A phase 2 clinical trial has demonstrated that metastasis-directed radiotherapy administered without concurrent systemic therapy provides durable disease control and manageable toxicity in patients with oligometastatic clear cell renal cell carcinoma (RCC). The findings, presented at the 2025 Kidney Cancer Research Summit, suggest a potentially transformative approach that could delay or eliminate the need for costly systemic therapies while maintaining excellent outcomes.
Efficacy Results Show Promising Long-Term Control
With a median follow-up of 36.3 months, the trial (NCT03575611) achieved a median progression-free survival (PFS) of 34.0 months and a median systemic therapy-free survival (STFS) of 17.7 months. The 3-year overall survival reached 86.5%, demonstrating the durability of disease control with this targeted radiation approach.
These results compare favorably to surveillance alone, which was associated with a median STFS of 14.9 months in a previous phase 2 trial published in Lancet Oncology, according to the study investigators.
Biomarker Analysis Reveals Patient Selection Potential
The trial incorporated circulating tumor DNA (ctDNA) analysis to evaluate minimal residual disease (MRD) status as a potential biomarker for treatment selection and monitoring. At baseline, 60% of patients were MRD-positive, with a median tumor fraction of 22.5 parts per million. Notably, 25% of MRD-positive patients converted to MRD-negative status within three months of treatment.
Patients who were MRD-negative demonstrated significantly improved STFS compared to those who were MRD-positive since enrollment (HR, 2.75; 95% CI, 1.29-5.86; P = .006). This advantage was even more pronounced when assessed at the 3-month timepoint (HR, 4.42; 95% CI, 2.06-9.5; P <.0001).
Treatment Protocol and Patient Population
The trial enrolled patients with oligometastatic RCC with clear cell histology, up to 5 metastases, and either no prior systemic therapy or more than one month off prior systemic therapy. The treatment protocol involved standard-of-care imaging and biopsy, followed by stereotactic radiation with or without surgical local therapy to all sites of disease. Patients who experienced progression could restart the treatment cycle, while those without progression initiated systemic therapy.
Safety Profile Significantly Superior to Systemic Therapies
The safety profile of metastasis-directed therapy proved markedly superior to standard systemic treatments. Grade 2 or higher adverse events occurred in 20.8% of patients, while grade 3 or higher adverse events affected only 6.7% of patients. Only one patient experienced grade 3 toxicities, and there was a single grade 4 adverse event (hyperglycemia).
The most common grade 2 adverse events included musculoskeletal pain (n = 10), pneumonitis (n = 5), cough (n = 3), and dyspnea (n = 2). Grade 3 adverse events were primarily musculoskeletal pain (n = 5) and leukocytosis (n = 2).
This contrasts sharply with systemic therapies, where grade 3 or higher toxicities occur in 45% to 85% of patients receiving immunotherapy or tyrosine kinase inhibitors.
Economic Advantages Over Standard Care
The economic implications of this approach are substantial. While immunotherapy alone or in combination, or tyrosine kinase inhibitor therapy costs approximately $150,000 to $300,000 per year, stereotactic body radiation therapy costs only $15,000 to $40,000 per round. Additionally, the reduced clinic visit frequency—1 to 2 visits per radiation round versus at least monthly visits for systemic therapy—further reduces healthcare resource utilization.
Clinical Implications and Future Directions
"Metastasis directed therapy without systemic therapy offers advantages in costs, toxicities, and clinic visits over frontline systemic therapies," wrote presenting study author Chad Tang, MD, an associate professor in the departments of Radiation Oncology, Translational Molecular Pathology, and Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center.
Tang and his coauthors emphasized that biomarkers are needed both at baseline to select appropriate patients and after metastasis-directed therapy to guide decisions between surveillance and systemic therapy. They noted that circulating tumor DNA via second-generation assays has the potential to inform both roles.
The trial's co-primary endpoints were PFS per RECIST v1.1 and STFS, with the goal of achieving a median STFS greater than 25 months. While the achieved median STFS of 17.7 months fell short of this ambitious target, the overall survival and safety benefits, combined with the significant cost advantages, suggest this approach merits further investigation and potential integration into clinical practice for carefully selected patients with oligometastatic RCC.
