Renal cell carcinoma (RCC) is a significant malignancy that arises from the epithelial lining of the renal tubules. Within the spectrum of urinary tract malignancies encountered in clinical practice, RCC accounts for 3–5% of all adult cancer diagnoses. Major risk factors include smoking, obesity and hypertension (1). According to data from the Centers for Disease in the United States, patients with localized RCC have a 80–90% 5-year survival rate, contrasting sharply with the rates for recurrent or metastatic disease (10–40%) (2). In China, the incidence of kidney cancer ranks third among urological tumors, following bladder cancer and prostate cancer (3). In patients with kidney cancer, ~30% present with distant metastases at the time of initial diagnosis (4). Therefore, the implementation of effective treatment strategies is critical for improving patient outcomes.

With the success of the CLEAR, KEYNOTE and CheckMate series of studies, the management of recurrent or metastatic RCC has entered an era of combined targeted and immune therapy (target-immunotherapy). In the treatment guidelines for kidney cancer from the National Comprehensive Cancer Network (5), the European Association of Urology (6) and the Chinese Society of Clinical Oncology (7), the combination of axitinib and programmed cell death protein 1 (PD-1) inhibitors is recommended as one of the first-line therapeutic options for recurrent or metastatic RCC. This combination significantly prolongs the median progression-free survival (PFS) time compared with targeted therapy alone (15.4 vs. 11.1 months; P<0.0001) (8). Toripalimab, a PD-1 monoclonal antibody developed in China, has demonstrated promising results in the RENOTORCH study (axitinib combined with toripalimab), achieving a median PFS time of 18 months in patients with advanced RCC (9). In April 2024, the combination of axitinib and toripalimab was officially approved by the National Medical Products Administration of China as a first-line treatment for patients with recurrent or metastatic RCC.

Despite these advances, most patients experience disease progression within 1–2 years of initiating combined targeted and immunotherapy (9–13). Extending overall survival (OS) time for patients with advanced RCC remains a notable challenge. The potential of incorporating lesion radiotherapy to improve PFS warrants further exploration.

Previous studies have demonstrated that RCC is not particularly sensitive to conventional fractionated radiotherapy (14,15). However, previous evidence suggests that stereotactic ablative body radiotherapy (SABR), characterized by high single-dose fractions, high biological efficacy and fewer treatment sessions, can markedly enhance the radiosensitivity of RCC (16). SABR has demonstrated notable efficacy and safety in treating recurrent and metastatic RCC lesions (17–19), with reported 1-year local control (LC) rates >90% (20). Higher biological effective dose (BED) values are associated with improved LC rates, with 1-year LC rates reaching 100% when the BED is 117 Gy (21).

Based on these findings, a single-center, prospective study was initiated to evaluate the combination of axitinib and toripalimab with SABR for the treatment of recurrent or metastatic RCC.

The present study explored the application of SABR in conjunction with targeted therapy using axitinib and immunotherapy with toripalimab for patients with recurrent or metastatic RCC. To the best of our knowledge, the present study is the only prospective study to date that integrates targeted therapy, immunotherapy and radiotherapy in a triple-modality approach for recurrent or metastatic RCC, and preliminary results indicate promising efficacy.

The treatment landscape for recurrent or metastatic RCC has entered the era of combined targeted therapy and immunotherapy. Since 2018, multiple large-scale, international, multicenter clinical trials have demonstrated that immunotherapy with PD-1/L1 monoclonal antibodies, when combined with targeted therapy, markedly improves first-line treatment outcomes for advanced RCC compared with the TKI sunitinib. Notable randomized controlled trials such as JAVELIN Renal 101, KEYNOTE-426, CheckMate 9ER and CLEAR have reported median PFS times ranging from 13.3 to 23.3 months, which is markedly superior to those for sunitinib monotherapy (10–13). However, the application of combined targeted therapy and immunotherapies remains limited in China due to the lack of regulatory approval.

Toripalimab, the first approved fully human monoclonal antibody targeting the PD-1 receptor in China, exhibits higher affinity for PD-1 compared with pembrolizumab and nivolumab, and possesses a unique IgG4 binding site that does not rely on glycosylation modifications (24). Clinical studies across various disease areas have demonstrated its efficacy (25–27), and it is currently approved for the treatment of advanced melanoma, nasopharyngeal carcinoma and urothelial carcinoma. Phase I clinical trials have reported effective treatment responses in patients with advanced RCC (28). The results of the randomized controlled phase III trial, RENOTORCH, presented at the 2023 European Society for Medical Oncology Congress, indicated a median PFS time of 18.0 months for patients with advanced RCC treated with the combination of axitinib and toripalimab compared with sunitinib, with a favorable safety profile (9). Notably, the patients included in the RENOTORCH study were categorized as intermediate- to high-risk, and comparisons with high-risk cohorts from the JAVELIN Renal 101, KEYNOTE-426, CheckMate 9ER and CLEAR studies revealed longer median PFS times for the axitinib plus toripalimab combination compared with sunitinib, with PFS remaining a critical focus in the comprehensive treatment of advanced RCC.

SABR has emerged as a principal non-surgical treatment modality for patients with recurrent or metastatic RCC in conjunction with targeted therapy and immunotherapy, gaining increasing recognition in current clinical guidelines (5,6). However, the current guidelines primarily position SABR as a means to enhance LC rates, without fully acknowledging its potential role in improving OS as part of a combination treatment strategy.

Previous studies have reported positive outcomes for the combination of targeted therapy and SABR in patients with oligometastatic RCC. Preliminary results from a prospective phase II clinical trial presented at the 2023 American Society of Clinical Oncology meeting indicated that the combination of sunitinib and SABR in treatment-naïve patients with oligometastatic RCC achieved a significantly longer median PFS time of 18.6 months compared with the sunitinib monotherapy group (7.1 months; P=0.003), with no notable difference in the incidence of treatment-related adverse events between the two groups (29). A retrospective analysis by Ma et al (30) of patients receiving TKI therapy combined with SABR for oligometastatic RCC from 2015 to 2020, involving 100 lesions with 90% classified as intermediate to high-risk, indicated a median PFS time of 22 months for those receiving combined treatment during first-line therapy. Notably, preclinical evidence suggests that SABR can synergistically enhance the sensitivity of associated pathways inhibited by targeted therapy, including AKT and mTOR pathways, which provides a further biological basis for clinical research (31–33). Additionally, accumulating evidence has demonstrated that SABR-induced immunogenic cell death facilitates the release of tumor-associated antigens, which subsequently triggers dendritic cell maturation and initiates systemic cytotoxic T-cell responses, thereby remodeling the immunosuppressive tumor microenvironment (34,35). Based on these research outcomes, previous studies have investigated the efficacy of immunotherapy combined with SABR; however, the median PFS time reported (5.6 to 15.6 months) has not been optimal, possibly related to insufficient radiation dose and delayed treatment lines (36–38).

The present study preliminarily explored the efficacy and safety of combining axitinib with toripalimab, an anti-PD-1 monoclonal antibody developed in China, and SABR for patients with recurrent or metastatic RCC. The present study included patients who had received second-line or subsequent therapies, with a high proportion of intermediate to high-risk patients (66.7%) and 30.0% being non-clear cell RCC. Preliminary results indicated a median PFS1 time of 20.3 months, with patients receiving first-line targeted therapy and immunotherapy combined with radiotherapy achieving a PFS1 time of 28.6 months. This outcome surpasses data from studies that utilized axitinib combined solely with immunotherapy (median PFS time ranging from 13.8 to 18.0 months) (9,11,13). The median OS time reached 44.8 months, showing no notable difference compared with previous studies (9,11,13), potentially due to insufficient follow-up duration.

Subgroup analyses revealed that PFS1 time was significantly longer for patients who received radiotherapy before treatment failure compared with those who received it afterward. Early radiotherapy intervention before first-line treatment failure may lead to better PFS due to lower tumor burden, a more favorable immune microenvironment and the opportunity to proactively control disease progression (20,31). The OS subgroup analysis revealed a significant survival gradient across IMDC risk strata: Median OS was not reached in the low-risk group, while median OS time was 47.2 months in the intermediate-risk group and declined to 24.6 months in the high-risk group, which implies that combining radiation with systemic therapy may amplify benefits in less aggressive disease states, while high-risk tumors likely harbor intrinsic resistance mechanisms that diminish therapeutic impact.

In terms of safety, the observed 50.0% incidence of grade ≥3 adverse events with the axitinib-toripalimab-SABR triple-modality therapy were below the rates reported in contemporary TKI/immune-checkpoint inhibitor combinations (67–70% in CheckMate 9ER/KEYNOTE-426) (10,13). There were no occurrences of grade ≥3 radiotherapy-associated adverse reactions, suggesting that the triple-modality regimen may not inherently exacerbate the toxicity profile of the underlying targeted therapy-immunotherapy combination. The most common reasons for discontinuation of targeted therapy and immunotherapy were hepatic dysfunction, diarrhea and gastrointestinal bleeding. These findings indicate the need for heightened vigilance regarding liver function and gastrointestinal responses when administering the axitinib and toripalimab combination.

Furthermore, challenges arose in administering adequate SABR doses due to the presence of large metastatic lesions or their proximity to critical organs. The present study introduced the p-SABR technique, which allowed for dose escalation at the tumor center while maintaining a total dose of 50–60 Gy, thereby optimizing tumor targeting while protecting adjacent critical structures. The institutional protocol prioritizes SABR as the primary radiotherapy modality. The p-SABR approach (combining SABR for tumor core with MHFRT for peripheral regions) is reserved for larger tumors with notable adjacent normal tissue involvement, while MHFRT is typically employed for smaller tumors surrounded by critical structures. For example, in the present study cohort, one patient's tumor was located in the abdominal wall and near the bowel, but the patient chose SABR technology for personal reasons. A controlled dose compromise was strategically accepted in the peripheral target area to maximize SABR coverage of the predominant tumor volume while maintaining bowel sparing. However, the patient experienced a recurrence due to marginal underdosage in the tumor target area. This outcome indicated that choosing p-SABR technology for suitable patients may provide greater benefits compared with traditional SABR technology.

The limitations of the present study include its single-arm design, small sample size and short follow-up for OS endpoints. Due to the exploratory trial design and the ongoing nature of this research, the present publication presents preliminary findings based on a limited sample size (n=30), which inherently restricts the statistical power of the analyses. To enhance the validity of these observations, patient enrollment is actively being expanded and extended follow-up protocols will be implemented in subsequent phases of the investigation. The single-arm design introduces potential confounding factors such as heterogeneous disease burden, variability in prior therapies and IMDC risk stratification, which may compromise outcome interpretation. While propensity score weighting could theoretically mitigate some confounding factors, its applicability remains limited in small single-arm cohorts (n<100). Future randomized trials stratified by confounding factors are warranted to validate the present findings. Future studies will also investigate potential biomarkers associated with the immune-activating effects of SABR in metastatic RCC, such as circulating free DNA and microRNAs, which have been identified as predictors of immunotherapy response in patients with oligoprogressive lung cancer receiving combined SABR and immunotherapy (39). These investigations will aim to further evaluate the efficacy of the triple combination therapeutic regimen.

In conclusion, the combination of axitinib, toripalimab and SABR for the treatment of recurrent or metastatic RCC demonstrates manageable adverse effects and shows preliminary efficacy in clinical practice. Whether this combination ultimately improves PFS and OS will require further validation through long-term follow-up results. In the future, a two-arm randomized trial of axitinib and toripalimab vs. the triple-modality of axitinib, toripalimab and SABR will be performed, to confirm the efficacy and safety of the triple combination therapy and explore the correlative biomarkers.