Evaluation of: Vermorken JB, Stohlmacher-Williams J, Davidenko I et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label Phase 3 randomised trial. Lancet Oncol. 14(8), 697-710 (2013). In recent decades, significant progress has been achieved in the biological understanding of squamous cell carcinoma of the head and neck (SCCHN) and the role of human papillomavirus (HPV) has become more evident. The EGF receptor (EGFR) signaling pathway represents the main target of the new therapeutic agents currently in development and has proven to be efficacious in locally advanced SCCHN. The role of HPV in recurrent and metastatic disease for predicting response to EGFR monoclonal antibodies is still unknown. Today, cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of SCCHN in patients with recurrent or metastatic disease, in association with platinum-based chemotherapy. The identification of novel tumor targets has stimulated the search for other anti-EGFR agents with a more favorable side-effect profile, such as aspanitumumab, but the SPECTRUM study failed to meet its primary end point, stipulating the need to test these agents in clinical trials with a more appropriate choice of study end point. Overall survival, considered a gold standard, may be difficult to interpret if treatment only takes place in a small subinterval of overall survival, therefore, progression-free survival should be used as a surrogate end point for regulatory approval.