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

PRIMARY OBJECTIVE: I. To compare overall survival (OS) between immunotherapy plus consolidative radiotherapy (CoRT) and immunotherapy alone following non-progression with systemic chemoimmunotherapy. SECONDARY OBJECTIVES: I. To compare progression-free survival (PFS) between the two arms. II. To compare time-to-treatment failure (TTF) between the two arms. III. To determine the risk of non-hematologic high-grade (3 or higher) toxicity with the addition of CoRT. IV. To establish the prognostic value of quantitative positron emission tomography (PET) biomarkers at baseline (standardized uptake value maximum \[SUVmax\], metabolic tumor volume \[MTV\], total lesion glycolysis \[TLG\]) for overall survival in both arms. V. To establish the predictive value of (a) structured qualitative read (Hopkins Criteria) and (b) quantitative analysis for assessment of the post-radiotherapy or chemotherapy restaging PET/computed tomography (CT) to evaluate its association with overall survival in both arms. HEALTH-RELATED QUALITY-OF-LIFE (HRQL) OBJECTIVES: I. To compare the time-to-definitive-deterioration (TTDD) between the two arms. (PRIMARY) II. To compare the mean early change in the Functional Assessment of Cancer Therapy - Head \& Neck (FACT-HN) trial outcome index (TOI) between the arms, defined as the difference between the cycle 7 time point and randomization. (SECONDARY) III. To compare the time-to-deterioration (TTD) between the arms (first deterioration). (SECONDARY) IV. To compare the nadir of the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM) score over the course of study participation between the arms. (EXPLORATORY) V. To compare quality-adjusted survival between the arms. (EXPLORATORY) EXPLORATORY OBJECTIVES: I. To identify differences in patterns-of-failure with respect to local regional and distant recurrences following CoRT versus immunotherapy alone. II. To evaluate the risk of tracheostomy and/or gastrostomy in patients treated with CoRT versus immunotherapy alone. OUTLINE: STEP 1: Patients who have not completed initial systemic therapy prior to enrollment are assigned to Arm T and patients who have completed initial systemic therapy prior to enrollment are assigned to Arm S. ARM T: Patients receive pembrolizumab intravenously (IV) with carboplatin IV and paclitaxel IV, or with cisplatin IV and fluorouracil IV, or with carboplatin IV and fluorouracil IV on study. ARM S: Patients proceed directly to Step II. STEP II: Patients are randomized to 1 of 2 arms. ARM A: Patients receive one cycle of pembrolizumab IV with carboplatin IV and paclitaxel IV, or with cisplatin IV and fluorouracil IV, or with carboplatin IV, and fluorouracil IV on study and then receive pembrolizumab IV with radiation therapy on study. Patients also undergo CT, PET/CT, and/or magnetic resonance imaging (MRI) throughout the trial. ARM B: Patients receive one cycle of pembrolizumab IV with carboplatin IV and paclitaxel IV, or with cisplatin IV and fluorouracil IV, or with carboplatin IV, and fluorouracil IV on study and then receive pembrolizumab IV monotherapy on study. Patients also undergo CT, PET/CT, and/or MRI throughout the trial.