1. First line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer – a Cochrane Collaboration meta-analysis Green JA, Dwan K, Jain P, Boland A, Bates V, Dundar Y, Vecchio F, Greenhalgh J University of Liverpool, UK L69 3BX and Clatterbridge Cancer Centre UK CH63 4JY Prisma Diagram Background : EGFR M+ has been recognised as a subtype of NSCLC associated with non-smoking women, asian ethnic origin, adenocarcinoma histology and young age. Methods: Randomised controlled trials comparing EGFR-targeted agents alone or in combination with cytotoxic agents or best supportive care (BSC) with cytotoxic chemotherapy (single or doublet or in combination with EGFR- targeted therapies) or best standard of care (BSC) in chemotherapy-naive patients with locally advanced or metastatic (Stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent were studied. Results: Eighteen trials entering a total of 2085 EGFR M+ patients met the inclusion criteria, of whom 1343 were from Asian countries. Six of these exclusively recruited 1455 patients with EGFR M+ NSCLC, the remaining trials recruited a mixed population and reported results for patients with EGFR M+ NSCLC as subgroup analyses. Erlotinib was the intervention treatment in 8 trials, gefitinib in 6 trials, afatinib in 2 trials and cetuximab in 2 trials. No OS benefit was demonstrated for any intervention, although crossover was allowed in the majority of studies. For PFS, a pooled analysis of 3 studies (n=378) demonstrated a clear benefit of erlotinib compared with CTX (HR=0.30; 95% CI: 0.23 to 0.40). In a pooled analysis with 491 patients, two studies (IPASS; NEJSG) demonstrated a clear benefit of gefitinib compared with paclitaxel with carboplatin (HR=0.39; 95% CI:0.32 to 0.48). The two trials featuring afatinib (n=709) showed a pooled PFS benefit when compared with chemotherapy of HR 0.42 (95% CI;0.34,0.53). No PFS benefit for cetuximab plus CTX (n=81) was reported in either of the two trials. Commonly reported AEs for TKI monotherapy were rash, diarrhoea and mucositis. Quality of life and symptom control were assessed by different methods and showed improvement in the six trials in which they were performed. Conclusion: Erlotinib, gefitinib or afatinib should be the first-line treatment of choice for EGFR M+ NSCLC. Cytotoxic chemotherapy is less effective than erlotinib, gefitinib or afatinib and produces greater toxicity in this population. Interpretation Afatinib, erlotinib and gefitinib are effective in EGFR M+ NSCLC patients with acceptable toxicity and our recommendation is that all non-squamous tumours be tested for the EGFR mutation. The majority of studies included patients with performance status 1 and 2, but the adverse event data suggest some performance status 3 patients might tolerate these agents better than cytotoxic chemotherapy. Future studies of these agents should comprise patients with known EGFR mutations, and stratify patients by mutation subtype for the common mutations using quality controlled methodology. Preliminary data suggests patients harbouring Del19 mutations have improved survival and PFS following treatment with TKIs. Patients with mutations known to be resistant to these agents should be treated with alternative therapies. Future trials should also incorporate standardised methodology for quality of life and symptom control. Methods Criteria for considering studies for this review Only parallel randomised controlled trials (RCTs) were considered for this study. Chemotherapy naive patients with locally advanced or metastatic (Stage IIIB or IV) EGFR M+ NSCLC who were not suitable for treatment with surgery or radical radiotherapy were included in this review. Interventions analysed included EGFR M+ targeted agents, alone or in combination with cytotoxic agents, compared with cytotoxic agents used alone or in combination, or best supportive care (BSC). Studies comparing single agents or combinations of cytotoxic chemotherapy without a targeted therapy in either arm were excluded, as were studies of maintenance therapy. Analyses The primary outcome was overall survival. Secondary outcomes assessed were progression-free survival, tumour response, toxicity, symptom control and quality of life (QoL). The following electronic databases were searched for relevant published literature: CENTRAL (Cochrane Central Register of Controlled Trials) CDSR (Cochrane Database of Systematic Reviews) DARE (Database of Abstracts of Reviews of Effectiveness). EMBASE, Health Technology Assessment (HTA) database, ISI Web of Science, MEDLINE. Selection of studies Review authors independently scanned the titles and abstracts of references identified by searching. Full details of possibly relevant studies were obtained and assessed independently for inclusion in the review by two authors. If a disagreement occurred, the review authors attempted to reach a consensus by discussion, or involved a third review author. Ongoing studies that did not report relevant outcomes but met the inclusion criteria were listed for future use and not included in the meta-analysis. Authors were contacted for further information. Data extraction was carried out by one review author using pre-tested data extraction forms and the data was independently checked for accuracy by a second review author. Data relating to the outcome measures as well as information on study design and participants was extracted. Data from studies presented in multiple publications was extracted and reported as a single study. Included trials were independently assessed for risk of bias using the criteria of Higgins 12. Bias was reported as high, low or unclear. Statistical analyses For binary outcomes, where sufficient data was available, relative treatment effects are presented in the form of relative risks (RR) with 95% confidence intervals (CI). For continuous outcomes, mean differences (MD) and 95% CIs were calculated provided there was no evidence of skewed data. For time to event outcomes, log hazard ratios (log HR) were extracted with 95% CI. If the log HR was not reported, individual patient data were requested from authors. Statistical heterogeneity between studies was assessed visually by inspection of the forest plots and using the Chi 2 test (P 50%) and then a random-effects model was used. Summary of studies included in meta-analysis Common toxicities for each included study A afatinib E erlotinib G gefitinib