Targeting IGF-1R: throwing out the baby with the bathwater?

Abstract

There are intense commercial pressures in industry to develop drugs for large unselected populations, although this remains a risky and expensive strategy. Several examples now exist where targeted treatments are utilised in molecularly defined cancer patient populations. The EGFR tyrosine kinase inhibitor (TKI) gefitinib is a case in point, failing to show a clear benefit in non-small-cell lung cancer (NSCLC) patients when given with first-line chemotherapy. Gefitinib has nevertheless re-emerged as an important therapeutic following the confirmation that mutations in the TK domain of EGFR confer sensitivity to it (Mok et al, 2009), with evidence that this population is enriched within Asian, female and never-smoker patients with adenocarcinoma (Lynch et al, 2004; Paez et al, 2004). More recently, two large-phase III trials, investigating the addition of the fully human monoclonal antibody (mAb) to the insulin-like growth factor 1 receptor (IGF-1R) figitumumab (CP-751,871, Pfizer) to carboplatin/paclitaxel (ADVIGO 1016) and to the EGFR TKI erlotinib (ADVIGO 1018), in advanced NSCLC patients have been suspended after planned interim analyses indicated futility (Jassem et al, 2010). These data raise several important questions: Was there sufficient evidence to support these phase III trials? Could we have learnt more from early-phase data to identify the patients who are most likely to benefit? Is IGF-1R a key target in NSCLC? How should we design our trials to identify predictive biomarkers that decrease the risk of such late and costly failures?