INTRODUCTION ORIGINAL ARTICLE

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1 ORIGINAL ARTICLE PRISM: Phase 2 trial with panitumumab monotherapy as second-line treatment in patients with recurrent or metastatic squamous cell carcinoma of the head and neck Danny Rischin, MD, 1 * David R. Spigel, MD, 2 Douglas Adkins, MD, 3 Richard Wein, MD, 4 Susanne Arnold, MD, 5 Nimit Singhal, FRACP, 6 Oliver Lee, PhD, 7 Swami Murugappan, MD, PhD 8 1 Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia, 2 Sarah Cannon Research Institute, Nashville, Tennessee, 3 Washington University School of Medicine, St. Louis, Missouri, 4 Department of Otolaryngology Head and Neck Surgery, Tufts Medical Center, Boston, Massachusetts, 5 University of Kentucky, Markey Cancer Center, Lexington, Kentucky, 6 Royal Adelaide Hospital and University of Adelaide, Adelaide, SA, Australia, 7 Amgen, South San Francisco, California, 8 Amgen, Thousand Oaks, California. Accepted 20 September 2015 Published online 17 December 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Panitumumab Regimen In Second-line Monotherapy of Head and Neck Cancer (PRISM) trial evaluated the safety and efficacy of panitumumab as second-line monotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods. This was an open-label, single-arm, multicenter trial that enrolled patients with progressive disease or intolerance to first-line systemic chemotherapy for recurrent or metastatic SCCHN. Patients received panitumumab 9 mg/kg Q3W. The primary endpoint was overall response rate; secondary endpoints included disease control rate, overall survival (OS), progression-free survival (PFS), and safety. Results. The overall response rate was 4% (2 of 51 patients) and the disease control rate was 39% (20 of 51 patients). Median PFS was 1.4 months (95% confidence interval [CI] months). Median OS was 5.1 months (95% CI months). The most common adverse events were rash/dermatitis acneiform (69%), fatigue (33%), dry skin (21%), and hypomagnesemia (21%). There was one treatmentrelated death (angioedema). Conclusion. Panitumumab monotherapy had limited activity in previously treated patients with recurrent or metastatic SCCHN. VC 2015 Wiley Periodicals, Inc. Head Neck 38: E1756 E1761, 2016 KEY WORDS: recurrent or metastatic squamous cell carcinoma of the head and neck, panitumumab, Panitumumab Regimen In Secondline Monotherapy of Head and Neck Cancer (PRISM) trial, monotherapy, human papillomavirus (HPV), p16 INTRODUCTION Approximately 10% of newly diagnosed squamous cell carcinomas of the head and neck (SCCHN) will present with distant metastases at diagnosis, whereas failure of primary management can result in up to 50% of cases experiencing local, regional, and/or distant recurrence not amenable to curative salvage therapy. Platinum-based *Corresponding author: D. Rischin, Division of Cancer Medicine, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia. danny.rischin@petermac.org Contract grant sponsor: The research for this study was supported by Amgen, Thousand Oaks, CA.. Additional Supporting Information may be found in the online version of this article. This work was presented at the European Society for Medical Oncology (ESMO) 2010 meeting, Milan, Italy, October 8 12, 2010; and at the Multidisciplinary Head and Neck Cancer Symposium 2012 meeting, Phoenix, AZ, January 26 28, Conflict of interest: D.R. has received research funding from Merck Serono and has participated as a consultant for Threshold Pharmaceuticals. D.A. has received research funding from Amgen, Eli Lilly, Celgene, Pfizer, GlaxoSmithKline, Galera, and AstraZeneca. R.W. has participated on the speaker s bureau for Bristol Myers Squibb. O.L. and S.M. are employees of Amgen and have stock ownership interests. D.S., S.A., and N.S. have no conflicts to declare. regimens with or without cetuximab are the standard-ofcare for first-line treatment of recurrent or metastatic SCCHN. 1 The combination of cetuximab with platinum and fluorouracil has been shown to be superior to chemotherapy alone in the first-line treatment of recurrent or metastatic SCCHN. 2 However, a significant proportion of patients may not be fit enough to be treated with a triplet regimen and may have progressed without receiving anti-epidermal growth factor receptor (EGFR) therapy in the first-line. Panitumumab, a fully human antibody targeting the EGFR, has also shown antitumor activity in first-line treatment of recurrent or metastatic SCCHN. 3 In the phase 3 Study of Panitumumab Efficacy in Patients with Recurrent and/or Metastatic Head and Neck Cancer (SPECTRUM) trial, a statistically significant improvement in progressionfree survival (PFS) and a trend toward improved overall survival (OS) were observed when panitumumab was combined with cisplatin and fluorouracil. 3 In the randomized phase 2 Panitumumab Added to Regimen for Treatment of Head and Neck Cancer Evaluation of Response (PART- NER) study, the PFS and overall response rates were higher in the panitumumab plus docetaxel/cisplatin arm compared with the docetaxel/cisplatin-alone arm. 4 E1756 HEAD & NECK DOI /HED APRIL 2016

2 PANITUMUMAB MONOTHERAPY IN PATIENTS WITH RECURRENT OR METASTATIC SCCHN Options are limited for patients with SCCHN that progress on or are intolerant to platinum-based therapy. Cetuximab has been approved by the Food and Drug Administration for patients with recurrent or metastatic SCCHN who have progressed after platinum-based chemotherapy. This approval was based on a single arm, phase 2, monotherapy study. 5 In this trial, cetuximab achieved an overall response rate of 13% and a disease control rate of 46%. There is no information, however, on the activity of panitumumab as a single agent in patients who are refractory to chemotherapy. Oropharyngeal cancer associated with human papillomavirus (HPV) is recognized as a distinct entity from HPV-negative SCCHN, with significant differences in risk factors, clinical features, and prognosis. 6 In clinical practice, p16-ink4a (p16) expression is widely used in oropharyngeal cancer as a surrogate marker of HPV status. In a retrospective analysis of the SPECTRUM trial, patients treated with panitumumab that had p16-negative tumors seemed to derive greater benefit than patients with p16-positive tumors, indicating a possible predictive role for panitumumab treatment. 3 Currently, no data has been published on the role of p16 or HPV status in patients with recurrent or metastatic SCCHN refractory to chemotherapy who are receiving anti-egfr therapy. In this study, we report the results of Panitumumab Regimen In Second-line Monotherapy of Head and Neck Cancer (PRISM) trial, an open-label, multicenter, single arm, phase 2 trial with panitumumab monotherapy for second-line treatment of recurrent or metastatic SCCHN. A retrospective analysis of the treatment effect by p16 status will also be reported. PATIENTS AND METHODS Patients Eligible patients were 18 years of age, had histologically or cytologically confirmed SCCHN of the oropharynx, oral cavity, hypopharynx, or larynx, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 or Karnofsky performance score (KPS) of 60. Diagnosis of recurrent disease determined to be incurable by surgery or radiotherapy, and/or metastatic disease according to the investigator and documented disease progression, or intolerance to one prior chemotherapy regimen for recurrent/metastatic disease was required. Patients who had received radiation as primary therapy were eligible if locoregional recurrence in the field of radiation had occurred >24 weeks after the completion of radiotherapy. In addition, at least 1 unidimensional measurable lesion of 20 mm using conventional techniques or 10 mm with spiral CT scan per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 was required at baseline. Patients were excluded if they had nasopharyngeal carcinoma, salivary gland, or primary skin SCCHN; had not recovered from all previous acute radiotherapy-related toxicities grade 1 (Common Terminology Criteria for Adverse Events [CTCAE]); had received >1 chemotherapy regimen for the treatment of metastatic or recurrent disease; or had concomitant chemotherapy for recurrent disease administered solely for the purpose of radiation sensitization during reirradiation. Prior anti-egfr antibody therapy (eg, panitumumab, cetuximab) or treatment with small molecule EGFR inhibitors (eg, gefitinib, erlotinib, lapatinib) for recurrent or metastatic disease was not allowed with the following exceptions: if received as part of prior multimodality treatment (eg, as radiation sensitizer) and completed >24 weeks before randomization; or patients who received no more than one dose of cetuximab and discontinued before progression because of documented severe infusion reaction. The study protocol was approved by the institutional review boards or the ethics committees at the participating institutions. Written informed consent was provided by all patients before any study-related treatment was conducted. Study design and treatment This was a global, multicenter, open-label, single-arm, phase 2 trial of panitumumab monotherapy for secondline treatment of patients with recurrent/metastatic SCCHN. Patients received panitumumab 9 mg/kg intravenously every 3 weeks until disease progression, panitumumab intolerability, death, or withdrawal from the study. Tumor response was assessed by the investigator using modified RECIST version 1.0 every 6 weeks (61 week) from day 1 of cycle 1 of panitumumab treatment. If withdrawal from study treatment occurred before disease progression, per a modified version of the RECIST criteria, tumor assessments continued every 12 weeks 61 week until disease progression or the end of the study, whichever came first. For patients who had a complete response (CR) or partial response (PR), confirmation of response by the investigator was required no less than 28 days after the criteria for response were first met. Adverse events (AEs) were coded using the MedDRA dictionary version 13.1 and severity graded using the CTCAE version 3.0, with the exception of some dermatology/skin AEs that were graded using the CTCAE version 3.0 with modifications. p16 human papillomavirus analyses Paraffin-embedded tumor tissue from archived tumor tissue or from screening biopsy was used for p16 analysis. Tumor specimens were sent to HistoRx (Branford, CT) and a single SCCHN expert pathologist evaluated the submitted samples. The p16 status was measured using the commercially available CINtec Histology kit (Ventana Medical Systems, Tucson, AZ), a semiquantitative, immunocytochemical assay for the evaluation of overexpressed cyclin-dependent kinase inhibitor, p16ink4a protein, in formalin fixed, paraffin-embedded tissue sections. Patient tumor specimens were scored as positive or negative according to a prespecified immunohistochemistry scoring guideline used in a previous panitumumab study. 3 A patient was scored as having a p16-positive tumor when uniform p16 protein expression was detected in at least 10% of tumor cells, consistent with previous studies. 3,4,7,8 A patient was scored as having a p16-negative tumor when the p16 protein was not present or observed in <10% of tumor cells. HEAD & NECK DOI /HED APRIL 2016 E1757

3 RISCHIN ET AL. TABLE 1. Characteristics Baseline patient demographics and disease characteristics. Statistical analysis All patients (n 5 52) Sex, men, no. of patients (%) 36 (69) Age, median y (min, max) 61 (42, 82) Race, white, no. of patients (%) 48 (92) KPS, no. of patients (%) * 20 (38) 80 70* 32 (62) Site of primary tumor diagnosis, no. of patients (%) Oropharynx 18 (35) Hypopharynx 1 (2) Larynx 13 (25) Oral cavity 20 (38) Disease pattern, no. of patients (%) Distant metastatic disease only 16 (31) Locally recurrent disease only 11 (21) Both metastatic and recurrent disease 25 (48) Prior therapy, no. of patients (%) Radiotherapy 48 (92) Platinum-based chemotherapy 48 (92) Taxane 34 (65) Fluoropyrimidine 21 (40) EGFR inhibitor therapy 5 (10) Reason for ending first-line treatment, no. of patients (%) Disease progression 49 (94) Chemotherapy intolerance 3 (6) Abbreviations: KPS, Karnofsky performance score; EGFR, epidermal growth factor receptor. * Eastern Cooperative Oncology Group (ECOG) performance status was reported for 18 patients at baseline. Three patients with ECOG performance status of 0 were converted to KPS of and 15 patients with ECOG performance status of 1 were converted to KPS of The primary endpoint of this study was to estimate the effect of second-line panitumumab monotherapy on the overall response rate in patients with recurrent/metastatic SCCHN. Secondary endpoints included disease control rate, PFS, OS, and safety. PFS and OS were analyzed based on the Kaplan Meier method with 95% confidence intervals (CIs). This was an estimation study by design and a formal hypothesis was not tested. However, with a sample size of 50 patients, the study would have had over 90% power to distinguish no activity (overall response rate 5 1%) from an overall response rate of 12% at 5% significance level. All patients in the intent-to-treat population with formalin-fixed paraffin-embedded tumor samples were assessed for p16 status and exploratory analyses for overall response rate, PFS, OS, and safety for each p16 group. RESULTS Patient demographics and disease characteristics From October 2007 through December 2009, 52 patients from 22 sites from 3 countries (United States, Canada, and Australia) were enrolled in this study (Table 1). All patients received at least 1 panitumumab dose. The median age was 61 years and 69% of the patients were men. KPS performance status was 90 in 20 patients (38%) and between 70 and 80 in 32 patients (62%). The distribution of the primary tumor sites were oral cavity (38%), oropharynx (35%), larynx (25%), and hypopharynx (2%). Seventy-nine percent of patients had metastatic disease and 21% had locoregionally recurrent disease only. Ninety-two percent of patients received prior radiotherapy, 92% had prior platinum-based chemotherapy, 65% had prior taxane, 40% had prior fluoropyrimidine, and 10% had prior EGFR inhibitor therapy. Ninety-four percent of patients ceased first-line chemotherapy treatment because of disease progression and 6% because of chemotherapy intolerance. Efficacy Overall response rate. Two patients were confirmed by RECIST criteria to have a PR (Table 2). No patient had a CR. The overall response rate was 4% (95% CI ) and the disease control rate was 39% (95% CI ). One patient had prolonged and continued disease stabilization (n 5 25 cycles). Nine patients had a sum of the longest diameter reduction >30% on RECIST defined target lesions (see Figure 1). Two of these patients had a PR; 2 patients had unconfirmed PRs and 1 patient had an unconfirmed CR (all were considered to have stable disease by RECIST criteria); and 4 patients had disease progression on non-target lesions or new nontarget lesions and were considered to have progressive disease. Progression-free survival and overall survival. For PFS analysis, 49 of 52 patients (94%) had events of disease progression (85%) or death (10%; Figure 2A). Median PFS was 1.4 months (95% CI months). At the time of the OS analysis, a total of 43 patients (83%) had died (Figure 2B). Median OS was 5.1 months (95% CI months). Panitumumab treatment exposure The median number of cycles of panitumumab received was 3.0 (range, 1 23) and the median duration of treatment exposure was 9.0 weeks (range, weeks). The median adjusted dose administered was 26.8 mg/kg (range, mg/kg) and the median relative dose intensity was 99.6% (range, ). The most TABLE 2. Response Objective response rate. All patients* (n 5 51) Objective response rate, no. of patients (%) 2 (4) CR 0 (0) PR 2 (4) Stable disease, no. of patients (%) 18 (35) Progressive disease, no. of patients (%) 28 (55) Not done, no. of patients (%) 3 (6) Disease control (CR 1 PR 1 stable disease), 20 (39) no. of patients (%) With at least 1 radiographic assessment of PR, 5 (10) no. of patients (%) Unconfirmed response (CR or PR), 3 (6) no. of patients (%) Abbreviations: CR, complete response; PR, partial response. * Includes only patients with baseline measurable disease per central review. E1758 HEAD & NECK DOI /HED APRIL 2016

4 PANITUMUMAB MONOTHERAPY IN PATIENTS WITH RECURRENT OR METASTATIC SCCHN FIGURE 1. Best percentage change of the sum of longest diameters of tumor size from baseline to post-baseline. *Two patients were confirmed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria to have a partial response. 95% CI, 95% confidence interval. common reasons for discontinuing panitumumab treatment were due to disease progression (86%) and AEs (6%). Safety AEs that occurred in >10% of patients are listed in Table 3. The most common AEs were rash/dermatitis acneiform (69%), fatigue (33%), dry skin (21%), and hypomagnesemia (21%). Infusion reactions occurred in 3 patients (6%), all were grade 1 or 2. Eighteen patients (35%) had a worst grade 3 AE and 4 patients (8%) had a worst grade 4 AE. Five patients died on study with 1 patient deemed as treatment-related death (angioedema). p16 analyses Of 52 patients in the intent-to-treat population, 30 (58%) had samples evaluable for p16 status. Of the 30 evaluable patients, 6 (20%) had p16-positive tumors and 24 (80%) had p16-negative tumors (Supplemental Table S1, online only). All 6 patients (100%) with p16-positive FIGURE 2. Kaplan Meier curves for (A) progression-free survival and (B) overall survival in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) treated with panitumumab monotherapy. 95% CI, 95% confidence interval. HEAD & NECK DOI /HED APRIL 2016 E1759

5 RISCHIN ET AL. TABLE 3. Adverse events occurring in >10% of patients. No. of patients (%) (N 5 52) Adverse Event Any grade Grade 3 Rash/dermatitis acneiform 36 (69) 4 (8) Fatigue 17 (33) 1 (2) Dry skin 11 (21) 0 (0) Hypomagnesemia 11 (21) 1 (2) Diarrhea 8 (15) 1 (2) Dyspnea 8 (15) 2 (4) Nausea 8 (15) 1 (2) Pruritus 8 (15) 0 (0) Constipation 7 (13) 0 (0) Decreased appetite 7 (13) 2 (4) Vomiting 7 (13) 2 (4) Cough 6 (12) 1 (2) Dysphagia 6 (12) 2 (4) tumors were men and <65 years of age compared with 15 men (63%) and 15 patients <65 years of age (63%) for patients with p16-negative tumors. Three patients (50%) had p16-positive tumors in the oropharynx, 2 (33%) in the oral cavity, and 1 (17%) in the larynx. For patients with p16-negative tumors, 8 (33%) were in the oropharynx, 8 (33%) in the oral cavity, 7 (29%) in the larynx, and 1 (4%) in the hypopharynx. The disease control rate was 17% in patients with p16- positive tumors and 46% in patients with p16-negative tumors. One patient with p16-positive SCCHN of the larynx (30% of cells were p16-positive) had a PR and 1 patient with p16-negative SCCHN of the oropharynx had a PR. Median PFS was 1.3 months and median OS was 3.4 in patients with p16-positive tumors. Median PFS was 2.0 months and median OS was 6.8 months in patients with p16-negative tumors. Median treatment cycles, median duration of treatment exposure, and median adjusted cumulative dose were 2.0 cycles, 6.1 weeks, and 18.0 mg/kg in patients with p16-positive tumors and 3.5 cycles, 10.9 weeks, and 31.8 mg/kg, respectively, in patients with p16-negative tumors. AEs were generally similar for the p16 groups. DISCUSSION Treatment options beyond first-line cytotoxic chemotherapy are limited for patients with recurrent or metastatic SCCHN. In this single arm monotherapy trial, PRISM evaluated the effect of panitumumab monotherapy in patients with SCCHN who had progressed on systemic chemotherapy. The overall response rate in PRISM was 4% (95% CI ) and a lower than reported overall response rate of 13% (95% CI ) with single agent cetuximab. 5 However, the disease control rate and the PFS were similar. Differences in response assessment (RECIST vs World Health Organization) and patient characteristics (eg, anatomic tumor subtypes, HPV status) make cross trial comparisons difficult. The observed safety profile in PRISM was consistent with other panitumumab studies and toxicities expected in patients with recurrent or metastatic SCCHN. Panitumumab-related AEs of skin toxicities, diarrhea, and hypomagnesemia occurred at expected frequencies and were mostly grades 1 to 2. Both panitumumab and cetuximab have demonstrated benefit when combined with chemotherapy in the firstline recurrent or metastatic SCCHN setting. 2,3 The activity of both drugs as single agents in the second-line recurrent or metastatic SCCHN setting has been modest, although neither drug has been tested in a phase 3 trial. Zalutumumab, a fully human immunoglobulin G1 monoclonal antibody targeting EGFR, has been tested in a phase 3 trial compared with best supportive care (with optional methotrexate) in patients who have progressed after platinum-based chemotherapy. 9 Zalutumumab resulted in a small but statistically significant increase in PFS, but the difference in OS was not statistically significant. The response rate to zalutumumab was 6.3% (95% CI ) with a disease control rate of 48% (95% CI ). Several anti-egfr tyrosine kinase inhibitors have also been investigated in SCCHN, including gefitinib and afatinib in phase 3 trials. Although gefitinib 500 mg daily achieved a response rate of 7.6%, no improvement in OS compared to methotrexate was found. 10 In a recently reported trial of afatinib compared to methotrexate, a small but statistically significant improvement in PFS and in quality of life, but not OS, was found in patients with recurrent or metastatic SCCHN who had progressed after platinum-based chemotherapy. 11 The overall response rate was 10% and the disease control rate was 49%. Taken together, currently available anti-egfr treatments have modest but limited activity in patients with recurrent or metastatic SCCHN who have progressed after platinum-based chemotherapy. In view of the findings of the SPECTRUM study that suggested greater benefit with the addition of panitumumab in patients with p16-negative SCCHN, we conducted an exploratory analysis in this monotherapy trial. Patients with p16-negative tumors seemed to fare better than patients with p16-positive tumors in PRISM. However, interpretation of these results was limited by the size of the trial, the ascertainment rate of 58%, the low p16-positive rate of 20%, and the fact that there were only 3 patients with p16-positive oropharyngeal cancer, only 2 of whom would have been classified as p16-positive with the widely used cutoff of 70% cells with moderate or strong staining. Patients with recurrent or metastatic p16-positive oropharyngeal cancer have been reported to have longer survival than patients with recurrent or metastatic p16- negative oropharyngeal cancer. 12 Although p16 has been demonstrated to be an excellent surrogate marker of HPV status in oropharyngeal cancer, it is not the case in nonoropharyngeal SCCHN. It is recognized that p16-positive nonoropharyngeal cancers may be a mix of HPV-positive and HPV-negative cases. 13 Studies exploring the prognostic significance of p16 in patients with nonoropharyngeal cancers receiving definitive treatment have yielded mixed results Further studies are required to better understand the prognostic significance of p16 and HPV status in nonoropharyngeal SCCHN, and to determine whether there is an interaction between outcomes with EGFR inhibitors and HPV/p16 status. CONCLUSION In conclusion, panitumumab monotherapy has limited activity in previously treated patients with recurrent or E1760 HEAD & NECK DOI /HED APRIL 2016

6 PANITUMUMAB MONOTHERAPY IN PATIENTS WITH RECURRENT OR METASTATIC SCCHN metastatic SCCHN. Better understanding of the molecular mechanisms of resistance to EGFR inhibitors in SCCHN will hopefully lead to more effective treatment approaches incorporating anti-egfr antibodies. Acknowledgments The authors thank the patients and caregivers for their participation in the study. We also thank Shawn Lee, a medical writer from Amgen, for providing writing assistance. Amgen reviewed this article for data accuracy. REFERENCES 1. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Head and Neck Cancers version Fort Washington, PA: National Comprehensive Cancer Network; Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. NEngJMed2008;359: Vermorken JB, St ohlmacher 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 2013;14: Wirth LJ, Dakhil SR, Kornek G, et al. PARTNER: a randomized phase II study of docetaxel/cisplatin (doc/cis) chemotherapy with or without panitumumab (pmab) as first-line treatment (tx) for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). J Clin Oncol 2013;31 Suppl 15: abstract Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007;25: Psyrri A, Rampias T, Vermorken JB. The current and future impact of human papillomavirus on treatment of squamous cell carcinoma of the head and neck. Ann Oncol 2014;25: Mesia R, Henke M, Fortin A, et al. Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial. Lancet Oncol 2015;16: Giralt J, Trigo J, Nuyts S, et al. Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamouscell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial. Lancet Oncol 2015;16: Machiels JP, Subramanian S, Ruzsa A, et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncol 2011;12: Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 2009;27: Machiels JP, Haddad RI, Fayette J, et al. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamouscell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 2015;16: Fakhry C, Zhang Q, Nguyen Tan PF, et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. J Clin Oncol 2014;32: Seiwert TY. Ties that bind: p16 as a prognostic biomarker and the need for high-accuracy human papillomavirus testing. J Clin Oncol 2014;32: Chung CH, Zhang Q, Kong CS, et al. p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol 2014;32: Lim AM, Do H, Young RJ, et al. Differential mechanisms of CDKN2A (p16) alteration in oral tongue squamous cell carcinomas and correlation with patient outcome. Int J Cancer 2014;135: Harris SL, Thorne LB, Seaman WT, Hayes DN, Couch ME, Kimple RJ. Association of p16(ink4a) overexpression with improved outcomes in young patients with squamous cell cancers of the oral tongue. Head Neck 2011;33: HEAD & NECK DOI /HED APRIL 2016 E1761