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1.  Treatment of Recurrent Metastatic Head and Neck Cancer: Focus on Cetuximab 
EGFR belongs to the ErbB family of receptor tyrosine kinases and is associated with worse prognosis in head and neck squamous cell carcinoma (HNSCC). Cetuximab is a monoclonal antibody to the extracellular domain of EGFR and inhibits its downstream actions via multiple mechanisms. Besides its proven efficacy in locally advanced and incurable HNSCC, cetuximab has the distinct advantage of having a relatively tolerable side effect profile and not potentiating radiation toxicity. Though therapies for advanced HNSCC are evolving, locoregional recurrence and/or distant metastases occur in a large percentage of patients. Though some patients can be salvaged with surgery or radiation therapy, the majority are incurable, and are treated palliatively with systemic therapy. In the setting of first line therapy for recurrent/metastatic HNSCC, the EXTREME trial provided level 1 evidence that cetuximab improves overall survival when combined with cisplatinum and 5 FU. Following progression on first line chemotherapy, several phase II trials suggest that cetuximab monotherapy is a reasonable choice in this setting. Future studies should concentrate on clinical and molecular markers that may allow more personalized approaches to treating HNSCC, and combining EGFR inhibitors with other agents in a synergistic approach.
doi:10.4137/CMENT.S5129
PMCID: PMC3791949  PMID: 24179404
recurrent; metastatic; SCC; squamous cell carcinoma; EGFR; epidermal growth factor receptor; cetuximab
2.  The Role of Cetuximab for the Treatment of Squamous Cell Carcinoma of the Head and Neck 
Squamous cell carcinoma of the head and neck (HNSCC) while curable in many cases with surgery, radiation, and chemotherapy, remains a disease that is associated with significant morbidity and mortality. Agents that target the epidermal growth factor receptor (EGFR) have demonstrated activity in this disease. Cetuximab, a monoclonal antibody, is FDA-approved in conjunction with radiation for locally advanced, potentially curable disease, and as a single agent for incurable recurrent/metastatic disease. In addition, there are more recent data showing a survival benefit for patients with recurrent/metastatic disease who were treated with a 1st-line regimen of platinum, fluorouracil and cetuximab. These promising results have had a significant impact on the standard of care for HNSCC, and have prompted further research on the role of EGFR inhibitors in the treatment of HNSCC. In the following review, we will discuss the history, mechanism, and clinical trials that pertain to the role of cetuximab in the treatment of HNSCC.
PMCID: PMC2745918  PMID: 18997665
3.  Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer 
Current Oncology  2010;17(3):37-48.
Question
What are the benefits associated with the use of anti–epidermal growth factor receptor (anti-egfr) therapies in squamous cell carcinoma of the head and neck (hnscc)? Anti-egfr therapies of interest included cetuximab, gefitinib, lapatinib, zalutumumab, erlotinib, and panitumumab.
Perspectives
Head-and-neck cancer includes malignant tumours arising from a variety of sites in the upper aerodigestive tract. The most common histologic type is squamous cell carcinoma, and most common sites are the oral cavity, the oropharynx, the hypopharynx, and the larynx. Worldwide, hnscc is the sixth most common neoplasm, and despite advances in therapy, long-term survival in hnscc patients is poor. Primary surgery followed by chemoradiation, or primary chemoradiation, are the standard treatment options for patients with locally advanced (stages iii–ivb) hnscc; however, meta-analytic data indicate that the benefit of concurrent platinum-based chemotherapy disappears in patients over the age of 70 years.
Cetuximab is a monoclonal antibody approved for use in combination with radiation in the treatment of patients with untreated locally advanced hnscc and as monotherapy for patients with recurrent or metastatic (stage ivc) hnscc who have progressed on platinum-based therapy.
Given the interest in anti-egfr agents in advanced hnscc, the Head and Neck Cancer Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-Based Care (pebc) chose to systematically review the literature pertaining to this topic so as to develop evidence-based recommendations for treatment.
Outcomes
Outcomes of interest included overall and progression-free survival, quality of life, tumour response rate and duration, and the toxicity associated with the use of anti-egfr therapies.
Methodology
The medline, embase, and Cochrane Library databases, the American Society of Clinical Oncology online conference proceedings, the Canadian Medical Association InfoBase, and the National Guidelines Clearinghouse were systematically searched to locate primary articles and practice guidelines. The reference lists from relevant review articles were searched for additional trials. All evidence was reviewed, and that evidence informed the development of the clinical practice guideline. The resulting recommendations were approved by the Report Approval Panel of the pebc, and by the Head and Neck Cancer dsg. An external review by Ontario practitioners completed the final phase of the review process. Feedback from all parties was incorporated to create the final practice guideline.
Results
The electronic search identified seventy-four references that were reviewed for inclusion. Only four phase iii trials met the inclusion criteria for the present guideline. No practice guidelines, systematic reviews, or meta-analyses were found during the course of the literature search.
The randomized controlled trials (rcts) involved three distinct patient populations: those with locally advanced hnscc being treated for cure, those with incurable advanced recurrent or metastatic hnscc being treated with first-line platinum-based chemotherapy, and those with incurable advanced recurrent or metastatic hnscc who had disease progression despite, or who were unsuitable for, first-line platinum-based chemotherapy.
Practice Guideline
These recommendations apply to adult patients with locally advanced (nonmetastatic stages iii–ivb) or recurrent or metastatic (stage ivc) hnscc.
Platinum-based chemoradiation remains the current standard of care for treatment of locally advanced hnscc.
In patients with locally advanced hnscc who are medically unsuitable for concurrent platinumbased chemotherapy or who are over the age of 70 years (because concurrent chemotherapy does not appear to improve overall survival in this patient population), the addition of cetuximab to radical radiotherapy should be considered to improve overall survival, progression-free survival, and time to local recurrence.
Cetuximab in combination with platinum-based combination chemotherapy is superior to chemotherapy alone in patients with recurrent or metastatic hnscc, and is recommended to improve overall survival, progression-free survival, and response rate.
The role of anti-egfr therapies in the treatment of locally advanced hnscc is currently under study in large randomized trials, and patients with hnscc should continue to be offered clinical trials of novel agents aimed at improving outcomes.
Qualifying Statements
Chemoradiation is the current standard of care for patients with locally advanced hnscc, and to date, there is no evidence that compares cetuximab plus radiotherapy with chemoradiation, or that examines whether the addition of cetuximab to chemoradiation is of benefit in these patients. However, five ongoing trials are investigating the effect of the addition of egfr inhibitors concurrently with, before, or after chemoradiotherapy; those trials should provide direction about the best integration of cetuximab into standard treatment.
In patients with recurrent or metastatic hnscc who experience progressive disease despite, or who are unsuitable for, first-line platinum-based chemotherapy, gefitinib at doses of 250 mg or 500 mg daily, compared with weekly methotrexate, did not increase median overall survival [hazard ratio (hr): 1.22; 96% confidence interval (ci): 0.95 to 1.57; p = 0.12 (for 250 mg daily vs. weekly methotrexate); hr: 1.12; 95% ci: 0.87 to 1.43; p = 0.39 (for 500 mg daily vs. weekly methotrexate)] or objective response rate (2.7% for 250 mg and 7.6% for 500 mg daily vs. 3.9% for weekly methotrexate, p > 0.05). As compared with methotrexate, gefitinib was associated with an increased incidence of tumour hemorrhage (8.9% for 250 mg and 11.4% for 500 mg daily vs. 1.9% for weekly methotrexate).
PMCID: PMC2880902  PMID: 20567625
Head-and-neck cancer; epidermal growth factor receptor; egfr inhibitors; overall survival; progression-free survival; tumour response rate
4.  Rationale and design of LUX-Head & Neck 1: a randomised, Phase III trial of afatinib versus methotrexate in patients with recurrent and/or metastatic head and neck squamous cell carcinoma who progressed after platinum-based therapy 
BMC Cancer  2014;14:473.
Background
Patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) receiving platinum-based chemotherapy as their first-line treatment have a dismal prognosis, with a median overall survival (OS) of ~7 months. Methotrexate is sometimes used following platinum failure or in patients not fit enough for platinum therapy, but this agent has not demonstrated any OS improvement. Targeted therapies are a novel approach, with the EGFR-targeting monoclonal antibody cetuximab (plus platinum-based chemotherapy) approved in the US and Europe in the first-line R/M setting, and as monotherapy following platinum failure in the US. However, there is still a high unmet medical need for new treatments that improve outcomes in the second-line R/M setting following failure on first-line platinum-containing regimens. Afatinib, an irreversible ErbB family blocker, was recently approved for the first-line treatment of EGFR mutation-positive metastatic non-small cell lung cancer. Afatinib has also shown clinical activity similar to cetuximab in a Phase II proof-of-concept HNSCC trial. Based on these observations, the Phase III, LUX-Head & Neck 1 study is evaluating afatinib versus methotrexate in R/M HNSCC patients following progression on platinum-based chemotherapy in the R/M setting.
Methods/Design
Patients with progressive disease after one first-line platinum-based chemotherapy are randomised 2:1 to oral afatinib (starting dose 40 mg once daily) or IV methotrexate (starting dose 40 mg/m2 once weekly) administered as monotherapy with best supportive care until progression or intolerable adverse events. Efficacy of afatinib versus methotrexate will be assessed in terms of progression-free survival (primary endpoint). Disease progression will be evaluated according to RECIST v1.1 by investigator and independent central review. Secondary endpoints include OS, tumour response and safety. Health-related quality of life and biomarker assessments will also be performed.
Discussion
If the LUX-Head & Neck 1 trial meets its primary endpoint, it will demonstrate the ability of afatinib to elicit an improved treatment benefit versus a commonly used chemotherapy agent in the second-line treatment of R/M HNSCC patients who have failed on first-line platinum-based therapy, confirm the clinical efficacy of afatinib observed in the Phase II proof-of-concept study, and establish a new standard of care for this patient population.
doi:10.1186/1471-2407-14-473
PMCID: PMC4079914  PMID: 24973959
Afatinib; Methotrexate; Head and neck; Phase III; Recurrent; Metastatic
5.  Recent results of cetuximab use in the treatment of squamous cell carcinoma of the head and neck 
OncoTargets and therapy  2009;2:243-250.
Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth factor receptor. The role of cetuximab is paramount in several subsets of head and neck cancer. In particular, the EXTREME study has indicated cetuximab as the only drug to improve survival when associated with cisplatin and 5-fluorouracil in patients with recurrent/metastatic disease. Furthermore, cetuximab, both alone and in combination with cisplatin, is active in patients with recurrent/metastatic disease who have failed prior platinum-based chemotherapy. Cetuximab, given in association with radiation therapy, is a treatment of choice in first-line therapy of patients with locally advanced inoperable disease. In the same setting, the role of induction chemotherapy has gained considerable interest over the last few years and a number of efforts are being pursued to optimally integrate induction chemotherapy with radiation therapy plus cetuximab. The combination of cetuximab and other targeted therapies is among the most promising new perspectives for patients with head and neck cancer.
PMCID: PMC2886337  PMID: 20616911
cetuximab; head and neck cancer; locally advanced; recurrent/metastatic
6.  Efficacy of gemcitabine and cetuximab combination treatment in head and neck squamous cell carcinoma 
Molecular and Clinical Oncology  2013;1(5):918-924.
Head and neck squamous cell carcinoma (HNSCC) may be curable with surgery, radiation and chemotherapy in its early stages. However, recurrence and metastasis often prevail following primary treatment in advanced stage cases and are associated with significant morbidity and mortality. In this study we investigated the combination therapy of gemcitabine and cetuximab for HNSCC. The UM-SCC-6 and UM-SCC-23 HNSCC cell lines were analyzed following treatment with gemcitabine and cetuximab. To determine the mechanism of action of this combination treatment, the cell cycle distributions following gemcitabine and/or cetuximab treatment were analyzed by flow cytometry and apoptosis assay. Gemcitabine and cetuximab combination treatment exerted an enhanced cytotoxic effect. The cell cycle analysis demonstrated that cells accumulated in the S phase following gemcitabine treatment and G1 arrest occurred following cetuximab treatment. An increase in sub-G1 phase cells was also observed following treatment with the two drugs. In an apoptosis assay, caspase 3/7 activity was found to be higher when administering a combination of gemcitabine and cetuximab compared to each agent administered alone. Gemcitabine and cetuximab are individually effective against HNSCC and an enhanced growth inhibitory effect may be expected when these agents are used in combination.
doi:10.3892/mco.2013.159
PMCID: PMC3916031  PMID: 24649271
head and neck squamous cell carcinoma; chemotherapy; cetuximab; gemcitabine; cell cycle
7.  Approval Summary: Cetuximab in Combination With Cisplatin or Carboplatin and 5-Fluorouracil for the First-Line Treatment of Patients With Recurrent Locoregional or Metastatic Squamous Cell Head and Neck Cancer 
The Oncologist  2013;18(4):460-466.
The present cetuximab U.S. Food and Drug Administration submission seeks to expand the squamous cell head and neck cancer indication to include recurrent locoregional or metastatic disease. Cetuximab, in combination with platinum-based therapy and 5-fluorouracil (FU), is compared to platinum-based therapy and 5-FU alone.
Learning Objectives
Compare survival outcomes among patients with SCCHN treated with a platinum/5 -FU regimen with and without cetuximab.Compare adverse event profiles among patients with SCCHN treated with a platinum/5 -FU regimen with and without cetuximab.Describe potential risk-benefit issues identified in the EU and US studies.
On November 7, 2011, the U.S. Food and Drug Administration approved cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil for the first-line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer. Approval was based on a randomized study of 442 patients conducted outside the U.S. Cisplatin (100 mg/m2 intravenously) or carboplatin (area under the curve 5 intravenously) on day 1 with 5-fluorouracil (1,000 mg/m2/day continuous intravenous infusion days 1–4) were administered every 3 weeks. Cetuximab, 400 mg/m2 intravenously, was administered initially followed by cetuximab, 250 mg/m2 intravenously weekly. After completion of six planned treatment courses, cetuximab patients without progression continued cetuximab 250 mg/m2 weekly. The study used European Union (EU)-approved cetuximab rather than U.S.-approved cetuximab. U.S.-approved cetuximab provides approximately 28% higher exposure relative to EU-approved cetuximab in a pharmacokinetic comparability study in monkeys. Overall survival, the primary efficacy endpoint, was significantly improved in cetuximab-treated patients (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.64–0.98; p = .034, stratified log-rank test). Median survival times were 10.1 and 7.4 months, respectively. Progression-free survival (PFS) was also significantly improved in patients receiving cetuximab (HR: 0.57; 95% CI: 0.46–0.72; p < .0001). Median PFS times were 5.5 and 3.3 months, respectively. Response rates were 35.6% and 19.5% (odds ratio: 2.33; 95% CI: 1.50–3.60; p = .0001). Adverse reactions (≥25%) from cetuximab plus chemotherapy treatment included nausea, anemia, vomiting, neutropenia, rash, asthenia, diarrhea, and anorexia. Conjunctivitis occurred in 10% of cetuximab patients. Other adverse reactions, sometimes severe, included infusion reactions, hypomagnesemia, hypocalcemia, and hypokalemia.
doi:10.1634/theoncologist.2012-0458
PMCID: PMC3639534  PMID: 23576486
Cetuximab; Erbitux; Head and neck cancer; Advanced disease
8.  Impact of human papilloma virus infection on the response of head and neck cancers to anti-epidermal growth factor receptor antibody therapy 
Cell Death & Disease  2014;5(2):e1091-.
Infection with human papillomaviruses (HPVs) characterizes a distinct subset of head and neck squamous cell cancers (HNSCCs). HPV-positive HNSCC preferentially affect the oropharynx and tonsils. Localized HPV-positive HNSCCs have a favorable prognosis and treatment outcome. However, the impact of HPV in advanced or metastatic HNSCC remains to be defined. In particular, it is unclear whether HPV modulates the response to cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), which is a mainstay of treatment of advanced HNSCC. To this end, we have examined the sensitivity of HPV-positive and -negative HNSCC models to cetuximab and cytotoxic drugs in vitro and in vivo. In addition, we have stably expressed the HPV oncogenes E6 and E7 in cetuximab-sensitive cancer cell lines to specifically investigate their role in the antibody response. The endogenous HPV status or the expression of HPV oncogenes had no significant impact on cetuximab-mediated suppression of EGFR signaling and proliferation in vitro. Cetuximab effectively inhibited the growth of E6- and E7-expressing tumors grafted in NOD/SCID mice. In support, formalin-fixed, paraffin-embedded tumor samples from cetuximab-treated patients with recurrent or metastatic HNSCC were probed for p16INK4a expression, an established biomarker of HPV infection. Response rates (45.5% versus 45.5%) and median progression-free survival (97 versus 92 days) following cetuximab-based therapy were similar in patients with p16INK4A-positive and p16INK4A-negative tumors. In conclusion, HPV oncogenes do not modulate the anti-EGFR antibody response in HSNCC. Cetuximab treatment should be administered independently of HPV status.
doi:10.1038/cddis.2014.62
PMCID: PMC3944273  PMID: 24577089
HNSCC; cetuximab; HPV; resistance; EGFR; ADCC
9.  Autophagic action of new targeting agents in head and neck oncology 
Cancer Biology & Therapy  2012;13(11):978-991.
The survival rates of patients with squamous cell carcinoma of the head and neck (HNSCC) have not improved significantly despite multi-modality therapy, including surgery, radiation therapy, and chemotherapy. Recently, molecular targeted agents have shown significant improvement in clinical outcomes; for example, in chronic myelogeneous leukemia with imatinib, breast cancer with trastuzumab, colon cancer with bevacizumab and cetuximab, and renal cell cancer with sorafenib and sunitinib. In HNSCC, the epidermal growth factor receptor antibody cetuximab has shown promising results in combination with radiation. Targeted agents including cetuximab induce stresses to activate prosurvival autophagy. Combining autophagy inhibitors with agents that induce autophagy as a prosurvival response may therefore increase their therapeutic efficacy. Whether autophagy contributes to the prosurvival response or to the antitumor effect of chemotherapeutic drugs is largely unknown. This review will discuss the possible role of autophagy as a novel target for anticancer therapy agents in HNSCC.
doi:10.4161/cbt.21079
PMCID: PMC3461820  PMID: 22825332
head and neck squamous cell carcinoma; molecular targeted agents; epidermal growth factor; autophagy; autophagic cell death; autophagic resistance; apoptosis
10.  Cost-Effectiveness of Adding Cetuximab to Platinum-Based Chemotherapy for First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer 
PLoS ONE  2012;7(6):e38557.
Purpose
To assess the cost effectiveness of adding cetuximab to platinum-based chemotherapy in first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) from the perspective of the Canadian public healthcare system.
Methods
We developed a Markov state transition model to project the lifetime clinical and economic consequences of recurrent or metastatic HNSCC. Transition probabilities were derived from a phase III trial of cetuximab in patients with recurrent or metastatic HNSCC. Cost estimates were obtained from London Health Sciences Centre and the Ontario Case Costing Initiative, and expressed in 2011 CAD. A three year time horizon was used. Future costs and health benefits were discounted at 5%.
Results
In the base case, cetuximab plus platinum-based chemotherapy compared to platinum-based chemotherapy alone led to an increase of 0.093 QALY and an increase in cost of $36,000 per person, resulting in an incremental cost effectiveness ratio (ICER) of $386,000 per QALY gained. The cost effectiveness ratio was most sensitive to the cost per mg of cetuximab and the absolute risk of progression among patients receiving cetuximab.
Conclusion
The addition of cetuximab to standard platinum-based chemotherapy in first-line treatment of patients with recurrent or metastatic HNSCC has an ICER that exceeds $100,000 per QALY gained. Cetuximab can only be economically attractive in this patient population if the cost of cetuximab is substantially reduced or if future research can identify predictive markers to select patients most likely to benefit from the addition of cetuximab to chemotherapy.
doi:10.1371/journal.pone.0038557
PMCID: PMC3379991  PMID: 22745668
11.  Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: retrospective analysis of the phase III EXTREME trial 
Annals of Oncology  2014;25(4):801-807.
Adding cetuximab to chemotherapy improved survival in patients with recurrent/metastatic squamous cell carcinoma of the head and neck. Although HPV and p16 statuses have prognostic value, the observed survival benefit conferred by cetuximab is independent of both. This pattern remained in a combined analysis of both p16 and HPV and in patients with oropharyngeal cancer separately.
Background
Tumor human papillomavirus (HPV) status is an important prognostic factor in locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Prognostic value in recurrent and/or metastatic (R/M) disease remains to be confirmed. This retrospective analysis of the EXTREME trial, comparing chemotherapy plus cetuximab with chemotherapy first line in R/M SCCHN, investigated efficacy and prognosis according to tumor p16 and HPV status.
Patients and methods
Paired tissue samples were used: p16INK4A expression was assessed by immunohistochemistry, and HPV status determined in extracted DNA samples using oligonucleotide hybridization assays.
Results
Altogether, 416 of 442 patients had tumor samples available for p16 and HPV: 10% of tumors were p16 positive and 5% were HPV positive. Adding cetuximab to chemotherapy improved survival, irrespective of tumor p16 or HPV status. This pattern remained in a combined analysis of p16 and HPV. p16 positivity and HPV positivity were associated with prolonged survival compared with p16 negativity and HPV negativity. Subgroup analysis of patients with oropharyngeal cancer demonstrated a similar pattern to all evaluable patients.
Conclusion
The results from this analysis suggest that p16 and HPV status have prognostic value in R/M SCCHN and survival benefits of chemotherapy plus cetuximab over chemotherapy alone are independent of tumor p16 and HPV status.
doi:10.1093/annonc/mdt574
PMCID: PMC3969553  PMID: 24577117
cetuximab; human papillomavirus; p16; recurrent and metastatic; squamous cell carcinoma of the head and neck
12.  Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab 
Cancer biology & therapy  2009;8(8):696-703.
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays a major role in oncogenesis. Cetuximab is an EGFR-blocking antibody that is FDA approved for use in patients with metastatic colorectal cancer (mCRC) and head and neck squamous cell carcinoma (HNSCC). Although cetuximab has shown strong clinical benefit for a subset of cancer patients, most become refractory to cetuximab therapy. We reported that cetuximab-resistant NSCLC line NCI-H226 cells have increased steady-state expression and activity of EGFR secondary to altered trafficking/degradation and this increase in EGFR expression and activity lead to hyper-activation of HER3 and down stream signals to survival. We now present data that Src family kinases (SFKs) are highly activated in cetuximab-resistant cells and enhance EGFR activation of HER3 and PI(3)K/Akt. Studies using the Src kinase inhibitor dasatinib decreased HER3 and PI(3)K/Akt activity. In addition, cetuximab-resistant cells were resensitized to cetuximab when treated with dasatinib. These results indicate that SFKs and EGFR cooperate in acquired resistance to cetuximab and suggest a rationale for clinical strategies that investigate combinatorial therapy directed at both the EGFR and SFKs in patients with acquired resistance to cetuximab.
PMCID: PMC2895567  PMID: 19276677
EGFR; cetuximab; resistance; Src-family kinases; dasatinib
13.  Emerging drugs to treat squamous cell carcinomas of the head and neck 
Expert opinion on emerging drugs  2010;15(3):355-373.
Importance of the field
Head and neck squamous cell carcinoma (HNSCC) is the eighth leading cause of cancer death worldwide. Despite advances in surgery and chemoradiation therapy, there has been little improvement in survival rates over the past 4 decades. Additionally, surgery and chemoradiotherapy have serious side effects. The development of agents with greater efficacy and tolerability is needed.
Areas covered in this review
EGFR is the only proven molecular target for HNSCC therapy. Cetuximab, the sole FDA-approved molecular targeted HNSCC therapy, and other potential targeted therapies are being evaluated in preclinical, clinical and post-marketing studies. Here, we review the emerging targets for biological agents in HNSCC and the rationale for their selection.
What the reader will gain
Key information in the development of new drug targets and the emergence of new biomarkers are discussed. Readers will gain insight regarding the limitations of current therapies, the impact of recently approved targeted therapies and the influence that predictive biomarkers will have on drug development.
Take home message
The head and neck cancer drug market is rapidly evolving. Coordination between drug and biomarker development efforts may soon yield targeted therapies that can achieve the promise of personalized cancer medicine.
doi:10.1517/14728214.2010.497754
PMCID: PMC3133968  PMID: 20557270
carcinoma; cetuximab; EGFR; erlotinib; gefitinib; HNSCC; HPV; panitumumab; SCCHN; squamous
14.  Detection of Tumor Epidermal Growth Factor Receptor Pathway Dependence by Serum Mass Spectrometry in Cancer Patients 
Background:
We hypothesized that a serum proteomic profile predictive of survival benefit in non–small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) reflects tumor EGFR dependency regardless of site of origin or class of therapeutic agent.
Methods:
Pretreatment serum or plasma from 230 patients treated with cetuximab, EGFR-TKIs, or chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC) were analyzed by mass spectrometry. Each sample was classified into “good” or “poor” groups using VeriStrat, and survival analyses of each cohort were done based on this classification. For the CRC cohort, this classification was correlated with the tumor EGFR ligand levels and KRAS mutation status.
Results:
In the EGFR inhibitor–treated cohorts, the classification predicted survival (HNSCC: gefitinib, P = 0.007 and erlotinib/bevacizumab, P = 0.02; CRC: cetuximab, P = 0.0065) whereas the chemotherapy cohort showed no survival difference. For CRC patients, tumor EGFR ligand RNA levels were significantly associated with the proteomic classification, and combined KRAS and proteomic classification provided improved survival classification.
Conclusions:
Serum proteomic profiling can detect clinically significant tumor dependence on the EGFR pathway in non–small cell lung cancer, HNSCC, and CRC patients treated with either EGFR-TKIs or cetuximab. This classification is correlated with tumor EGFR ligand levels and provides a clinically practical way to identify patients with diverse cancer types most likely to benefit from EGFR inhibitors. Prospective studies are necessary to confirm these findings.
doi:10.1158/1055-9965.EPI-09-0937
PMCID: PMC2846615  PMID: 20086114
15.  Dacomitinib, an Irreversible Pan-ErbB Inhibitor Significantly Abrogates Growth in Head and Neck Cancer Models That Exhibit Low Response to Cetuximab 
PLoS ONE  2013;8(2):e56112.
Aberrant epidermal growth factor (EGF) signaling is associated with tumor growth in squamous cell carcinoma of the head and neck in humans (HNSCC), and is a major focus of targeted therapy. Cetuximab, a monoclonal antibody against EGFR, has been successful at prolonging survival but has only a 10% tumor shrinkage response rate in a clinical setting. The goal of this study was to compare dacomitinib (PF-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple HER family receptors (HER-1 (EGFR), HER-2 and HER-4 tyrosine kinases), to cetuximab, the current FDA approved anti-EGFR medication for HNSCC and erlotinib, an EGFR specific small molecule tyrosine kinase inhibitor. Dacomitinib, erlotinib and cetuximab were tested in a panel of 27 HNSCC cell lines. Treatment with 100 ug/ml of cetuximab or 1 uM of erlotinib inhibited growth by at least 50% in 7/27 cell lines, while treatment with 1 uM of dacomitinib had similar growth inhibition in 17/27 lines. Cell lines representing three levels of sensitivity to dacomitinib were further examined using Western blots, cell cycle and apoptosis analysis. Treatment with 100 nM of dacomitinib reduced EGFR activity and downstream AKT and ERK pathways more effectively than treatment with 100 ug/ml of cetuximab in all ten tested lines. Although both compounds induced apoptosis at similar levels, dacomitinib caused greater G0/G1 arrest. Sensitivity to EGFR blockade was associated with levels of EGFR and ERK and was not associated with common oncogenic mutations and copy number variations. Phosphorylated and total EGFR and ERK levels correlate with sensitivity to both cetuximab and dacomitinib. Three of the four lines in the exquisitely sensitive group had the highest levels of phosphorylated and total EGFR and ERK among the ten lines selected, while the three resistant lines collectively had the lowest levels. Neither pAKT nor tAKT was associated with sensitivity.
doi:10.1371/journal.pone.0056112
PMCID: PMC3566064  PMID: 23405260
16.  Lentiviral vector-based therapy in head and neck cancer (Review) 
Oncology Letters  2013;7(1):3-9.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common neoplasm worldwide. Despite advances in multimodality treatments involving surgery, radiation and chemotherapy, the five-year survival rate has remained at ~50% for the past 35 years. Therefore, the early detection of recurrent or persistent disease is extremely important. Replication-incompetent HIV-1-based lentiviral vectors have emerged as powerful and safe tools for gene delivery. Commonly, HNSCC is a locoregional disease that presents at or close to the body surface. Thus, HNSCC is amendable to intratumoral injections of gene therapy vectors aimed at correcting defects associated with tumor suppressor genes to induce the direct cytotoxicity of cancer cells or immune modulation to promote antitumor immunity. Current investigations analyzing HNSCC gene mutations and stem cell markers and the cancer immunoediting concept are creating exciting therapeutic opportunities for lentiviral and other gene transfer vectors. The present review reports specific examples of the current applications of lentiviral vectors in HNSCC.
doi:10.3892/ol.2013.1652
PMCID: PMC3861563  PMID: 24348811
lentiviral vectors; head and neck cancers; immunotherapy
17.  The role of EGFR-targeting strategies in the treatment of head and neck cancer 
OncoTargets and therapy  2012;5:127-131.
With its targeted mechanism of action and synergistic activity with current treatment modalities, cetuximab is a potentially valuable treatment option for patients with recurrent and/or metastatic squamous cell cancer of the head and neck who have progressed on cisplatin-based chemotherapy. The use of cetuximab in combination with radiotherapy as definitive treatment for locoregionally advanced squamous cell cancer of the head and neck is generally restricted to patients unfit to receive cisplatin-based chemoradiation, which is still considered the standard of care. The effect of this epidermal growth factor receptor antagonist occurs without any change in the pattern and the severity of toxicity usually associated with head and neck radiation.
doi:10.2147/OTT.S31863
PMCID: PMC3412570  PMID: 22888261
cetuximab; SCCHN; radiotherapy
18.  Dasatinib blocks cetuximab- and radiation-induced nuclear translocation of the epidermal growth factor receptor in head and neck squamous cell carcinoma 
Background and Purpose
The aberrant expression of epidermal growth factor receptor (EGFR) has been linked to the etiology of head and neck squamous cell carcinoma (HNSCC). The first major phase III trial combining cetuximab with radiation confirmed a strong survival advantage. However, both cetuximab and radiation can promote EGFR translocation to the nucleus where it enhances resistance to both of these modalities. In this report we sought to determine how to block cetuximab and radiation–induced translocation of EGFR to the nucleus in HNSCC cell lines.
Material and Methods
We utilized three established HNSCC cell lines, SCC1, SCC6 and SCC1483 and measured nuclear translocation of EGFR after treatment with cetuximab or radiation. We then utilized dasatinib (BMS-354825), a potent, orally bioavailable inhibitor of several tyrosine kinases, including the Src Family Kinases, to determine if SFKs blockade could abrogate cetuximab and radiation-induced nuclear EGFR translocation.
Results
Cetuximab and radiation treatment of all three HNSCC lines lead to translocation of the EGFR to the nucleus. Blockade of SFKs abrogated cetuximab and radiation-induced EGFR translocation to the nucleus.
Conclusions
The data presented in this report suggests that both cetuximab and radiation can promote EGFR translocation to the nucleus and dasatinib can inhibit this process. Collectively these findings may suggest that dasatinib can limit EGFR translocation to the nucleus and may enhance radiotherapy plus cetuximab in HNSCC.
doi:10.1016/j.radonc.2010.06.010
PMCID: PMC2974772  PMID: 20667610
EGFR; cetuximab; radiation; Src family kinases; dasatinib; head and neck cancer
19.  New approaches to EGFR inhibition for locally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN) 
Despite recent advances in radiotherapy and chemotherapy, survival rates for squamous cell carcinoma of the head and neck (SCCHN) have remained poor. The focus of SCCHN therapy has more recently shifted to the molecular level, particularly the epidermal growth factor receptor (EGFR/ErbB) pathway. Several agents that target the EGFR pathway, including monoclonal antibodies and tyrosine kinase inhibitors, are under investigation for SCCHN. Searches of PubMed and results of key oncology congresses were performed to identify relevant articles and abstracts. The EGFR-targeted monoclonal antibody cetuximab is approved for the treatment of locally advanced SCCHN in combination with radiotherapy, for first-line treatment of recurrent or metastatic SCCHN in combination with platinum-based chemotherapy and 5-fluorouracil, and for recurrent or metastatic SCCHN following progression with platinum-based chemotherapy. Other investigational EGFR-targeted monoclonal antibodies (e.g., panitumumab, nimotuzumab, zalutumumab) are in clinical development for SCCHN. Inhibition of the tyrosine kinase domain of EGFR has also been explored as a therapeutic approach in SCCHN using small-molecule reversible inhibitors, such as gefitinib and erlotinib. However, a key challenge in SCCHN is the development of resistance, and strategies are being pursued to delay or overcome resistance to EGFR-targeted agents. These strategies include development of agents 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.
doi:10.1007/s12032-012-0159-2
PMCID: PMC3466428  PMID: 22252310
Epidermal growth factor receptor (EGFR); Monoclonal antibody; Tyrosine kinase inhibitor; Resistance; Squamous cell carcinoma of the head and neck
20.  Cetuximab: its unique place in head and neck cancer treatment 
Head and neck cancer is the sixth most common cancer worldwide. At present, globally about 650,000 new cases of squamous cell carcinoma of the head and neck (SCCHN) are diagnosed each year. The epidermal growth factor receptor (EGFR) is almost invariably expressed in SCCHN. Overexpression of the EGFR is a strong and independent unfavorable prognostic factor in SCCHN. Cetuximab is a chimeric monoclonal antibody, which binds with high affinity to the extracellular domain of the human EGFR, blocking ligand binding, resulting in inhibition of the receptor function. It also targets cytotoxic immune effector cells towards EGFR-expressing tumor cells (antibody dependent cell-mediated cytotoxicity). The addition of cetuximab to radiotherapy (RT) improves locoregional control and survival when compared to RT alone. The addition of cetuximab to platinum-based chemoradiation (CRT) is feasible but does not lead to an improved outcome. Cetuximab plus RT has never been compared prospectively to CRT, which therefore remains the standard treatment for patients with locoregionally advanced SCCHN for whom surgery is not considered the optimal treatment, provided they can tolerate CRT. The addition of cetuximab to platinum-based chemotherapy prolongs survival in patients with recurrent or metastatic SCCHN. The combination of a platinum-based regimen and cetuximab should be considered as the standard first line regimen for patients who can tolerate this treatment.
doi:10.2147/BTT.S43628
PMCID: PMC3665438  PMID: 23723688
SCCHN; cetuximab; recurrent metastatic; locoregionally advanced; chemoradiation
21.  Adaptive and innovative Radiation Treatment FOR improving Cancer treatment outcomE (ARTFORCE); a randomized controlled phase II trial for individualized treatment of head and neck cancer 
BMC Cancer  2013;13:84.
Background
Failure of locoregional control is the main cause of recurrence in advanced head and neck cancer. This multi-center trial aims to improve outcome in two ways. Firstly, by redistribution of the radiation dose to the metabolically most FDG-PET avid part of the tumour. Hereby, a biologically more effective dose distribution might be achieved while simultaneously sparing normal tissues. Secondly, by improving patient selection. Both cisplatin and Epidermal Growth Factor Receptor (EGFR) antibodies like Cetuximab in combination with Radiotherapy (RT) are effective in enhancing tumour response. However, it is unknown which patients will benefit from either agent in combination with irradiation. We will analyze the predictive value of biological markers and 89Zr-Cetuximab uptake for treatment outcome of chemoradiation with Cetuximab or cisplatin to improve patient selection.
Methods
ARTFORCE is a randomized phase II trial for 268 patients with a factorial 2 by 2 design: cisplatin versus Cetuximab and standard RT versus redistributed RT. Cisplatin is dosed weekly 40 mg/m2 for 6 weeks. Cetuximab is dosed 250mg/m2 weekly (loading dose 400 mg/m2) for 6 weeks. The standard RT regimen consists of elective RT up to 54.25 Gy with a simultaneous integrated boost (SIB) to 70 Gy in 35 fractions in 6 weeks. Redistributed adaptive RT consists of elective RT up to 54.25 Gy with a SIB between 64-80 Gy in 35 fractions in 6 weeks with redistributed dose to the gross tumour volume (GTV) and clinical target volume (CTV), and adaptation of treatment for anatomical changes in the third week of treatment.
Patients with locally advanced, biopsy confirmed squamous cell carcinoma of the oropharynx, oral cavity or hypopharynx are eligible.
Primary endpoints are: locoregional recurrence free survival at 2 years, correlation of the median 89Zr-cetuximab uptake and biological markers with treatment specific outcome, and toxicity. Secondary endpoints are quality of life, swallowing function preservation, progression free and overall survival.
Discussion
The objective of the ARTFORCE Head and Neck trial is to determine the predictive value of biological markers and 89Zr-Cetuximab uptake, as it is unknown how to select patients for the appropriate concurrent agent. Also we will determine if adaptive RT and dose redistribution improve locoregional control without increasing toxicity.
ClinicalTrials.gov Identifier: NCT01504815
doi:10.1186/1471-2407-13-84
PMCID: PMC3599345  PMID: 23433435
Head and neck; Squamous cell carcinoma; Adaptive radiotherapy; Dose painting; Zirconium; Cetuximab; Cisplatin
22.  Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study 
Annals of Oncology  2010;22(5):1078-1087.
Background: The phase III EXTREME study demonstrated that combining cetuximab with platinum/5-fluorouracil (5-FU) significantly improved overall survival in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) compared with platinum/5-FU alone. The aim of this investigation was to evaluate elevated tumor EGFR gene copy number as a predictive biomarker in EXTREME study patients.
Patients and methods: Dual-color FISH was used to determine absolute and relative EGFR copy number. Models of differing stringencies were used to score and investigate whether increased copy number was predictive for the activity of cetuximab plus platinum/5-FU.
Results: Tumors from 312 of 442 patients (71%) were evaluable by FISH and met the criteria for statistical analysis. A moderate increase in EGFR copy number was common, with high-level amplification of the gene occurring in a small fraction of tumors (∼11%). Considering each of the models tested, no association of EGFR copy number with overall survival, progression-free survival or best overall response was found for patients treated with cetuximab plus platinum/5-FU.
Conclusion: Tumor EGFR copy number is not a predictive biomarker for the efficacy of cetuximab plus platinum/5-FU as first-line therapy for patients with R/M SCCHN.
doi:10.1093/annonc/mdq588
PMCID: PMC3082162  PMID: 21048039
cetuximab; copy number; EFGR; EXTREME; FISH; platinum/5-fluorouracil
23.  Molecular Characterization of Head and Neck Cancer: How Close to Personalized Targeted Therapy? 
Molecular diagnosis & therapy  2012;16(4):209-222.
Molecular targeted therapy in squamous head and neck cancer (HNSCC) continues to make strides and holds much promise. Cetuximab remains the sole FDA-approved molecular targeted therapy available for HNSCC, though there are several new biological agents targeting the epidermal growth factor receptor (EGFR) and other pathways in the regulatory approval pipeline. While targeted therapies have the potential to be personalized, their current use in HNSCC is not personalized. This is illustrated for EGFR targeted drugs, where EGFR as a molecular target has yet to be individualized for HNSCC. Future research needs to identify factors that correlate with response (or lack of one) and the underlying genotype-phenotype relationship that dictates this response. Comprehensive exploration of genetic and epigenetic landscapes in HNSCC is opening new frontiers to further enlighten, mechanistically inform, and set a course for eventually translating these discoveries into therapies for patients. This opinion offers a snap shot of the evolution of molecular subytping in HNSCC, its current clinical applicability, as well as new emergent paradigms with implications for controlling this disease in the future.
doi:10.2165/11635330-000000000-00000
PMCID: PMC3707609  PMID: 22873739
Cetuximab; EGFR; HPV; DNA methylation; HNSCC
24.  Current role of EGF receptor monoclonal antibodies and tyrosine kinase inhibitors in the management of head and neck squamous cell carcinoma 
Expert review of anticancer therapy  2012;12(9):1149-1159.
New agents and treatment strategies that can be safely and effectively integrated into current treatment paradigms for head and neck squamous cell carcinoma (HNSCC) are urgently needed. To date, the anti-EGF receptor (EGFR) monoclonal antibody, cetuximab, is the first and only molecularly targeted therapy to demonstrate a survival benefit for patients with recurrent or metastatic disease. Other anti-EGFR-targeted therapies, including monoclonal antibodies (e.g., panitumumab and zalutumumab) and reversible and irreversible ErbB family tyrosine kinase inhibitors (e.g., lapatinib, afatinib and dacomitinib) are being actively investigated in Phase II and Phase III clinical trials. In addition, validated biomarkers are needed to predict clinical benefit and resistance to anti-EGFR therapy in HNSCC. This review will compare and contrast the mechanisms of action of anti-EGFR monoclonal antibodies and tyrosine kinase inhibitors and also discuss their role in the management of HNSCC and the potential impact of human papillomavirus status in the development of these targeted agents.
doi:10.1586/era.12.91
PMCID: PMC3715045  PMID: 23098115
epidermal growth factor receptor; head and neck squamous cell carcinoma; HER tyrosine kinase receptor family; therapeutic monoclonal antibody; tyrosine kinase inhibitor
25.  A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma 
Oral oncology  2013;49(5):461-467.
SUMMARY
Objectives
The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of anti-EGFR therapy.
Materials and methods
Erlotinib 150 mg daily and temsirolimus 15 mg weekly were administered to patients with platinum-refractory R/M HNSCC and ECOG performance status 0–2. The primary endpoint was progression-free survival (PFS). Correlative studies determined PIK3CA and HRAS mutation status; p16, EGFR, pS6K, pAkt and PTEN expression; and pre- and post-treatment plasma levels of 20 immunomodulatory cytokines.
Results
Twelve patients enrolled; six withdrew within 6 weeks due to toxicity or death, prompting early closure of the trial. Grade ≥3 toxicities included fatigue, diarrhea, gastrostomy tube infection, peritonitis, pneumonia, dyspnea, and HN edema. Median PFS was 1.9 months. Median overall survival was 4.0 months. Six/12 tumors were p16(+), 9/11 lacked measurable PTEN expression, and 1/12 harbored a PIK3CA mutation. On exploratory analysis, high baseline plasma VEGF and interferon-gamma levels marginally associated with tumor progression.
Conclusions
The combination of erlotinib and temsirolimus was poorly tolerated. Low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in R/M disease. Investigation of more tolerable combinations of EGFR and PI3K/Akt/mTOR pathway inhibitors in selected HNSCC patients is warranted.
doi:10.1016/j.oraloncology.2012.12.016
PMCID: PMC3805493  PMID: 23384718
Temsirolimus; Erlotinib; Platinum-refractory; Head and neck squamous cell carcinoma; mTOR; EGFR; PIK3CA

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