POLARIS: Polymetastatic lesion ablative radiotherapy with immunotherapy study.

TPS2683 Background: Patients with polymetastatic disease, most commonly defined as >5 metastatic lesions, often have limited treatment options and poor overall prognosis 1,2 . The emergence of immunotherapy (IO) has slowed disease progression in some patients; however, its efficacy is limited by tumor heterogeneity and patient-specific factors, including baseline health status 3 . Emerging data suggest a synergistic effect when combining IO with radiotherapy (RT), a strategy that has led to FDA-approved treatment approaches in non-small cell lung cancer (NSCLC) 4-6 . As multimodal cancer therapies evolve, robust methods to assess treatment response are increasingly important. Circulating tumor DNA (ctDNA) is a minimally invasive biomarker that has been shown to correlate with clinical response to therapy 7,8 . However, the kinetics and clinical significance of ctDNA in patients receiving combined IO and ablative RT remain poorly characterized. Methods: POLARIS is a pilot phase II, double-arm clinical trial evaluating the addition of ablative radiotherapy in patients with polymetastatic disease receiving immunotherapy. Twenty-eight patients with polymetastatic disease, defined as having at least 3 and no more than 10 metastatic lesions, and receiving immunotherapy alone for at least 30 days prior to registration will be enrolled at the University of Illinois Hospital & Health Sciences System (UIH). Patients will be stratified into two cohorts based on their response to immunotherapy after ≥3 months: Cohort A includes patients with investigator-assessed stable disease or partial response, while Cohort B includes patients with oligoprogression, defined as 1–5 sites of progressive disease within 3 months of registration. Both cohorts will receive ablative RT targeting up to 10 metastatic lesions in combination with ongoing immunotherapy. The primary endpoint is the proportion of patients achieving a molecular response, defined as a >50% reduction in ctDNA levels, at 8 weeks following ablative RT. Secondary endpoints include overall survival and progression-free survival at 6 and 12 months, objective response rate, and treatment-related adverse events (TRAEs). This trial is the first to prospectively evaluate ablative radiotherapy as an adjunct to immunotherapy while integrating ctDNA as a biomarker of treatment response in polymetastatic disease. Clinical trial information: NCT07269080 .