Impact of K-ras status on the effects of EGFR-targeted monoclonal antibody (MAb) therapy in advanced colorectal cancer (ACRC): A systematic review and meta-analysis of randomized controlled trials (RCTs).
Vale C., Tierney JF., Meade A., Fisher D., Kaplan R., Adams RA., Maughan TS., Parmar MK.
4122 Background: A recent systematic review, based largely on non-randomised, retrospective studies, suggested that K-ras mutations may identify patients who do not benefit from cetuximab and panitumumab. In support of this hypothesis, four RCTs have shown a lack of benefit or detriment of EGFR-targeted therapy in patients with K-ras mutations. In this systematic review, we aim to provide a comprehensive and unbiased synthesis of the effects of these MAbs, by K-ras status, in both chemotherapy (CT) responsive and CT-refractory ACRC patients. METHODS: A systematic review and meta-analysis of all relevant RCTs is ongoing. Progression-free survival (PFS) is the primary outcome, with survival and response as secondary outcomes. We have conducted systematic searches of a number of trial sources. Data on trial and patient characteristics, and outcome have been extracted from trial reports or presentations, for all patients and for K-ras wild-type and mutant cohorts. Where possible, trial results were pooled in a stratified-by- trial meta-analysis. For unpublished RCTs, or those published with insufficient information, we are seeking further data. RESULTS: Searches identified 15 eligible RCTs in CT-responsive patients, 12 using cetuximab and 3 panitumumab. Three of these trials included bevacizumab in both arms. PFS has only been reported for 6 RCTs, so further data are needed to ensure an unbiased analysis. Only two RCTs were identified in CT-refractory patients. Together, these showed an improvement in PFS with anti-EGFR MAb (HR=0.61, 95% CI 0.49-0.76, p<0.0001). Furthermore, there was a significant difference in the size of the effect by K-ras status (interaction p<0.0001), with an improvement in PFS for patients with wild type K-ras, (HR=0.43, 95% CI 0.35-0.52, p<0.0001), but not those with mutant K-ras (HR=0.99 95% CI 0.80-1.23, p=0.93). CONCLUSIONS: These preliminary results suggest that the benefits of anti-EGFR MAb therapy, at least in CT-refractory patients, are confined to those with wild type K-ras. Results for CT-responsive patients, and updated analyses for CT-refractory patients, will be presented. [Table: see text].