Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. (ClinicalTrials.gov number, NCT00004227.)

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Background Patients with HPV-positive oropharyngeal squamous cell carcinoma (OPC) have high survival rates when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab, an antibody against the epidermal growth factor receptor, can preserve high survival rates and reduce treatment toxicity is unknown. Methods In a randomized, non-inferiority, multicenter trial, patients with locoregionally-advanced p16-positive OPC were stratified by American Joint Committee on Cancer T (T1-T2 vs. T3-T4) and N (N0-N2a vs. N2b-N3), Zubrod Performance Status (0 vs. 1), and tobacco smoking history (≤ vs. >10 pack-years) and randomized 1:1 to radiotherapy plus cetuximab 400 milligrams per square meter of body surface area (mg/m2), followed by 250 mgs/m2 for seven weekly doses or cisplatin 100 mgs/m2 for two doses, 21 days apart. The sample size was 800 eligible patients. The primary endpoint was overall survival (OS) with non-inferiority margin 1.45 (hazard ratio). Findings From June 2011 through July 2014, 849 patients (805 eligible; 399 cetuximab; 406 cisplatin) were randomized at 182 centers in the United States and Canada. With median follow-up 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criterion for OS. Estimated 5-year OS was 77·9% (95% confidence interval [CI] 73·4-82·5) in cetuximab group versus 84·6% (95%CI=80·6-88·6) in cisplatin group (hazard ratio [HR], 1·45, 1-sided 95% upper CI, 1·94; non-inferiority p=0·5056; 1-sided log-rank p=0.0163). PFS was significantly lower in cetuximab group than in cisplatin group (HR 1·72, 95%CI=1·29-2·29; 5-year rates, 67·3% vs. 78·4%), and LRF was significantly higher (HR 2·05, 95%CI=1·35-3·10; 5-year rates, 17·3% vs. 9·9%). The rate of moderate-to-severe toxicity that was acute (77·4% vs. 81·7%, p=0·1586) and late (16·5 vs. 20·4%, p=0·1904) was similar in the cetuximab and cisplatin groups, respectively. Interpretation For patients with HPV-positive OPC, radiotherapy plus cetuximab demonstrated inferior OS and PFS compared to radiotherapy plus cisplatin; toxicity rates were similar (NCT01302834). Funding National Cancer Institute USA, Eli Lilly and The Oral Cancer Foundation

EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. Following ligand binding, EGFR stimulates downstream cell signaling cascades that influence cell proliferation, apoptosis, migration, survival and complex processes, including angiogenesis and tumorigenesis. EGFR has been strongly implicated in the biology of human epithelial malignancies, with therapeutic applications in cancers of the colon, head and neck, lung, and pancreas. Accordingly, targeting EGFR has been intensely pursued, with the development of a series of promising molecular inhibitors for use in clinical oncology. As is common in cancer therapy, challenges with respect to treatment resistance emerge over time. This situation is certainly true of EGFR inhibitor therapies, where intrinsic and acquired resistance is now well recognized. In this Review, we provide a brief overview regarding the biology of EGFR biology, preclinical and clinical development of EGFR inhibitors, and molecular mechanisms that underlie the development of treatment resistance. A greater understanding of the mechanisms that lead to EGFR resistance may provide valuable insights to help design new strategies that will enhance the impact of this promising class of inhibitors for the treatment of cancer.

The epidermal growth factor receptor (EGFR) is a central regulator of proliferation and progression in human cancers. Five EGFR inhibitors, two monoclonal antibodies and three TKIs, have recently gained FDA approval in oncology (cetuximab, panitumumab, erlotinib, gefitinib and lapatinib). These strategies of EGFR inhibition demonstrate major tumor regressions in approximately 10-20% of advanced cancer patients. However, many tumors eventually manifest acquired resistance to treatment. In this study we established and characterized a model to study molecular mechanisms of acquired resistance to the EGFR monoclonal antibody cetuximab. Using high-throughput screening we examined the activity of 42 receptor tyrosine kinases in resistant tumor cells following chronic exposure to cetuximab. Cells developing acquired resistance to cetuximab exhibited increased steady-state EGFR expression secondary to alterations in trafficking and degradation. In addition, cetuximabresistant cells manifested strong activation of HER2, HER3 and cMET. EGFR upregulation promoted increased dimerization with HER2 and HER3 leading to their transactivation. Blockade of EGFR and HER2 led to loss of HER3 and PI(3)K/Akt activity. These data suggest that acquired resistance to cetuximab is accompanied by dysregulation of EGFR internalization/degradation and subsequent EGFR-dependent activation of HER3. Taken together these findings suggest a rationale for the clinical evaluation of combinatorial anti-HER targeting approaches in tumors manifesting acquired resistance to cetuximab.