This phase II trial tests the safety of positron emission tomography (PET) guided stereotactic body radiation therapy (SBRT) and how well it works to treat non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC) that has up to 5 sites of progression (oligoprogression) compared to standard SBRT. SBRT uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. A PET scan is an imaging test that looks at your tissues and organs using a small amount of a radioactive substance. It also checks for cancer and may help find cancer remaining in areas already treated. Using a PET scan for SBRT planning may help increase the dose of radiation given to the most resistant part of the cancer in patients with oligoprogressive NSCLC, melanoma, and RCC.

PRIMARY OBJECTIVE:

I. PET adaptive SBRT is both feasible and safe and allows for a higher total dose of radiation through an inter-fraction simultaneous integrated boost (SIB) based on inter-fraction PET uptake, leading to improved local control outcomes compared to current standard SBRT planning without a SIB.

SECONDARY OBJECTIVES:

I. Determine the duration of local and distant control followed PET adaptive SBRT treatment compared to standard external beam radiation therapy (EBRT).

II. Evaluate the utility of measuring circulating tumor deoxyribonucleic acid (DNA) (ctDNA) before, during and after SBRT in conjuction with biological imaging to assess early disease response.

III. Identify genomic predictors to predict for distant progression. IV. Determine durability of current systemic therapy with SBRT to oligoprogressive sites.

EXPLORATORY OBJECTIVES:

I. Biomarker changes based on ctDNA before, during and after treatment. II. Changes in fludeoxyglucose (FDG) uptake with SBRT and combined checkpoint inhibitor during and after treatment and correlation with local and distant control.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo 5 SBRT treatments every other day on study. Patients also undergo computed tomography (CT) or PET/CT and blood collection throughout study.

ARM II: Patients undergo 3 SBRT treatments every other day week 1, undergo PET/CT and replanning one month post SBRT, then undergo 2 additional treatments with SIB on study. Patients also undergo CT or PET/CT and blood collection throughout study.

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative

  • Assent, when appropriate, will be obtained per institutional guidelines

• Agreement to allow the use of archival tissue from diagnostic tumor biopsies

  • If unavailable, exceptions may be granted with study principal investigator (PI) approval

• Age: >= 18 years

• Eastern Cooperative Oncology Group (ECOG) =< 2

• Histologically or cytologically confirmed NSCLC with 1-5 sites of disease progression while on or following systemic therapy with a checkpoint inhibitor with or without chemotherapy for at least 3 months with radiographic evidence of progression based on Response Evaluation Criteria in Solid Tumors (RECIST) or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST)

• Lesion(s) must all be amenable to SBRT which will be determined by the radiation oncologists. Active lesions should be a minimum size of >= 1 cm

• Primary tumor should be controlled for > 3 months in the metachronous setting; for synchronouos progression of the primary and oligoprogressive site(s), the primary should be treated with curative/local control intent

• Patients eligible for the study must have at least one lesion for which the planned radiation dose achieves a biologic effective dose (BED) < 100 (alpha/beta = 10) due to organs at risk and dose constraints

• 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 after discussion with the study PI but at least one lesion must be treated with SBRT in this scenario

• Patients with brain metastases can be included but brain metastases must be treated prior to enrollment and are not considered as a site of oligoprogression

• Life expectancy >= 3 months in the opinion of the treating investigators

Exclusion Criteria:

• Judgement by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions, and requirements
• Those not eligible for SBRT after review by a radiation oncologist
• Unable to undergo a Pet/CT or do not have Pet active disease
• Pregnant and/or breastfeeding women are excluded from this study as these agents may have the potential for teratogenic or abortifacient effects. Female patients of childbearing potentially must have a negative urine or serum pregnancy test within 72 hours prior to receiving therapy
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)