The purpose of this study is to determine efficacy, safety of Stereotactic Body Radiotherapy (SBRT) in combination with immunotherapy in participants with metastatic non-small cell lung cancer (NSCLC) who are eligible for an immunotherapy agent.

Blockade of the PD-1/PD-L1 T-cell checkpoint pathway is an effective and well tolerated approach to stimulating the immune response which is a critical option in the treatment of metastatic NSCLC. However, progression free survival (PFS) is increased by only 2-4 months and median overall survival (OS) by 3-9 months.

There is compelling evidence that PFS is increased up to 3 fold and OS by 2 fold in patients receiving a course of radiation therapy while on immunotherapy. Radiotherapy is known to induce immunogenic tumor cell death and upregulation of dendritic cells and antigen presentation leading to activation of cytotoxic T-Cells. Dramatic T-cell activation has been demonstrated where tumor regression occurs outside the radiation treatment field in a phenomenon termed the abscopal effect and is associated with high dose radiation delivered via SBRT.

As such, SBRT activation of T-cells could be complementary to immunotherapy and enhance T-cell mediated killing via PD-L1 blockade which could lead to lasting and durable tumor response with improved progression free survival and overall survival.

Inclusion Criteria:

• Histologically or cytologically confirmed Stage IV NSCLC according to the 7th AJCC staging manual.

• Eligible for an immunotherapy agent. Patients who progress after drug therapy (3 months) for ALK, EGFR or ROS mutation positive lung cancer are eligible.

• At least 2 lesions that are safely amenable to SBRT. ECOG <=2.

• At least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria for response assessment or at least 1 lesion with FDG avidity and CT correlate that can be monitored for PET-CT response by SUV Max increase or decrease.

• Normal Hepatic and renal function.

• Bone marrow reserve:

  1. ANC ≥ 1.5 x 109/L
  2. Hemoglobin ≥9.0 g/dL
  3. Platelet count ≥75 x 109/L

• Ability to comply with follow-up visits and evaluations, treatment planning and studies and other study related procedures and visits.

• Ability to sign informed consent.

Exclusion Criteria:

• Patients with active CNS metastases
• Active, known or suspected auto-immune disease.
• Patients with medical conditions that require systemic immunosuppression.
• Patients with a history of interstitial lung disease.
• Prior treatment with immune checkpoint inhibitors/immonotherapy.
• Other active malignancy requiring intervention.
• Prior lung radiation, with the only metastatic targets in the lungs.
• Unresolved toxicity from prior chemotherapy or anti-cancer treatment.
• Current or prior enrollment in clinical trial with an investigational drug within 4 weeks.
• Pregnancy or positive pregnancy test.