Split Course Adaptive Radiation Therapy With Pembrolizumab With/Without Chemotherapy for Treating Stage IV Lung Cancer

PRIMARY OBJECTIVES: I. Evaluate the safety of adaptive split course hypo-fractionated radiation therapy (RT) with immunotherapy containing systemic regimens. II. Evaluate efficacy of the use of adaptive split course hypo-fractionated RT with immunotherapy containing systemic regimens. SECONDARY OBJECTIVES: I. Evaluate progression and survival benefit of split course adaptive radioimmunotherapy (SiCARIO) regimen. II. Identify potential functional radiomic biomarkers of response to SiCARIO regimen. III. Develop real-world clinical and treatment planning workflows for implementation of the Ethos platform for anatomic and biologically adaptive RT. OUTLINE: PRIMARY OBJECTIVES: I. Evaluate the safety of adaptive split course hypo-fractionated radiation therapy (RT) with immunotherapy containing systemic regimens. II. Evaluate efficacy of the use of adaptive split course hypo-fractionated RT with immunotherapy containing systemic regimens. SECONDARY OBJECTIVES: I. Evaluate progression and survival benefit of split course adaptive radioimmunotherapy (SiCARIO) regimen. II. Identify potential functional radiomic biomarkers of response to SiCARIO regimen. III. Develop real-world clinical and treatment planning workflows for implementation of the Ethos platform for anatomic and biologically adaptive RT. OUTLINE: Patients are assigned to 1 of 11 standard treatment regimens, in combination with radiation therapy, as determined by the tumor histology and PD-L1 status. Patients with non-squamous histology and any PD-L1 status are assigned to arms 1-4. ARM I: Patients receive carboplatin, pemetrexed, and pembrolizumab on day 1 of each cycle. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive pemetrexed and pembrolizumab on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. ARM II: Patients receive carboplatin, pemetrexed and cemiplimab-rwlc on day 1 of each cycle. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive pemetrexed and cemiplimab-rwlc on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. ARM III: Patients receive carboplatin, paclitaxel and cemiplimab-rwlc on day 1 of each cycle. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive pemetrexed and cemiplimab-rwlc on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. ARM IV: Patients receive carboplatin, pemetrexed and nivolumab on day 1 of each cycle and ipilimumab on day 1 of every other cycle. Treatment repeats for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then continue to receive ipilmumab and nivolumab on the same schedule for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. Patients with squamous histology and any PD-L1 histology are assigned to arms 5-7 ARM V: Patients receive carboplatin, paclitaxel, and pembrolizumab on day 1 of each cycle. Treatment repeats every 3 weeks for 4 up to cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. Patients then receive pembrolizumab on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. ARM VI: Patients receive carboplatin, paclitaxel, and cemiplimab-rwlc on day 1 of each cycle. Treatment repeats every 3 weeks for 4 up to cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. Patients then receive cemiplimab-rwlc on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. ARM VII: Patients receive carboplatin, paclitaxel and nivolumab on day 1 of each cycle and ipilimumab on day 1 of every other cycle. Treatment repeats for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then continue to receive ipilmumab and nivolumab on the same schedule for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. Patients with PD-L1 ≥ 50% are assigned to arms 8-10 ARM VIII: Patients receive pembrolizumab on day 1 of each cycle. Cycles repeat every 3 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. ARM IX: Patients receive atezolizumab on day 1 of each cycle. Cycles repeat every 3 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. ARM X: Patients receive cemiplimab-rwlc on day 1 of each cycle. Cycles repeat every 3 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. Patients with any PD-L1 status or histology who are not a chemotherapy candidate are assigned to arm 11 ARM XI: Patients receive ipilmumab every 6 weeks and nivolumab every 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on day 1 of each cycle over 5 treatment fractions. All patients also receive fludeoxyglucose F-18 intravenously and fluorine F 18 florilglutamic acid IV and undergo PET/ CT during screening and on study. Patients also undergo collection of blood samples, as well as CT and MRI throughout the trial. After completion of study treatment, patients are followed up at 4 weeks, 12 weeks, and then every 12 weeks for 2 years.