This phase I/II trial tests the safety and efficacy of split-course adaptive radiation therapy in combination with immunotherapy with or without chemotherapy for the treatment of patients with stage IV lung cancer or lung cancer that that has spread to nearby tissue or lymph nodes (locally advanced). Radiation therapy is a standard cancer treatment that uses high energy rays to kill cancer cells and shrink tumors. Split-course adaptive radiation therapy uses patient disease response to alter the intensity of the radiation therapy. Immunotherapy with monoclonal antibodies such as pembrolizumab, ipilimumab, cemiplimab, atezolizumab or nivolumab may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs like carboplatin, pemetrexed, and paclitaxel work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving split-course adaptive radiation therapy with standard treatments like immunotherapy and chemotherapy may be more effective at treating stage IV or locally advanced lung cancer than giving them alone.
Age >= 18 years at time of informed consent
• Histologically documented or cytologically confirmed diagnosis of stage IVA or IVB (M1b or M1c) or locally advanced (not eligible for standard of care [SOC] chemoradiation) non-small cell lung cancer with evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria
Available tumor material (< 6 months old) adequate for confirmation of programmed cell death 1 ligand 1 (PD-L1) expression per local standard of care testing
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
Mixed small cell histology
Confirmed candidate (per study physician) for alternative systemic therapy if preferred by treating physician (i.e. mEGFR, ALK, KRAS G12C or ROS1 mutations). Testing not required for enrollment
Brain metastases that would require administration of whole brain radiotherapy for management on required screening brain MRI within 21 days of day 1 of study treatment
Symptomatic malignant ascites or malignant pleural effusion (sampling not required). Pleural metastases are allowed if deemed targetable with radiotherapy
Parallel
Biospecimen Collection
Procedure/SurgeryCorrelative studies
Carboplatin
DrugGiven carboplatin
Computed Tomography
Procedure/SurgeryUndergo PET/CT
Fludeoxyglucose F-18
Other interventionGiven IV
Nab-paclitaxel
DrugGiven nab-paclitaxel
Pembrolizumab
Biological/VaccineGiven pembrolizumab
Pemetrexed
DrugGiven pemetrexed
Positron Emission Tomography
Procedure/SurgeryUndergo PET/CT
Radiation Therapy
RadiationUndergo radiation therapy
[18-F] (fluoropropyl)-L-glutamate (FSPG) PET scan
Other interventionUndergo PET scan
Ipilimumab
Biological/VaccineGiven Ipilimumab
Nivolumab
Biological/VaccineGiven Nivolumab
Cemiplimab
Biological/VaccineGiven Cemiplimab
Atezolizumab
Biological/VaccineGiven Atezolizumab
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Treatment groupsSee each treatment group below.
Incidence of adverse events
Safety endpoints will be tabulated using descriptive statistics, and by appropriate subgroups. The incidence of adverse events will be summarized according to organ system in terms of severity by Common Terminology Criteria for Adverse Events and relationship to treatment
Best overall response rate
By Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Exact binomial test and 95% confidence interval (CI) will be used.
Progression free survival (PFS)
Estimation of the treatment effect by a Cox proportional hazards model (stratified by chemotherapy regimen and PD-L1 expression, each stratum defines separate baseline hazard function); ties handled by replacing the proportional hazards model by the discrete logistic model; 95% CI for the hazard ratio will be calculated. Kaplan-Meier estimates and associated statistics (PFS rates at 6, 9, 12; median PFS) and corresponding 95% CI will be presented by treatment group.
Overall survival
Estimation of the treatment effect by a Cox proportional hazards model (stratified by chemotherapy regimen and PD-L1 expression, each stratum defines separate baseline hazard function); ties handled by replacing the proportional hazards model by the discrete logistic model; 95% CI for the hazard ratio will be calculated. Kaplan-Meier estimates and associated statistics and corresponding 95% CI will be presented by treatment group.
New metastasis free survival
Any new lesions different from the ones present at screening are considered as new metastases.
Quantitative and qualitative markers of planning and treatment resource utilization
Develop real-world clinical and treatment planning workflows for implementation of the Ethos platform for anatomic and biologically adaptive radiation therapy (RT).
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Vanderbilt-Ingram Cancer Center
Lead sponsor
National Cancer Institute (NCI)
Collaborator
Varian Medical Systems
Collaborator
