Randomized Study of Stereotactic Body Radiation Therapy (SBRT) in Patients With Oligoprogressive Metastatic Cancers of the Breast and Lung

Inclusion Criteria

- Age 18 or older - Willing and able to provide informed consent - Metastatic disease detected on imaging and histologically confirmed: Triple negative breast cancer TNBC (ER <1%, PR <1%, her-2-neu 0- 1+ by IHC or FISH-negative or as determined by MD discretion) OR NSCLC (without known EGFR mutation or ALK/ROS1 rearrangement) OR Other high-risk breast cancer (per physician's discretion) progressed on hormone or systemic therapy, regardless of ER/HER2 status OR NSCLC with EGFR, ALK, or ROS1 targetable molecular alterations with disease progression on first-line tyrosine kinase inhibitor Note: - Biopsy of metastasis prior to enrollment is per treating physician's discretion per standard of care. It is preferred but not required. - These patients are selected for the study given the similar survival outcomes when given standard of care therapies - Patient has received at least first-line prior treatment with systemic therapy (either cytotoxic or targeted, including maintenance therapies). - Patients who received prior immunotherapy are allowed. - Patients who had any prior radiation therapy near or overlapping with the oligoprogressive sites are allowed to enroll. - Patients with the following medical conditions precluding them from participating in other systemic therapy or drug trials are allowed: - active liver disease, including viral or other hepatitis, or cirrhosis - any other significant medical condition not under control, including any acute coronary syndrome within the past 6 months. - a permanent pacemaker - a QTc > 480 ms in the baseline EKG - peripheral neuropathy of grade >/= 2 per NCI CTCAE - history or known autoimmune disease - current chronic systemic steroid therapy or any immunosuppressive therapy - history of primary immunodeficiency or solid organ transplant - known positive human immunodeficiency virus (HIV), chronic or active hepatitis B or C, or active hepatitis A - active infection requiring systemic antibiotic therapy - Patients can have more than 5 metastases but can only have 1-5 oligo-progressive lesions. - Oligoprogression, defined as Response Evaluation Criteria in Solid Tumors (RECIST) or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) documented progression in up to 5 individual lesions Using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria as a guide: 1. At least a 20% increase in the sum of the longest diameter (LD) of the lesion, taking as reference the smallest sum LD recorded since the last imaging OR 2. The appearance of one or more new lesions OR 3. New/malignant FDG uptake in the absence of other indications of progressive disease or an anatomically stable lesion OR 4. >/= 5mm increase in the diameter sum of the lesion OR Using Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) as a guide: 1. >30% increase in 18F-FDG SUV peak, with >0.8 SUV units increase in tumor SUV from the baseline scan in pattern typical of tumor and not of infection/treatment effect OR 2. Visible increase in the extent of 18F-FDG tumor uptake OR 3. New 18F-FDG avid lesions typical of cancer (including new bone lesion) and not related to treatment effect and/or infection OR Development of a new soft tissue metastatic lesion at least 5mm in size or any new bone metastasis OR Progressive enlargement of a known metastasis on 2 consecutive imaging studies at least 2 months apart with a minimum 5mm increase in size - All sites of oligoprogression can be safely treated - Maximum 5 progressing metastases in any single extra-cranial organ system (i.e. lung, liver, bone) a. If the clinical scenario deem that other forms of local therapy may be more suitable for the metastatic disease, such as surgical resection and interventional radiology-guided ablation, patients would be able to undergo other forms of local therapy with discussion with the PI - No restriction on the total number of metastases - Note: If the clinical scenario deem that other forms of local therapy may be more suitable for the metastatic disease, such as surgical resection and interventional radiology-guided ablation, patients would be able to undergo other forms of local therapy with discussion with the PI. - For patients with brain metastases and oligoprogression elsewhere where stereotactic radiation to the brain is warranted, the brain lesions can be treated prior to randomization. This will not be counted toward the 5 progressive lesions. - Any symptomatic metastatic sites requiring prompt palliative radiation (e.g. cord compression) can also be treated with standard of care radiation prior to randomization. This will not be counted toward the 5 progressive lesions. 1. If the clinical scenario deem that other forms of local therapy may be more suitable for the metastatic disease, such as surgical resection and interventional radiology-guided ablation, patients would be able to undergo other forms of local therapy with discussion with the PI.

Exclusion Criteria

- Pregnancy. - Leptomeningeal disease. - Serious medical comorbidities precluding radiotherapy, such as ataxia-telangiectasia or scleroderma. - Any other condition which in the judgment of the investigator would make the patient inappropriate for entry into this study.