Patient selection for cetuximab in NSCLC: A systematic review of candidate predictive biomarkers.

Abstract

7548 Background: Cetuximab improved overall survival (OS) in first-line advanced NSCLC in a pivotal trial including all histologies (FLEX). Other phase II/III trials have tested cetuximab with several platinum doublets. Putative predictive-marker candidates have been explored retrospectively in some of these trials. Methods: Investigators have evaluated comprehensively the retrospective data available to date from studies of cetuximab plus chemotherapy (CT), analyzing the correlation between biomarker status (K-Ras and EGFR mutations, EGFR protein expression by IHC and EGFR gene copy number [GCN] by FISH) and incremental benefit from cetuximab (phase III and randomized phase II studies), or overall outcome (single arm phase II trials). Results: Tissue collection was not mandatory and tumor-sample ascertainment rates ranged from 20%-30% (except for mandatory tissue collection for EGFR IHC testing in FLEX). Biomarker evaluable populations were representative of ITT populations for baseline factors, although their outcomes differed in some trials. Response rates (RR) in single arm trials were similar regardless of EGFR or K-Ras mutational status. EGFR FISH positivity was associated with better outcomes in the S0342 trial of sequential or concomitant cetuximab plus CT, but this effect was not consistently found in other randomized trials. In randomized phase III trials, benefit from the addition of cetuximab to CT was seen regardless of K-Ras or EGFR mutations, while results for EGFR GCN by FISH have been conflicting. EGFR IHC was a selection criterion in some trials; in the others, only 15% of patients tested negative, data are therefore insufficient to rule out a predictive effect. In randomized studies, the magnitude of benefit from cetuximab seems similar regardless of EGFR IHC expression-based selection. Conclusions: No predictive biomarker for cetuximab benefit in NSCLC has yet been confirmed. Benefit from cetuximab was observed regardless of K- Ras mutations, a strong predictor of lack of cetuximab benefit in CRC, or EGFR mutational status. EGFR FISH is being prospectively evaluated in S0819. Additional studies are ongoing to identify novel predictive biomarkers of cetuximab benefit in NSCLC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Infinity Pharmaceuticals, Merck KGaA, Response Genetics Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, ImClone Systems, Lilly, Merck, Merck Serono, Novartis, Pfizer, Roche, sanofi-aventis Bristol-Myers Squibb, Infinity Pharmaceuticals AstraZeneca, Lilly, Merck KGaA, Merck Serono, None, Roche Abbott Laboratories, Bristol-Myers Squibb, Genentech, ImClone Systems, Lilly, Merck, Merck KGaA, Novartis, Pfizer