Stereotactic ablative radiotherapy (SABR) is gaining traction as a promising approach in the management of renal cell carcinoma (RCC), offering potential benefits in both oligometastatic and oligoprogressive disease settings. Recent data presented at the 2024 American Society for Radiation Oncology (ASTRO) Annual Meeting and in various publications highlight the strategies and evidence supporting SABR's role in metastasis-directed therapy (MDT) and its potential to improve patient outcomes.
SABR for Oligometastatic RCC
In patients with oligometastatic RCC (≤5 metastatic lesions), SABR has shown promise as a systemic therapy-sparing strategy. A single-arm phase II feasibility trial led by Dr. Chad Tang demonstrated that MDT with SABR resulted in a median progression-free survival of 22.7 months, with a 1-year progression-free survival of 64%. Notably, many participants underwent multiple rounds of SABR, and the treatment was associated with a favorable toxicity profile, with only 10% experiencing grade 3 or 4 adverse events.
These findings are supported by an analogous phase II trial from UT Southwestern, which reported a 1-year progression-free survival of 83% and a 1-year systemic therapy-free survival of 91%, with a grade ≥3 toxicity rate of 4%.
The EA8211/SOAR trial, an ongoing phase III randomized trial, is further investigating SABR in oligometastatic RCC. This non-inferiority trial randomizes patients to SABR alone (with systemic therapy at progression) versus systemic therapy alone, with overall survival as the primary endpoint. The rationale behind this design is that SABR is significantly less expensive ($20-50K annually) compared to doublet immunotherapy regimens ($150-300K annually), has a more favorable toxicity profile, and requires less frequent healthcare visits, according to Dr. Tang.
SABR and Pembrolizumab
Further evidence supporting MDT comes from the KEYNOTE-564 trial of adjuvant pembrolizumab. This trial showed that adjuvant pembrolizumab significantly improved overall survival in high-risk RCC patients who underwent nephrectomy (HR: 0.62, 95% CI: 0.44–0.87, p=0.005). Subgroup analysis revealed the highest survival benefit in the M1 NED subgroup, which received upfront MDT.
The phase II RAPPORT trial evaluated the sequential combination of MDT followed by pembrolizumab in 30 patients with oligometastatic clear cell RCC. Patients received SABR (20 Gy in 1 fraction) or palliative radiotherapy (30 Gy in 10 fractions) followed by 6 months of pembrolizumab. The median progression-free survival was 16 months, with a favorable adverse event profile (grade 3: 13%), and 63% of patients experienced a complete or partial response.
Building on these results, Dr. Tang and colleagues have initiated a randomized phase II trial comparing radiotherapy to all sites of visible disease followed by pembrolizumab for 1 year versus observation in oligometastatic RCC patients. The primary endpoint is progression-free survival.
SABR for Oligoprogressive Disease
In patients with oligoprogressive RCC, defined as those with a limited number of growing lesions despite active systemic therapy, MDT with SABR has also shown promise. Two trials (Cheung et al., European Urology, 2021; Hannan et al., European Urology Oncology, 2022) evaluated SABR to all sites of progressive disease while continuing systemic therapy. Both trials demonstrated similar results, with a median progression-free survival of approximately 1 year and a grade ≥3 toxicity rate of ≤5%.
The EXTEND-OP trial is randomizing oligoprogressive patients to next-line systemic therapy versus local consolidative therapy to all oligoprogressive sites and continued same-line systemic therapy.
SABR for Primary RCC Lesions and Variant Histologies
SABR is also being explored for the treatment of primary RCC lesions. The CYTOSHRINK trial (NCT04090710) is randomizing patients with untreated, IMDC intermediate/poor risk RCC to SABR to the primary RCC lesion plus ipilimumab/nivolumab versus ipilimumab/nivolumab alone. NRG GU-012 (NCT05327686) is randomizing IMDC intermediate/poor risk RCC patients to standard immunotherapy with or without SABR to the primary tumor.
The ITALIC-RCC trial randomizes patients based on primary tumor lesion size, evaluating anti-PD-1-based therapy with or without radiotherapy or surgery for tumors ≤4 cm and anti-PD-1-based therapy with or without surgery for tumors >4 cm.
SABR is also being investigated for variant histology RCC, particularly renal medullary carcinoma, a rare and aggressive disease. A case series of 5 renal medullary carcinoma patients who had progressed on 1–3 lines of systemic therapy and received SABR to all sites of visible disease showed that 3/5 patients were rendered 'NED' and stopped systemic therapy without recurrence to date.
SABR for IVC tumor thrombi has also shown promise, with a multinational case series of 15 patients demonstrating symptom palliation in all patients and a radiographic response in 58%.
Dr. Tang concluded that SABR holds significant potential for treating advanced RCC patients, offering a range of applications from metastasis-directed therapy to treatment of primary lesions and variant histologies.
