While cetuximab has demonstrated activity in SCCHN, new agents and treatment strategies are needed that will provide both improved tolerability and efficacy. Future directions beyond cetuximab: inhibiting the ErbB family Several novel agents targeting the ErbB/HER receptor family are being evaluated in phase II and III clinical trials for the treatment of SCCHN (Table?1). Table?1 ErbB family inhibitors in phase II and III studies for the treatment of squamous cell carcinoma of the head and neck epidermal growth factor receptor, intravenous, monoclonal antibody, oral, tyrosine kinase inhibitor Anti-EGFR monoclonal antibodies Panitumumab (Vectibix?, Amgen; Thousand Oaks, CA, USA) is a fully human anti-EGFR mAb. that inhibit multiple ErbB receptors simultaneously (e.g., lapatinib) or that bind multiple ErbB family receptors irreversibly (e.g., afatinib, PF-00299804) and investigation of combinations of agents that target multiple pathways implicated in the pathogenesis of SCCHN. Ongoing large clinical trials are evaluating these emerging agents and combinations for the treatment of SCCHN. Cyhalofop gene copy number are associated RNASEH2B with decreased survival [7C12], resistance to radiotherapy [13], locoregional treatment failure [7C9], and increased rates of distant metastases [8, 14]. Open in a separate window Fig.?1 Epidermal growth factor receptor and ErbB family downstream signaling pathways potentially involved in squamous cell carcinomas of the head and neck. Downstream pathways activated by dimerization and activation of the ErbB family. Adapted with permission from Venook et al. [5]. ?2005 John Wiley & Sons, Inc. v-akt murine thymoma viral oncogene homolog, serine-threonine kinase 1, Bcl-2 antagonist of cell death, B-cell lymphoma, cyclin dependent kinase, epidermal growth factor receptor, Ets like gene 1, erythroblastic leukemia viral oncogene homolog, extracellular signal-regulated kinase, protooncogene c-fos, growth factor receptor-bound protein 2, hypoxia inducible factor-1, Janus kinase, mitogen-activated protein kinase kinase, mammalian target of rapamycin, nuclear factor-B, phosphatidylinositol-3-kinase, v-raf 1 murine leukemia viral oncogene homolog 1, retrovirus-associated DNA sequences, son of sevenless, signal transducers and activators of transcription, vascular endothelial growth factor Cetuximab (Erbitux?, Bristol-Myers Squibb; New York, NY, USA), a recombinant chimeric anti-EGFR monoclonal antibody (mAb), was the first molecularly targeted therapy approved for SCCHN. Cetuximab is approved in combination with radiation therapy for locally advanced disease, in combination with platinum-based chemotherapy and 5-fluorouracil (5-FU) for the first-line treatment of metastatic/recurrent disease, and as a single agent for metastatic/recurrent disease after failure of platinum-based chemotherapy [15]. This article will briefly review the clinical trial data associated with cetuximab in SCCHN, describe limitations of current therapy, and discuss data associated with investigational EGFR- and ErbB family targeted treatment strategies for SCCHN. Cetuximab: proof of concept of EGFR inhibition in locally advanced or metastatic SCCHN Results from several clinical trials have established the activity of cetuximab in the treatment of SCCHN. A landmark phase III study involving 424 patients with locoregionally advanced SCCHN compared cetuximab in combination with high-dose radiotherapy versus high-dose radiotherapy alone [16]. The combination of cetuximab and radiotherapy significantly improved median overall survival (OS; 49.0 vs. 29.3?months; hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57C0.97; squamous cell carcinoma of the head and neck, 5-fluorouracil Despite therapeutic advances, the 5-year survival rate for head and neck cancers in the US has remained approximately 55C65% since the mid-1970s [28, 38]. Both radiotherapy and chemotherapeutic approaches may have been optimized in terms of balancing efficacy and safety/tolerability [4], and the use of higher doses of chemotherapy in an attempt to overcome resistance has generally resulted in unacceptable toxicity and damage to healthy adjacent tissues [28]. While cetuximab has Cyhalofop demonstrated activity in SCCHN, new agents and treatment strategies are needed that will provide both improved tolerability and efficacy. Future directions beyond cetuximab: inhibiting the ErbB family Several novel agents targeting the ErbB/HER receptor family are being evaluated in phase II and III clinical trials for the treatment of SCCHN (Table?1). Table?1 ErbB family inhibitors in phase II and III studies for the treatment of squamous cell carcinoma of the head and neck epidermal growth factor receptor, intravenous, monoclonal antibody, oral, tyrosine kinase inhibitor Anti-EGFR monoclonal antibodies Panitumumab (Vectibix?, Amgen; Thousand Oaks, CA, USA) is a fully human anti-EGFR mAb. In a phase I study, the combination of panitumumab with carboplatin, paclitaxel, and intensity-modulated radiotherapy was evaluated in patients with locally advanced SCCHN ([66, 67], mutations in the tyrosine kinase domain of [67], and tumor cell surface expression of other members of the ErbB receptor family [68]. In an effort to address this issue, TKIs that block more than one member of the ErbB family and/or bind irreversibly to their targets are being investigated for Cyhalofop the Cyhalofop treatment of SCCHN. Afatinib (BIBW 2992, Boehringer.