Randomized Phase II/III Trial of Radiotherapy With Concurrent MEDI4736 (Durvalumab) vs. Radiotherapy With Concurrent Cetuximab in Patients With Locoregionally Advanced Head and Neck Cancer With a Contraindication to Cisplatin

• PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA

• Patients must have pathologically confirmed, previously untreated, unresected squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or carcinoma of unknown head/neck primary prior to step 1 registration; submission of hematoxylin and eosin (H\&E) stained slides and formalin-fixed and paraffin-embedded (FFPE) tissue block (or punch biopsy of FFPE block) to the biospecimen bank at University of California, San Francisco (UCSF) for central review for oropharyngeal and unknown primaries and for p16 analysis for all other non-oropharyngeal primaries is mandatory for all patients; investigators should check with their pathology department regarding release of biospecimens before approaching patients about participation in the trial; for oropharyngeal and unknown primaries, submission of H\&E and p16 stained slides (with the required block for PD-L1) to the biospecimen bank at UCSF for central review is also required prior to step 2 registration

‣ Note: fine needle aspirates (FNA) samples are not acceptable since they do not provide enough material for PD-L1 and p16 testing; however, if a cell block derived from the FNA is available, it is allowable if there are sufficient cells present in the block for PD-L1 testing; Dr. Jordan will determine this upon receipt; for sites submitting FNA cell blocks for ALL patients they must do so within 7-10 business days from registering the patient; sites must confirm with their cytology/pathology labs to make sure they can provide the required material as the bank must be able to retain these samples for the mandatory testing

• Patients must have locoregionally advanced head and neck squamous cell carcinoma (HNSCC)

‣ For p16-positive oropharyngeal/unknown primaries, American Joint Committee on Cancer \[AJCC\] 8th edition stage III and selected stage I-II based on smoking status in pack-years

⁃ For laryngeal, hypopharyngeal, and oral cavity primaries and p16-negative oropharyngeal/unknown primaries, AJCC 8th edition stage III-IVB

⁃ Based on the following minimum diagnostic workup within 60 days prior to step 1 registration:

• General history and physical examination by a radiation oncologist or medical oncologist or ear, nose and throat (ENT) or head \& neck surgeon

∙ For larynx, hypopharynx, and base of tongue primaries, a laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is required, unless the patient cannot tolerate or refuses

⁃ Imaging of the head and neck with a neck CT or magnetic resonance imaging (MRI) (with contrast, unless contraindicated) or PET/CT; note that the CT portion of the PET/CT must be of diagnostic quality, including contrast administration unless contraindicated. If the CT portion of the PET/CT study is low-dose (non-diagnostic), then an additional CT or MRI study with contrast (unless contraindicated) is required

⁃ Chest imaging: chest CT with and without contrast (unless contraindicated) or PET/CT

• Patients must have a contraindication to cisplatin as defined in the following bullet points; sites must complete the online tool at comogram.org prior to step 1 registration to determine if the patient is eligible; the scores must be recorded on a case report form (CRF)

‣ Age \>= 70 with moderate to severe comorbidity or vulnerability to cisplatin, defined as having one or more of the following conditions within 30 days prior to step 1 registration:

• Modified Charlson Comorbidity Index \>= 1

∙ Adult Comorbidity Evaluation (ACE)-27 Index \>= 1

∙ Generalized Competing Event Model for Cancer Risk (GCE) omega PFS score \< 0.80

∙ Geriatric screening (G-8) score =\< 14

∙ Cancer and Aging Research Group (CARG) toxicity score \>= 30%

∙ Cumulative Illness Rating scale for Geriatrics (CIRS-G) score \>= 4 OR

⁃ Age \< 70 with severe comorbidity or vulnerability to cisplatin, defined as having two or more of the following conditions within 30 days prior to step 1 registration

• Modified Charlson Comorbidity Index \>= 1

∙ ACE-27 Index \>= 1

∙ GCE omega PFS-score \< 0.80

∙ G-8 score =\< 14

∙ CARG Toxicity score \>= 30%

∙ CIRS-G score \>= 4 OR

⁃ Age \>= 18 with an absolute or relative contraindication to cisplatin, defined as one or more of the following within 30 days prior to step 1 registration:

• Creatinine clearance (CC) \> 30 and \< 60 cc/min; for this calculation, use the Cockcroft-Gault formula

∙ Zubrod performance status 2 prior to step 1 registration

∙ Pre-existing peripheral neuropathy grade \>= 1

∙ History of hearing loss, defined as either:

‣ Existing need of a hearing aid OR

⁃ \>= 25 decibel shift over 2 contiguous frequencies on a pretreatment hearing test as clinically indicated

• Absolute neutrophil count (ANC) \>= 1,000 cells/mm\^3 (within 14 days prior to step 1 registration)

• Platelets \>= 100,000 cells/mm\^3 (within 14 days prior to step 1 registration)

• Hemoglobin \>= 9.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin \[Hgb\] \>= 9.0 g/dl is acceptable) (within 14 days prior to step 1 registration)

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =\< 2.5 times institutional upper limit of normal (within 14 days prior to step 1 registration)

• Serum bilirubin =\< 1.5 x institutional upper limit of normal (within 14 days prior to step 1 registration)

• Measured creatinine clearance (CL) \> 30 mL/min or calculated creatinine CL \> 30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance (within 14 days prior to step 1 registration)

• For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to step 1 registration; Note: women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause; the following age-specific requirements apply:

‣ Women \< 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)

⁃ Women \>= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \> 1 year ago, had chemotherapy-induced menopause with last menses \> 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)

• The patient or a legally authorized representative must provide study-specific informed consent prior to step 1 registration

• PRIOR TO STEP 2 REGISTRATION INCLUSION CRITERIA

• For patients with oropharyngeal or unknown primaries: p16 determination by immunohistochemistry (defined as greater than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells), confirmed by central pathology review

‣ Note: for patients with oral cavity, laryngeal, and hypopharyngeal primaries, analysis of p16 status prior to step 2 registration/randomization is not required (p16 status will be analyzed centrally post-hoc); step 2 registration for these patients can be completed after step 1 registration