Metastasis-directed radiotherapy without systemic therapy for oligometastatic clear-cell renal-cell carcinoma: primary efficacy analysis of a single-arm, single-centre, phase 2 trial.

BACKGROUND

Select patients with metastatic clear-cell renal-cell carcinoma can be treated without systemic therapy, yet few studies have explored this population. We investigated the efficacy of metastasis-directed therapy without systemic therapy in oligometastatic clear-cell renal-cell carincoma.

METHODS

This investigator-initiated single-arm, phase 2 trial enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, histologically confirmed clear-cell renal-cell carcinoma, and one to five metastases. Patients remained off systemic therapy and underwent metastasis-directed therapy to all disease sites, with additional metastasis-directed therapy for limited progression. Co-primary endpoints were progression-free survival based on Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) in the per-protocol population (patients who received radiation to at least one metastatic lesion during their initial local treatment) and systemic therapy-free survival in the intention-to-treat population. Progression-free survival was defined as the interval from enrolment to the first instance of disease progression, according to RECIST 1.1, or clinical progression, or death from any cause. Systemic therapy-free survival was defined as time from enrolment to initiation of systemic therapy or death from clear-cell renal-cell carcinoma. A prespecified 24-month median systemic therapy-free survival was the threshold for success. Safety was analysed in the per-protocol population. This trial is registered with ClinicalTrials.gov, NCT03575611, and is closed to new patient enrolment.

FINDINGS: Between July 13, 2018, and May 2, 2023, 121 patients were enrolled and included in the intention-to-treat population, of whom 120 received at least one round of definitive radiotherapy and were included in the per-protocol and safety populations. Median follow-up time for the 121 enrolled patients was 36·3 months (IQR 26·5-51·1). Median progression-free survival was 17·7 months (95% CI 14·9-22·4), and median systemic therapy-free survival time was 34·0 months (28·3-54·1). The median and lower bound of 95% CI of the median systemic therapy-free survival time exceeded the prespecified 24-month target. Eight (7%) of 120 patients had grade 3-4 adverse events at least possibly attributable to metastasis-directed therapy. The most common grade 3 event was pain near the treatment site (four events). The single grade 4 event was hyperglycaemia. There were no treatment-related deaths.

INTERPRETATION: Select patients with oligometastatic disease can be managed with serial metastasis-directed therapy with prolonged time off systemic therapy, favourable progression-free survival, and limited adverse events.

FUNDING: Cancer Prevention and Research Institute of Texas, US National Cancer Institute, and Myriad Genetics.