2837 - Polymetastatic Lesion Ablative Radiotherapy with Immunotherapy Study (POLARIS): A ctDNA-Guided Phase II Trial for Patients with Metastatic Advanced Solid Tumors

Background: Stereotactic body radiotherapy (SBRT) provides durable local control and is associated with improved survival in selected oligometastatic patients (Palma, 2020). However, most prospective evidence has focused on limited metastatic burden (1–5 metastases) (Gomez, 2019; Iyengar, 2018). Patients with polymetastatic disease, often defined as >5 metastases, generally have poorer prognosis (American Cancer Society, 2025; NCCN, 2026). Immunotherapy (IO) alone can slow disease progression in some patients, but efficacy is constrained by tumor heterogeneity and patient-specific factors (Rui, 2023). We hypothesize that extending multisite SBRT and IO to patients with a higher metastatic burden may achieve similar outcomes to patients with <5 metastases. As multimodal therapy expands, robust early-response metrics are needed. Circulating tumor DNA (ctDNA) is a minimally invasive biomarker correlated with response to therapy, yet its kinetics and clinical significance during combined SBRT and IO are incompletely defined (Sivapalan, 2023; Ding, 2024). POLARIS prospectively evaluates multisite SBRT and IO in patients with advanced solid tumors with 3–10 metastases, integrating ctDNA as an early biomarker to assess response.

Methods: POLARIS is an ongoing pilot phase II, two-cohort, non-randomized trial enrolling 28 adults with advanced solid tumors and polymetastatic disease (3–10 metastases) who have received IO for =3 months and IO alone for =30 days prior to registration. Based on their response to IO, patients will be stratified into two cohorts. Cohort A includes patients with stable disease/partial response on IO. Cohort B includes patient with oligoprogression defined as 1–5 progressing metastases on IO after prior disease control. The primary endpoint is molecular response, defined as >50% reduction in ctDNA from baseline to 8 weeks following SBRT. Secondary endpoints include objective response rate per RECIST, progression-free survival, overall survival, and treatment-related adverse events. Each cohort will follow a Simon’s two-stage optimal design. IO is not administered on SBRT days, and no systemic anti-cancer therapy is permitted until completion of RT. Up to 10 metastases will be targeted using photon-based SBRT completed within 3 weeks (daily or every other day). SBRT dose is by site: 45Gy/3fx for peripheral lung, liver, and abdominal-pelvic targets; 50Gy/5fx for central lung and thoracic/cervical nodal targets; 30Gy/3fx for spine/paraspinal/other osseous targets. SBRT planning prioritizes organ at risk (OAR) constraints over planning target volume (PTV) coverage. POLARIS is a novel clinical trial that prospectively evaluates whether combination multisite SBRT and IO can induce early ctDNA responses in patients with 3-10 metastases, generating biomarker-linked efficacy and safety signals to inform larger studies. Current enrollment: 1. Clinical trial information: NCT07269080.

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