The purpose of this study is to see whether adding liver stereotactic ablative radiotherapy/L-SABR to standard drug therapy is better than standard drug therapy alone for people with metastatic non-small cell lung cancer/NSCLC.

Inclusion Criteria:

• Be greater than 18 years of age on day of signing informed consent.

• Have a histologically confirmed diagnosis of stage IV NSCLC (includes patients who have progressed on durvalumab for Stage III NSCLC) without known mutations in (EGFR) or BRAF or rearrangements in ALK (anaplastic lymphoma kinase) or ROS-1.

  o Patients with recurrent metastatic NSCLC following prior durvalumab for stage III disease are eligible provided this is their first immunotherapy course for metastatic disease (i.e., the planned anti-PD-(L)1-based regimen represents first-line systemic therapy in the metastatic setting).

• Newly diagnosed metastatic non-small cell lung cancer (NSCLC), including both de novo and secondary metastatic disease, with one or more liver metastases

• Plan to initiate standard of care anti-PD-(L)1 based immunotherapy +/- platinum based chemotherapy for at least 3 cycles

  o Regimens combining anti-CTLA-4 immunotherapy with anti-PD-1 (e.g., ipilimumab plus nivolumab) or anti-PD-L1 (e.g., tremelimumab plus durvalumab) immunotherapy are allowed.

• Have a performance status of 0-2 on the ECOG Performance Scale.

• Liver function tests:

  • Total Bilirubin ≤ 1.5 x ULN
  • AST/ ALT ≤ 5 x ULN

• Eligible for L- SABR to all liver metastases as determined by the treating radiation oncologist

• Patients with known HIV are eligible provided they are under treatment with effective anti-retroviral therapy with CD4 count >200 cells/microliter within 28 days prior to registration

Exclusion Criteria:

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen should be included.
• Patients with prior external beam radiation therapy to the liver.
• Patients with known active Hepatitis B or Hepatitis C.
• Patients with immunosuppression including pharmacological immunosuppression with chronic steroids or immune modulators like cyclosporin or methotrexate and patients with active autoimmune disease.
• Patients who are pregnant or breastfeeding
• Men or women not using effective contraception.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.