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table 6 evaluating adverse events

An investigator who is a qualified physician, will evaluate all adverse events as to:  
| V4.0            | CTCAE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Grade 1                                                                                                    | Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.   |
|-----------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------|
| Grading         | Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. |                                                                                                             |
| Grade 3         | Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated;  disabling; limiting self-care ADL.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                            |                                                                                                             |
| Grade 4         | Life threatening consequences; urgent intervention indicated.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                            |                                                                                                             |
| Grade 5         | Death related to AE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                            |                                                                                                             |
| Seriousness     | A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: †Results in death; or †Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an  adverse event that, had it occurred in a more severe form, might have caused death.); or †Results in a persistent or significant disability/incapacity (substantial disruption of one's ability to conduct normal life functions); or †Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the  hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting  condition which has not worsened does not constitute a serious adverse event.); or †Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or Is a new cancer; (that is not a condition of the study) or Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not  associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when,  based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes  listed previously (designated above by a †). |                                                                                                            |                                                                                                             |
| Duration        | Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                            |                                                                                                             |
| Action taken    | Did the adverse event cause the Merck product to be discontinued?                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                            |                                                                                                             |
| Relationship to | Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                            |                                                                                                             |
| test drug       | investigator who is a qualified physician. The investigator's signed/dated initials on the source document or worksheet that supports the causality noted on the AE  form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The  criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event  based upon the available information.  The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and  their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): Exposure Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill  count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? Time Course Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? Likely Cause Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental  factors                                                                                                                                                                                                                                                                                                              |                                                                                                            |                                                                                                             |  
46 Protocol/Amendment No.: Version 6.1 (10.10.2018)  
| Relationship                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | The following components are to be used to assess the relationship between the test drug and the AE: (continued)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| to Merck  product (continued)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Dechallenge                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Was the Merck product discontinued or dose/exposure/frequency reduced? If yes, did the AE resolve or improve? If yes, this is a positive dechallenge. If no, this is a negative dechallenge. (Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation  of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) |
| Rechallenge                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Was the subject re-exposed to the Merck product in this study? If yes, did the AE recur or worsen? If yes, this is a positive rechallenge. If no, this is a negative rechallenge. (Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or  (3) Merck product(s) is/are used only one time). NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN  CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL  SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL  MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| Consistency  with Trial  Treatment  Profile                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology  or toxicology?                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including  consideration of the above elements. Record one of the following Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). Yes, there is a reasonable  possibility of Merck product  relationship. There is evidence of exposure to the Merck product. The temporal sequence of the AE onset relative to the administration of the Merck product  is reasonable. The AE is more likely explained by the Merck product than by another cause. No, there is not a reasonable  possibility Merck product  relationship Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable  OR there is another obvious cause of the AE. (Also entered for a subject with overdose without an associated AE.) |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
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6.3.5 sponsor responsibility for reporting

All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance with all applicable global laws and regulations.
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7.0 statistical analysis plan 7.1

The primary objective of this phase II study is to determine the overall response rate in patients with squamous cell carcinoma of the head and neck who have residual disease following definitive radiation with or without systemic therapy. This will be a single arm study of 24 patients with Stage I-IVB HNSCC who have residual disease after being treated with definitive radiation with or without systemic therapy. The expected rate of resolution of disease without any further therapy is thought to be approximately 10%. This is derived from the Princess Margaret Hospital experience of 493 patients undergoing definitive chemoradiation for head and neck SCC, approximately 50% had less than a complete response to chemoradiation therapy at 8-12 week post therapy assessment26. An additional 33% achieved CR between weeks 12 and 24. Of patients taken to neck dissection with less than a complete response (CR) the rate of positive residual tumor cells within the neck was 35%. This is substantially higher than the rate of positive residual cells at neck dissection in patients who achieve a CR to initial therapy, which was 9%. Thus it is estimated, that approximately 10% of patients that would likely have had pathologic residual disease at the 8-12 week assessment will achieve pathologic CR by 24 weeks without any further intervention. This estimate is given by: the percentage of patients achieving a CR between weeks 12 and 24 x (the rate of pathologic positivity in non CR patients - the rate of pathologic positivity in CR patients) = 33% x (35%- 9%) = 8.7%, or approximately 10%. Thus, assuming a baseline response rate of 10% (based on the Princess Margaret experience discussed above) and an improvement in response rate to 27% after treatment of chemoradiation, we will have 81% power to detect this difference with 24 patients by exact one-sample binomial test at one-sided significance level of 0.10. If 27% or more of patients in the study develop a partial or complete response to pembrolizumab, this strategy will be deemed worth of further investigation. The primary endpoint of this trial will be overall response rate and the secondary endpoint will be progression-free survival. We will use descriptive statistics to calculate frequency and proportion for the response rate to pembrolizumab. 95% confidence interval will also be provided. Exact binomial test will be used to compare the observed response rate versus historical control. For the secondary endpoint, we will use Kaplan-Meier estimator to present the progression-free survival.
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8.0 labeling packaging storage and

The investigator shall take responsibility for and shall take all steps to maintain appropriate records and ensure appropriate supply, storage, handling, distribution and usage of investigational product in accordance with the protocol and any applicable laws and regulations.  
Clinical Supplies will be provided by Merck as summarized in Table 7.  
Table 7 Product Descriptions  
| Product Name & Potency    | Dosage Form            |
|---------------------------|------------------------|
| Pembrolizumab 100 mg/ 4mL | Solution for Injection |
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8.2 packaging and labeling information

Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
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8.3 clinical supplies disclosure

This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; random code/disclosure envelopes or lists are not provided.
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8.4 storage and handling requirements

Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified on the label. Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. Clinical supplies may not be used for any purpose other than that stated in the protocol.
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8.5 returns and reconciliation

The investigator is responsible for keeping accurate records of the clinical supplies received from Merck or designee, the amount dispensed to and returned by the subjects and the amount remaining at the conclusion of the trial. Upon completion or termination of the study, all unused and/or partially used investigational product will be destroyed at the site per institutional policy. It is the Investigator's responsibility to arrange for disposal of all empty containers, provided that procedures for proper disposal have been established according to applicable federal, state, local and institutional guidelines and procedures, and provided that appropriate records of disposal are kept.
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9.0 administrative and regulatory details

Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible for determining whether the trial and its results are subject to the requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted will allow subjects to identify potentially appropriate trials for their disease conditions and pursue participation by calling a central contact number for further information on appropriate trial locations and trial site contact information.
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9.2 quality management system 9.2.1

The Yale Cancer Center Data and Safety Monitoring Committee (DSMC) will provide the primary oversight of data and safety monitoring. The Yale DSMC will review and monitor compliance, toxicity and deviations from this study. The committee is composed of clinical specialists with experience in oncology and who have no direct relationship with the study. Information that raises any questions about participant safety will be addressed with the Principal Investigator. The DSMC will review this protocol at a minimum of once every six months. Information to be provided to the committee includes: a study narrative by the PI, a summary DSMC report produced by OnCore (which includes participant accrual, response, trial status history, SAEs, Adverse Events, Deviations and survival); audit results, and monitoring reports as applicable. Other information (e.g. scans, laboratory values) will be provided upon request.
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9.2.2 data monitoring

The study principal investigator and YCCI are responsible for monitoring the performance of all of the participating sites. This will be performed by conducting a study site initiation visit, as well as regularly scheduled monitoring visits and/or remote monitoring throughout the life of the protocol. At the end of the trial, the monitor will then perform a study site close-out visit at all participating sites. YCCI will utilize their institution's initiation, monitoring and close-out visit reports. Following each site visit, a visit report will be generated containing information on site activities, and a summary of pertinent points and action items together with a copy of the follow-up letter will be sent to each investigative site. During these monitoring visits, some of the items that will be reviewed are the following:
- Training of the sites - Site personnel qualifications to participate in the trial - That study related documents are current - That regulatory compliance is accomplished - That each subject has signed the informed consent - That the current and approved protocol is complied with (including reporting and logging of all protocol deviations) - That all SAEs and AEs have been reported to the local regulatory and Ethics/IRB Committees, YCCI and Merck, as appropriate - That source documentation matches CRFs - That required procedures for study drug accountability, distribution, and storage are followed.  
YCCI will document the required study monitoring activities in a Study Monitoring Plan.
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9.2.3 project team meetings

Scheduled meetings will be held and will include the protocol investigators and research staff involved with the conduct of the protocol.  
During these meetings the investigators will discuss:
- Safety of protocol participants (adverse events and reporting)
- Validity and integrity of the data (data completeness on case report forms and complete source documentation)
- Enrollment rate relative to expectation of target accrual, (eligible and ineligible participants).  
- Retention of participants, adherence to the protocol and protocol violations - Protocol amendments
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9.2.4 audit plan

The Yale Center for Clinical Investigation (YCCI) Office of Quality Assurance and Training will audit the trial at least annually or as determined by the YCC DSMC. The overall principal investigator, study coordinator and/or data manager may request access to all source documents and other study documentation for on-site or remote monitoring, audit or inspection. Involvement in this study as a participating investigator implies acceptance of potential audits or inspections, including source data verification, by representatives designated by the Principal Investigator or Yale. The purpose of these audits or inspections is to examine studyrelated activities and documents to determine whether these activities were conducted and data were recorded, analyzed, and accurately reported in accordance with the protocol, institutional policy, and any applicable regulatory requirements.
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9.3 data management

The investigators are required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the investigation on each individual treated in the investigation. Data that are derived from source documents and reported on the CRF must be consistent with the source documents or the discrepancies must be explained. OnCore will be the designated electronic data capture tool. All data should be entered onto OnCore within 2 weeks of each study visit. AEs need to be entered within 72 hours and SAEs need to the entered within 24 hours of the site becoming aware of the event.
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10.0 appendices 10.1 ecog performance

| Grade                                                                                                                                                                                                                                                                                                                        | Description                                                                                                                                                                                     |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0                                                                                                                                                                                                                                                                                                                            | Normal activity. Fully active, able to carry on all pre-disease  performance without restriction. Symptoms, but ambulatory. Restricted in physically strenuous                                  |
| 1                                                                                                                                                                                                                                                                                                                            | activity, but ambulatory and able to carry out work of a light or  sedentary nature (e.g., light housework, office work). In bed <50% of the time. Ambulatory and capable of all self-care, but |
| 2                                                                                                                                                                                                                                                                                                                            | unable to carry out any work activities. Up and about more than 50%  of waking hours.                                                                                                           |
| 3                                                                                                                                                                                                                                                                                                                            | In bed >50% of the time. Capable of only limited self-care, confined  to bed or chair more than 50% of waking hours.                                                                            |
| 4                                                                                                                                                                                                                                                                                                                            | 100% bedridden. Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair.                                                                                          |
| 5                                                                                                                                                                                                                                                                                                                            | Dead.                                                                                                                                                                                           |
| * As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E.,  McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology  Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis  M.D., Group Chair. |                                                                                                                                                                                                 |
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10.2 common terminology criteria for

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting.  
(http://ctep.cancer.gov/reporting/ctc.html)
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10.3 response evaluation criteria in

RECIST version 1.1* will be used in this study for assessment of tumor response. While either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study. * As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J.  
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. In addition, volumetric analysis will be explored by central review for response assessment.
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11.0 references

1. Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. *J Natl Cancer Inst.* Dec 15 1999;91(24):2081-2086.  
2. Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. *J Clin Oncol.* Apr 1998;16(4):1310-1317.  
3. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. *J Clin Oncol.* Jan 1 2003;21(1):9298.  
4. Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. *J Clin Oncol.* Mar 1 2013;31(7):845-852.  
5. Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. *N Engl J Med.* Jun 18 1998;338(25):1798-1804.  
6. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. *N Engl J Med.* Jun 13 1991;324(24):1685-1690.  
7. Fakhry C, Zhang Q, Nguyen-Tan PF, et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. *J Clin Oncol.* Oct 20 2014;32(30):3365-3373.  
8. Huang SH, O'Sullivan B, Xu W, et al. Temporal nodal regression and regional control after primary radiation therapy for N2-N3 head-and-neck cancer stratified by HPV status. *Int J Radiat Oncol Biol Phys.* Dec 1 2013;87(5):1078-1085.  
9. Clavel S, Charron MP, Belair M, et al. The role of computed tomography in the management of the neck after chemoradiotherapy in patients with head-and-neck cancer. *Int J Radiat Oncol Biol Phys.* Feb 1 2012;82(2):567-573.  
10. Prestwich RJ, Subesinghe M, Gilbert A, Chowdhury FU, Sen M, Scarsbrook AF.  
Delayed response assessment with FDG-PET-CT following (chemo) radiotherapy for locally advanced head and neck squamous cell carcinoma. *Clin Radiol.* Oct 2012;67(10):966-975.  
11. Marcus C, Ciarallo A, Tahari AK, et al. Head and neck PET/CT: therapy response interpretation criteria (Hopkins Criteria)-interreader reliability, accuracy, and survival outcomes. *J Nucl Med.* Sep 2014;55(9):1411-1416.  
12. Moeller BJ, Rana V, Cannon BA, et al. Prospective risk-adjusted
[18F]Fluorodeoxyglucose positron emission tomography and computed tomography assessment of radiation response in head and neck cancer. *J Clin Oncol.* May 20 2009;27(15):2509-2515.  
13. Cmelak A, Li S, Marur S, et al. E1308: Reduced-dose IMRT in human papilloma virus
(HPV)-associated resectable oropharyngeal squamous carcinomas (OPSCC) after clinical complete response (cCR) to induction chemotherapy (IC). *ASCO Meeting* Abstracts. June 11, 2014 2014;32(18_suppl):LBA6006.  
14. Simon C, Goepfert H, Rosenthal DI, et al. Presence of malignant tumor cells in persistent neck disease after radiotherapy for advanced squamous cell carcinoma of the oropharynx is associated with poor survival. *Eur Arch Otorhinolaryngol.* Apr 2006;263(4):313-318.  
15. Lango MN, Andrews GA, Ahmad S, et al. Postradiotherapy neck dissection for head and neck squamous cell carcinoma: pattern of pathologic residual carcinoma and prognosis. *Head Neck.* Mar 2009;31(3):328-337.  
16. Ganly I, Bocker J, Carlson DL, et al. Viable tumor in postchemoradiation neck dissection specimens as an indicator of poor outcome. *Head Neck.* Oct 2011;33(10):1387-1393.  
17. Seiwert TY, Burtness B, Weiss J, et al. A phase Ib study of MK-3475 in patients with human papillomavirus (HPV)-associated and non-HPV-associated head and neck (H/N) cancer. *ASCO Meeting Abstracts.* June 11, 2014 2014;32(15_suppl):6011.  
18. Zandberg DP, Strome SE. The role of the PD-L1:PD-1 pathway in squamous cell carcinoma of the head and neck. *Oral Oncol.* Jul 2014;50(7):627-632.  
19. Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. *J Clin Invest.* Feb 2014;124(2):687-695.  
20. Burnette B, Weichselbaum RR. Radiation as an immune modulator. *Semin Radiat* Oncol. Oct 2013;23(4):273-280.  
21. Zeng J, See AP, Phallen J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. *Int J Radiat Oncol Biol Phys.* Jun 1 2013;86(2):343-349.  
22. Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. *Sci Transl Med.* Mar 28 2012;4(127):127ra137.  
23. Saloura V, Zuo Z, Koeppen H, et al. Correlation of T-cell inflamed phenotype with mesenchymal subtype, expression of PD-L1, and other immune checkpoints in head and neck cancer. *ASCO Meeting Abstracts.* June 11, 2014 2014;32(15_suppl):6009.  
24. Keck MK, Zuo Z, Khattri A, et al. Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. *Clin Cancer Res.* Feb 15 2015;21(4):870-881.  
25. Narayan A, Carriero NJ, Gettinger SN, et al. Ultrasensitive measurement of hotspot mutations in tumor DNA in blood using error-suppressed multiplexed deep sequencing. Cancer Res. Jul 15 2012;72(14):3492-3498.  
26. Huang SH, O'Sullivan B Fau - Xu W, Xu W Fau - Zhao H, et al. Temporal nodal regression and regional control after primary radiation therapy for N2-N3 head-andneck cancer stratified by HPV status. 20131125 DCOM- 20140128 (1879-355X
(Electronic)).