR-TKI should be used as first-line treatment in previously untreated NSCLC patients with activated EGFR mutation. EGFR mutations were a predictor of benefit from tryosine kinase inhibitors and prospective EGFR mutation should be tested routinely before initiation of treatment in advanced NSCLC patients.

Research: The authors did not state any implications for research.

Funding

Scientific Research Foundation of Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Bibliographic details

Gao G, Ren S, Li A, Xu J, Xu Q, Su C, Guo J, Deng Q, Zhou C. Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: a meta-analysis from six phase III randomized controlled trials. International Journal of Cancer 2012; 131(5): E822-E829. [PubMed: 22161771]

Original Paper URL

http://onlinelibrary.wiley.com/doi/10.1002/ijc.27396/abstract

Indexing Status

Subject indexing assigned by NLM

MeSH

Carcinoma, Non-Small-Cell Lung /drug therapy /genetics /secondary; Clinical Trials, Phase III as Topic; Humans; Lung Neoplasms /drug therapy /genetics /pathology; Mutation /genetics; Prognosis; Protein Kinase Inhibitors /therapeutic use; Randomized Controlled Trials as Topic; Receptor, Epidermal Growth Factor /genetics

AccessionNumber

12012034302

Database entry date

18/12/2012

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.