Clinical Research Directory

Inclusion Criteria: * Age ≥ 18 years * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Estimated life expectancy ≥ 6 months * Histologically confirmed mucosal head and neck squamous cell carcinoma (HNSCC) of the nasal cavity, nasopharynx, oral cavity, oropharynx, hypopharynx, larynx, or other mucosal site * Disease not amenable to curative-intent local therapy * Radiographically evident disease at the planned pulsed RT target(s) * Patient must meet criteria for one of three cohorts: Cohort 1: Newly diagnosed locoregionally advanced or metastatic HNSCC unfit for curative-intent therapy, Cohort 2: Recurrent and/or metastatic disease after prior local therapy, Cohort 3: Oligoprogression (≤5 sites) on immunotherapy ± chemotherapy * Candidate for immunotherapy as determined by medical oncologist * For chemotherapy-eligible patients, candidate for platinum-based chemotherapy * Planned RT target(s) within the head and neck region amenable to delivery on Varian Ethos with online adaptive replanning for at least one site. * For patients with RT target(s) outside head and neck, they may be treated with online or offline adapted pulsed RT * Adequate organ function for initiation of immunotherapy as determined by the medical oncologist. * Women of childbearing potential must have a negative serum pregnancy test within 7 days of fifirst study treatment * Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life and/or health utility questionnaires in English. Inability (lack of comprehension in English, or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible. * Written informed consent obtained prior to any study-specific procedures. Exclusion Criteria: * Two or more prior courses of radiotherapy to a planned re-irradiation site * Laryngeal local recurrence requiring RT after prior ≥ 50 Gy to the larynx * Previous RT to the target lesion(s) completed within 6 months before enrollment * Uncontrolled brain metastases (controlled/treated brain metastases are permitted) * Active second malignancy requiring treatment, with the exception of localized cutaneous malignancy or in-situ disease * Head and neck target not amenable to RT delivery on Varian Ethos with online adaptive replanning * Contraindication to immune checkpoint inhibitors, including: Active autoimmune disease requiring systemic immunosuppressive therapy, Prior grade ≥ 3 immune-related adverse event attributable to prior ICI therapy, Active or recent (within 6 months) interstitial lung disease or pneumonitis requiring corticosteroids * Hypersensitivity to pembrolizumab * Pregnancy or breastfeeding * Inability to lie supine for online adaptive radiotherapy delivery * Any uncontrolled medical condition that, in the opinion of the investigator, would compromise patient safety or study compliance