This is a non-randomized two-arm trial, specifically a pilot study in which patients with advanced solid tumor cancer with 3-10 metastatic lesions who are on immunotherapy will receive ablative RT to up to 10 lesions. After study intervention, participants will undergo ctDNA collection at 8 weeks after completion of ablative RT Post-treatment disease assessments, including imaging and serial ctDNA monitoring, as well as any additional treatments, will be at the discretion of the treating oncologist. Approximately 28 subjects (14 per cohort) will be enrolled. For subjects who do not complete the full planned course of RT for any reason, a final study visit should be performed approximately 30 days after the last fraction of radiation. If a subject is discontinued from the study with an ongoing adverse event or an unresolved clinically significant laboratory result, the clinical investigative team will attempt to provide follow-up until a satisfactory clinical resolution of the laboratory result or adverse event is achieved.

Inclusion Criteria:

• Age ≥ 18 years of age at the time of consent

• ECOG (0, 1, or 2) within 30 days prior to registration.

• Subjects with advanced solid tumors with at least 3 but no more than 10 sites of metastatic disease, excluding the primary tumor.

• Disease site must be outside of the GI tract (including esophagus, stomach, small or large bowel, and mesenteric lymph nodes), brainstem, and skin.

• Demonstrates adequate organ function. All screening labs are to be obtained within 30 days prior to registration.

• Able to provide written informed consent and HIPAA authorization for release of personal health information via an approved UIC Institutional Review Board (IRB) informed consent form and HIPAA authorization. If a subject is unable to consent, a Legally Authorized Representative (LAR) may provide consent on their behalf.

• Women of childbearing potential must not be pregnant or breastfeeding. A negative serum or urine pregnancy test is required per institutional practice guidelines.

• As determined at the discretion of the enrolling physician or protocol designee, the ability of the subject to understand and comply with study procedures for the entire length of the study.

• Have a life expectancy of at least 3 months.

• Subjects receiving treatment for >3 months with an FDA-approved immunotherapy agent such as a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, or an LAG-3 inhibitor; either as monotherapy or in combination with another FDA-approved immunotherapy agent. Subjects may have received prior combination cytotoxic chemotherapy and immunotherapy, but must be receiving only immunotherapy for at least 30 days prior to registration.

  • Cohort A: Subjects with investigator-assessed stable disease or partial response after > 3 months of immunotherapy treatment prior to registration
  • Cohort B: Subjects with oligo-progression defined as having at least 3 sites of disease during their disease course, with at least 1 but up to 5 sites of progressive disease within 3 months of registration. Subjects must have investigator-assessed stable disease, partial response, or complete response as prior best response to immunotherapy and have been on immunotherapy for at least 3 months prior to registration.

Exclusion Criteria:

• Inability to treat all sites of disease
• >10 metastatic lesions at any point in the disease course
• History of interstitial lung disease or G3 or worse pneumonitis
• Malignant pleural effusion
• Active infection requiring IV antibiotics
• Active autoimmune disease requiring immunosuppression in the last two years from enrollment.
• Significant medical comorbidities precluding radiotherapy as determined by the treating physician.
• Use of systemic corticosteroids equivalent to prednisone ≥10 mg daily within 14 days prior to registration, or requirement for systemic corticosteroids at screening for disease control, unless used as physiologic replacement (e.g., adrenal insufficiency). Subjects who require systemic steroids ≥10 mg/day for clinical management will be ineligible.
• Substantial overlap with a previously treated radiation volume.
• For patients with liver metastases, moderate/severe liver dysfunction (Child-Pugh B or C)
• Patients with symptomatic brain metastases, a single metastasis greater than 5 cm in size, or any brain metastasis greater than 3 cm in size. Patients with total brain metastases volume exceeding 30 cc.
• Clinical or radiologic evidence of spinal cord compression.
• Metastatic disease involving the GI tract (esophagus, stomach, small or large bowel, mesenteric lymph nodes), disease in the brainstem, or skin
• Pregnant or nursing
• Any prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of this investigational regimen, as determined by the treating medical oncologist.
• Other major comorbidity, as determined by the study PI