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.
This trial enrolled 121 patients with oligometastatic ccRCC who were eligible to receive definitive radiotherapy to all sites of disease. Ninety percent had 1-2 metastasis. The majority of patients had ECOG and IMDC scores of 0-1. Pre-treatment included systemic therapy (30% pazopanib or nivolumab and ipilimumab), metastasectomy (32%), radiotherapy (16%) and ablation (8%). Ninety-eight percent of patients had undergone nephrectomy, with median interval of 71 months, and the median time from metastases detection was 10 months. The most common metastases sites were lungs and lymph nodes, and the median gross tumour volume was 5.7 cm3. The most common radiation fractionation was 40–50 Gy in four fractions and two patients underwent metastasectomy. Fifty-nine percent received subsequent rounds of metastases-directed therapy. Median progression-free survival was 17.7 months (14.9-22.4) and the median systemic therapy-free time was 34 months (28.3-54.1). Seven percent experienced grade 3 treatment-related adverse events.
In addition, the authors evaluated ctDNA molecular residual disease status as a potential biomarker to select patients for systemic therapy or metastases directed therapy.
This paper demonstrated that, for patients with a small number of metastases, subsequent focal treatment could prolong the systemic therapy-free interval, thereby reducing toxicity and extending the time between changes in systemic therapy lines – particularly important when limited systemic treatment options are available.
This trial includes the largest number of patients and the longest follow-up in this setting. However, these patients experienced a long interval between nephrectomy and the development of metastases, had been pretreated with various modalities, and generally had favourable disease characteristics. Therefore, careful patient selection for this approach is crucial (1).
The authors also evaluated patient selection using ctDNA, which may serve as a valuable biomarker to distinguish those who would benefit more from systemic therapy in aggressive disease versus focal therapy in more indolent cases.
Since this was a single-arm trial, it remains unclear whether a similar population would achieve better outcomes with active surveillance, continued systemic therapy, or a combination of systemic therapy and metastasis-directed treatment. Nevertheless, the progression-free survival observed in this study is comparable to that reported in patients receiving first-line doublet systemic therapy.
Currently, there are limited data on patients with good or intermediate prognostic profiles receiving dual immune checkpoint inhibition (ICI), both with and without focal therapy. However, the ongoing EXTEND-OP trial is assessing survival outcomes with focal therapy added to systemic therapy versus systemic therapy alone in various tumour types, including kidney cancer, and may provide further evidence in the near future.
Ref
1. The Role of Stereotactic Ablative Body Radiotherapy in Renal Cell Carcinoma. Ali, Muhammad et al. European Urology, Volume 82, Issue 6, 613 – 622