OBJECTIVES: Platinum-based chemotherapy is a common first-line treatment of NSCLC; tolerability impacts on choice of regimen. This research compared the tolerability of gefitinib and doublet chemotherapy in this setting in patients with activating epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutations (M+). METHODS: Systematic searching of CENTRAL, EMBASE and MEDLINE for randomised controlled trials (RCTs) comparing ≥2 doublet chemotherapies (carboplatin or cisplatin in combination with either docetaxel, gemcitabine, paclitaxel, pemetrexed, or vinorelbine) for the first-line treatment of advanced NSCLC was completed in May 2009. Data were extracted on the following grades 3/4/5 adverse events (AEs) most commonly reported with doublet chemotherapy or EGFR-TK inhibitors: anaemia, diarrhoea, fatigue, febrile neutropenia, nausea/vomiting, neutropenia, and rash. We performed a meta-analysis of the available gefitinib vs paclitaxel/carboplatin RCTs in EGFR-TK M+ patients. We then carried out a Mixed Treatment Comparison (MTC) of doublet chemotherapies in unselected advanced NSCLC patients using paclitaxel/carboplatin as a baseline. Treatment effect for the risk of AE occurrence was estimated as an odds ratio (OR>1.0 favours paclitaxel/carboplatin). RESULTS: Three RCTs were identified for gefitinib, of which two were comparisons with paclitaxel/carboplatin. Meta-analysis of these two trials gave the following statistically significant results: anaemia – OR 0.12, 95% Confidence Interval: 0.03-0.47; diarrhoea – OR 5.78, 95% CI: 1.01-33.11; neutropenia – OR 0.01, 95% CI: 0.00-0.03. Twenty-nine trials were appropriate for inclusion in the MTC. The alternative doublet chemotherapy regimens did not demonstrated a statistically significant reduction in risk of any of the AEs assessed vs paclitaxel/carboplatin, with the exception of gemcitabine/cisplatin, which had a lower risk of febrile neutropenia (OR 0.39, 95% Credible Interval: 0.12-0.96). CONCLUSIONS: In the absence of RCTs comparing all doublet chemotherapies with gefitinib in EGFR-TK M+ patients with advanced NSCLC, this adjusted indirect comparison suggests that gefitinib may have important tolerability advantages over other first-line treatments in this targeted population.