• Change in circulating tumor deoxyribonucleic acid levels as measured using CAncer Personalized Profiling by deep Sequencing [ Time Frame: Baseline up to 1 year after study entry ]
  Will correlate with radiographic response. Plasma biomarkers (e.g. cell free deoxyribonucleic acid level) will be summarized using medians and interquartile ranges; changes in biomarkers will be assessed using the Wilcoxon signed rank test. Correlation of biomarkers with radiographic response will be evaluated using a Wilcoxon rank sum test on patients with and without the event of interest. If feasible, these analyses will be supplemented by more formal analyses with the Cox model.
• Change in immune marker levels as measured from peripheral blood using flow cytometry performed by the Human Immune Monitoring Core at Stanford University [ Time Frame: Baseline up to 1 year after study entry ]
  Will correlate with radiographic response.
• Incidence of acute (0-6 months) and late (> 6 months) grade 3-5 toxicity [ Time Frame: Up to 4 years after study entry ]
  Measured with Common Terminology Criteria for Adverse Events version 4.
• Overall survival [ Time Frame: Time from study entry to death, assessed up to 4 years after study entry ]
  The electronic medical record will be monitored for patient deaths.

• Patterns of response and progression [ Time Frame: Up to 4 years ]
  Patterns of response and progression, including abscopal responses will be measured.
• Progression free survival [ Time Frame: Up to 4 years ]
  Evaluated with immune-related Response Criteria.
• Time to discontinuation of study immunotherapy agent [ Time Frame: Up to 4 years ]
  Time to discontinuation of study immunotherapy agent will be measured.

PRIMARY OBJECTIVES:

I. Determine if progression-free survival at 24 weeks with this treatment combination is improved compared to historical controls who received immunotherapy without radiation therapy.

SECONDARY OBJECTIVES:

I. Assess acute (0-6 months) and late (> 6 months) grade 3-5 toxicity. II. Assess overall survival. III. Correlate circulating tumor deoxyribonucleic acid (DNA) (ratio of post-radiation therapy [RT] to pre-RT level) with radiographic response.

IV. Correlate immune markers in peripheral blood with radiographic response.

TERTIARY OBJECTIVES:

I. Analyze progression-free survival with immune-related response criteria. II. Measure time to discontinuation of study immunotherapy agent. III. Assess patterns of progression.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients undergo radical-dose image guided radiation therapy daily for up to 10 days (within 2 weeks) while undergoing standard of care immunotherapy.

Arm II: Patients who decline to undergo radiation therapy receive standard of care immunotherapy.

After completion of study treatment, patients are followed up at 30 days and every 6 months thereafter.

• Biological: Immunotherapy (standard of care)
  Receive standard of care immunotherapy (nivolumab, pembrolizumab, atezolizumab)
  Other Name: biologic therapy
• Radiation: Image Guided Radiation Therapy
  Undergo image guided radiation therapy
  Other Names:

  • IGRT
  • image-guided radiation therapy
• Other: Laboratory Biomarker Analysis
  Correlative studies

• Experimental: Arm I (image guided radiation therapy)
  Patients undergo radical-dose image guided radiation therapy daily for up to 10 days (within 2 weeks) while undergoing standard of care immunotherapy.
  Interventions:

  • Biological: Immunotherapy (standard of care)
  • Radiation: Image Guided Radiation Therapy
  • Other: Laboratory Biomarker Analysis
• Active Comparator: Arm II (standard of care immunotherapy)
  Patients who decline to undergo radiation therapy receive standard of care immunotherapy.
  Interventions:

  • Biological: Immunotherapy (standard of care)
  • Other: Laboratory Biomarker Analysis

Inclusion Criteria:

• Has metastatic non-small cell lung cancer (NSCLC)
• Has been receiving anti-PD-1 or anti-PD-L1 immunotherapy for at least four weeks
• Has had restaging imaging after initiation of immunotherapy, at least 4 weeks after pre-immunotherapy baseline imaging; computed tomography (CT) or positron emission tomography (PET)/CT of at least chest/upper abdomen must be performed within 4 weeks prior to registration; for patients with history of brain metastases, brain magnetic resonance imaging (MRI) or CT is required within 4 weeks of registration; for other patients brain MRI or CT is required within 12 weeks of registration
• Is expected by the treating medical oncologist to continue on immunotherapy for at least three more months; imaging must show response, stable disease, or modest progression as determined by the treating medical oncologist; if there is modest progression, the patient must be clinically stable in terms of performance status and overall disease-related symptoms
• Has at least one extracranial tumor safely treatable with radical-dose radiation therapy
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Has the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Untreated brain metastases, if not planned to be treated in this course of radiation therapy
• Pregnancy or women of childbearing potential not willing/able to use contraception during protocol treatment