Immunotherapy SBRT Sensitization of the Programmed Death-1 (PD-1) Effect

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.