Quad Shot Radiotherapy in Combination With Immune Checkpoint Inhibition

Inclusion Criteria:

* Advanced, recurrent or metastatic head and neck squamous cell carcinoma, as defined by clinical or pathological diagnosis of any of the following:
* Locally advanced head and neck squamous cell carcinoma not suitable for curative local treatment.
* Locally recurrent head and neck squamous cell carcinoma not suitable for curative local treatment within or outside a previously irradiated tissue.
* Metastatic head and neck squamous cell carcinoma.
* Target site in the head and neck region amenable to quad-shot palliative radiotherapy, for which palliative radiotherapy is recommended, as determined by the treating radiation oncologist.
* Age 18 years or greater at time of registration.
* ECOG Performance Status of 0-2.
* Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
* Ability to understand and the willingness to sign an IRB-approved informed consent document (either directly or via a legally authorized representative).
* Willingness to provide blood and saliva samples for exploratory research purposes.
* Organ and Marrow Function as defined below: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, hemoglobin ≥ 9.0 g/dL, serum bilirubin ≤ 1.5 x ULN (institutional upper limit of normal), AST and ALT ≤ 2.5 x ULN (institutional upper limit of normal), serum creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:

MALES: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) (divided by) 72 x serum creatinine (mg/dL).

FEMALES: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 (divided by) 72 x serum creatinine (mg/dL)

Exclusion Criteria:

* Radiation therapy to the planned quad-shot radiotherapy target region within 30 days of registration.
* Prior radiotherapy to the head and neck that precludes safe delivery of study radiotherapy, as determined by the treating radiation oncologist.
* Active medical conditions that are contraindications to study radiotherapy (i.e. scleroderma), as determined by the treating radiation oncologist.
* Pregnant or lactating women are excluded from this study because radiotherapy is contraindicated in pregnancy and because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with immunotherapy.
* Participation in another clinical study with an investigational product during the last 3 months.
* Any previous treatment with a PD1 or PD-L1 inhibitor.
* Any anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) within the last 30 days. Note: this excludes palliative radiotherapy to the non-target site.
* Mean QT interval corrected for heart rate (QTc) ≥470 ms except for patients with pacemaker who have a paced ventricular rhythm.
* Current or prior use of immunosuppressive medication within 30 days, with exceptions of intranasal and inhaled corticosteroids, a brief, non-sustained corticosteroids treatment for incidental problems such as allergies (at the discretion of the treating physician) or sustained systemic corticosteroids treatment at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid except for short course of prednisone that is prescribed for acute allergic situations or for prevention of an allergy to contrast substance utilized for imaging studies.
* Any unresolved toxicity (\>CTCAE grade \> 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy).
* Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE \>Grade 1.
* Active or prior documented autoimmune disease within the past 2 years, NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
* Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
* History of primary immunodeficiency.
* History of allogeneic organ transplant.
* History of hypersensitivity to any excipient in pembrolizumab.
* History of pneumonitis or interstitial lung disease.
* Subjects with uncontrolled seizures.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
* Known history of active tuberculosis.
* Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving pembrolizumab.
* Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.