Combining Radiation Therapy With Immunotherapy for the Treatment of Metastatic Squamous Cell Carcinoma of the Head and Neck

Inclusion Criteria:

• STEP 1 REGISTRATION:

• Patient must be >= 18 years of age

• Patient must have biopsy-proven metastatic squamous cell carcinoma, originating inthe oral cavity, larynx, oropharynx, or hypopharynx, with active disease present inboth the head and neck and distant sites

• NOTE: The tumor from an oropharynx primary site must have known p16 status; p16positive cancer of unknown primary is allowed as well, provided the diseasepresentation in consistent with a head and neck primary

• Patient can have prior surgical resection of a primary cancer in the head and neckat any previous time, however, residual/recurrent disease in the head and neck mustbe present on baseline imaging

• Any effects from prior cancer therapy for other diseases must be fully resolved andnot pose a problem for giving the treatment on this trial

• Patient must have 4 or fewer metastatic sites prior to starting any treatment, withthoracic nodal disease considered a single site if encompassable in a tolerableradiotherapy hypofractionated field (i.e.,15 fractions or less)

• NOTE: Contiguous/adjacent metastases treatable in a single stereotactic fieldmay be considered a single site

• NOTE: Patients with additional indeterminate findings such that the totalnumber of metastatic sites would be more than 4 may be enrolled if anon-malignant etiology to these findings is a reasonable consideration

• Patient must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Patient must have the ability to understand and the willingness to sign a writteninformed consent document. Patients with impaired decision-making capacity (IDMC)who have a legally authorized representative (LAR) or caregiver and/or family memberavailable will also be considered eligible

• Patients must have measurable disease as follows:

• For patients who have not started any initial systemic therapy (withpembrolizumab + chemotherapy) must have measurable disease documented by CT ofthe neck and chest, and abdomen obtained within 28 days prior to Step 1registration

• For patients who have started or completed their 3 cycles of initial systemictherapy (with pembrolizumab + chemotherapy) must have measurable diseasedocumented by CT of the neck, chest and abdomen obtained within 28 days priorto the start of their initial systemic therapy

• Leukocytes >= 3,000/mcL (obtained =< 28 days prior to Step 1 registration or priorto the start of any chemotherapy if on Arm T)

• Absolute neutrophil count (ANC) >= 1,500/mcL (obtained =< 28 days prior to Step 1registration or prior to the start of any chemotherapy if on Arm T)

• Platelets >= 100,000/mcL (obtained =< 28 days prior to Step 1 registration or priorto the start of any chemotherapy if on Arm T)

• Total bilirubin =< institutional upper limit of normal (ULN). Patients with a totalbilirubin > 1.5 x ULN, that is attributed to confirmed Gilbert's syndrome, areallowed after consultation and approval from their treating physician (obtained =< 28 days prior to Step 1 registration or prior to the start of any chemotherapy if onArm T)

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =< 3.0 x institutional ULN (obtained =< 28 days prior to Step 1 registration orprior to the start of any chemotherapy if on Arm T)

• Creatinine clearance: Glomerular filtration rate (GFR) >= 50 mL/min/1.73m^2 (forpatients receiving carboplatin-based regimens, GFR > 30 mL/min/1.73m^2) (obtained =< 28 days prior to Step 1 registration or prior to the start of any chemotherapy if onArm T)

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months of Step 1 registration areeligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Patients on Arm S must have received chemoimmunotherapy

• Patients will be enrolled in the quality of life (QOL) study if the patient can readand understand English, Spanish, French or Chinese (simplified or traditionalcharacters)

• NOTE: Sites cannot translate the associated QOL forms

• Patients of childbearing potential and/or sexually active patients must not expectto conceive or father children by using an accepted and effective method(s) ofcontraception or by abstaining from sexual intercourse for the duration of theirparticipation in the study. Patients of childbearing potential must continuecontraceptive measures for 4 months after the last dose of protocol treatment andmust not breastfeed while on study treatment through 4 months after the last dose ofprotocol treatment

• STEP 2 RANDOMIZATION:

• Patient must have ECOG performance status 0-2

• Patient must have completed 3 cycles of initial systemic chemotherapy

• For patients registered to Arm S on Step 1, patients must have at least stabledisease after completing 3 cycles of pembrolizumab + chemotherapy

• Patient must have no signs of progression (complete response [CR]/partial response [PR] or stable disease [SD]) on restaging imaging (consisting of neck, chest, andabdomen CT). Restaging imaging must have been done after completion of initialsystemic chemotherapy with pembrolizumab + chemotherapy on Step 1 and within 7 daysprior to step 2 randomization. Patients with stable or responding radiologicresponse are eligible for Step 2

Exclusion Criteria:

• Patients must not have prior head and neck radiotherapy

• Patient must not have an active autoimmune disease (i.e., inflammatory boweldisease, systemic lupus erythematosus, rheumatoid arthritis, etc.) that has requiredsystemic treatment (i.e., disease modifying agents, corticosteroids, orimmunosuppressive drugs) in past 2 years. Replacement therapy (i.e., thyroxine,insulin, physiologic corticosteroid replacement) is not considered a form ofsystemic treatment and is allowed

• Patient must not be pregnant or breast-feeding due to the potential harm to anunborn fetus and possible risk for adverse events in nursing infants with thetreatment regimens being used. All patients of childbearing potential must have ablood test or urine study within 14 days prior to Step 1 registration to rule outpregnancy. A patient of childbearing potential is defined as anyone, regardless ofsexual orientation or whether they have undergone tubal ligation, who meets thefollowing criteria: 1) has achieved menarche at some point, 2) has not undergone ahysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) forat least 24 consecutive months (i.e., has had menses at any time in the preceding 24consecutive months)

• Patient must not have received any live vaccine within 30 days prior to Step 1registration and while participating in the study. Live vaccines include, but arenot limited to, the following: measles, mumps, rubella, chicken pox, yellow fever,rabies, bacillus Calmette Guerin (BCG), and typhoid (oral) vaccine. Patients arepermitted to receive inactivated vaccines and any non-live vaccines including thosefor the seasonal influenza and coronavirus disease 2019 (COVID-19) (Note: intranasalinfluenza vaccines, such as Flu-Mist trademark are live attenuated vaccines and arenot allowed). If possible, it is recommended to separate study drug administrationfrom vaccine administration by about a week (primarily, in order to minimize anoverlap of adverse events