A New Predictive Molecular Marker for Cetuximab Benefit in Rectal Cancer?

Abstract

Sclafani et al present data and suggest that tumor protein 53 (TP53) may be a predictive marker of cetuximab benefit in patients with rectal cancer undergoing neoadjuvant chemoradiation in this issue of the Journal (1). This article relies on an unplanned, retrospective analysis of molecular marker data on a subset of patients participating in the randomized phase II EXPERT-C clinical trial initially reported in 2012 (2). Patients with operable magnetic resonance imaging– defined high-risk rectal cancer received four cycles of capecitabine/ oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX-C). The primary endpoint was complete tumor response, which was modified during conduct of the study to include only the subset of patients whose tumors were KRAS/BRAF wild type. This was quite reasonably done when the impact of KRAS status on antitumor activity of epidermal growth factor receptor (EGFR)-inhibiting monoclonal antibodies was documented (3). However, the sample size of the study was not increased to assure the intended statistical power. One hundred and fifty eligible patients were randomly assigned. Based on a subset of patients with KRAS/BRAF wild-type tumors (46 patients who received cetuximab vs 44 patients who did not receive cetuximab as a component of treatment), the authors concluded that cetuximab led to a statistically significant increase in response rate and overall survival, but the primary end point of improved complete pathologic response was not met. Further follow-up revealed that contrary to the initial report, adding cetuximab was not associated with a statistically significant improvement in progression-free survival or overall survival in either KRAS/BRAF wild-type or unselected