This study is being done to determine if stereotactic body radiotherapy (SBRT) when delivered to all sites of disease in participants with 1-5 metastases will increase the length of time before participants' disease gets worse.

Inclusion Criteria:

• Metastatic disease detected on imaging and histologically confirmed

  • Metastatic breast cancer (all subtypes)
  • Non-small cell lung cancer (NSCLC) without known targetable molecular alterations in EGFR, ALK, or ROS1
  • NSCLC with EGFR, ALK, or ROS1 targetable molecular alterations who had a history of disease progression on first-line tyrosine kinase inhibitor

• Patient can either have newly diagnosed metastatic disease, or have non-progressive disease on systemic therapy (for at least 3 months on systemic imaging)

• Patients must have measurable disease at baseline (RECIST or PERCIST 2.0) and with 5 or fewer discrete disease sites that are technically amendable to SBRT (with the exception that if the primary disease is not amendable to SBRT it is allowed to be treated with conventionally fractionated or hypfractionated radiotherapy).

  • Two lesions in such close proximity to one another that treatment with one isocenter is more accurate and safer in the liver, lungs, or other similar anatomic locations should be viewed as one site of metastatic disease treatment
  • Disease in 2 contiguous vertebral bodies (with up to 6 cm of paraspinal extension) can represent one site of disease in the spine; non-contiguous lesions in vertebral bodies separated by one vertebral body free of disease should be viewed as 2 sites of treatment
  • 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 de novo stage IV patients (patients with metastatic disease at first presentation), primary disease must be treatable with local therapy. If the primary tumor or other locoregional disease has not been definitively treated and is not amendable to SBRT, it must be treated with conventionally fractionated or hypofractionated radiotherapy using a regimen that delivers a minimum BED of 48 Gy10. If the clinical scenario deem that other forms of local therapy may be more suitable for the primary and locoregional 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.

• If primary disease was previously treated with local therapy in the form of surgery or radiation, any new local/regional disease recurrence should be technically treatable with SBRT or hypofractionated radiation. If the clinical scenario deem that other forms of local therapy may be more suitable for the local/regional recurrent 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.

• Patients may receive palliative radiotherapy for symptomatic metastases or primary disease prior to enrollment provided that there is at least one other non-irradiated lesion amenable to SBRT at the time of enrollment.

• Patients with brain metastases are eligible if these lesions have been treated prior to enrollment.

• ECOG Performance status 0 - 2.

• Age >/= 18 years.

• Able to provide informed consent.

• Female subjects must either be of non-reproductive potential (i.e. post-menopausal by history: >/= 60 years old or no menses for 1> year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test within 2 weeks prior to starting treatment.

• Adequate baseline organ function to allow SBRT to all relevant targets, as determined by the treating radiation oncologist based on lesion location, lesion size, and proximity to relevant organs at risk.

Exclusion Criteria:

• Serious medical co-morbidities precluding radiotherapy, determined at the discretion of the treating investigator.
• Pregnant or lactating women.
• Other active malignancy within the last year, even if without evidence of disease.
• Clinical or radiological evidence of spinal cord compression
• Malignant pleural effusion or ascites.
• Patients whose entry to the trial will cause unacceptable clinical delays in their planned management.

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.