Radiation Therapy and Cisplatin With or Without Cetuximab in Treating Patients With HPV Positive, KRAS-Variant Stage III-IV Oropharyngeal Squamous Cell Carcinoma

PRIMARY OBJECTIVES: I. To determine the efficacy of radiation therapy with concurrent cisplatin combined with concurrent cetuximab in KRAS-variant oropharyngeal squamous cell carcinoma (OPSCC) patients in terms of overall survival (OS) at 2 years. SECONDARY OBJECTIVES: I. To determine the efficacy of radiation therapy with concurrent cisplatin combined with concurrent cetuximab in KRAS-variant OPSCC patients in terms of patterns of failure at 6 months and 2 years. II. To determine the efficacy of radiation therapy with concurrent cisplatin combined with concurrent cetuximab in KRAS-variant OPSCC patients in terms of progression-free survival (PFS) at 2 years. III. To determine the efficacy of radiation therapy with concurrent cisplatin combined with concurrent cetuximab in KRAS-variant OPSCC patients in terms of locoregional control (LRC) at 2 years. IV. To determine the efficacy of radiation therapy with concurrent cisplatin combined with concurrent cetuximab in KRAS-variant OPSCC patients in terms of distant metastasis-free survival (DMFS) at 2 and 5 years. V. To determine the efficacy of radiation therapy with concurrent cisplatin combined with concurrent cetuximab in KRAS-variant OPSCC patients in terms of OS at 5 years. VI. To determine the safety of radiation therapy with concurrent cisplatin combined with concurrent cetuximab in KRAS-variant OPSCC patients in terms of acute toxicity profiles at the end of radiation, at 1 month, and at 6 months. VII. To determine the safety of radiation therapy with concurrent cisplatin combined with concurrent cetuximab in KRAS-variant OPSCC patients in terms of late toxicity profiles at 1 and 2 years. VIII. To determine the safety of radiation therapy with concurrent cisplatin combined with concurrent cetuximab in KRAS-variant OPSCC patients in terms of patient-reported swallowing outcomes at 6 months and 1 and 2 years. IX. To assess the predictive value of fludeoxyglucose (FDG)-positron emission tomography (PET) at 10-14 weeks post-treatment. X. To assess the predictive value of additional blood and tissue biomarkers for disease outcomes at 2 years. EXPLORATORY OBJECTIVES: I. To evaluate the impact of cetuximab on the immune response as well as treatment outcome and toxicity. II. To evaluate biomarkers for immune response in HPV-associated OPSCC through saliva and blood samples to be collected prior to treatment and at each follow-up visit. III. To evaluate for additional checkpoint targets through tumor tissue taken at the time of initial biopsy and profiled for tumor infiltrating lymphocytes, activation markers, and antigen-specific T-cell receptor (TCR) utilization/diversity. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Beginning on day 0, patients undergo radiation therapy over 6 weeks for a total of 35 fractions. Patients also receive cisplatin intravenously (IV) over 1-2 hours on days 0 and 21. ARM II: Patients receive cetuximab IV over 120 minutes 5-7 days prior to start of radiation therapy and then IV over 60 minutes weekly on Monday or Tuesday for 7 weeks. Patients also undergo radiation therapy and receive cisplatin as in Arm I. After completion of study treatment, patients are followed up at 2-4 weeks, every 12 weeks for 2 years, and then every 3-12 months for up to 5 years.