In 2025, the field of renal cell carcinoma (RCC) advanced decisively along the dual pathways of precision and combination therapy. Landmark developments reshaped clinical practice across disease stages: perioperative targeted–immunotherapy combinations that altered surgical paradigms for locally advanced disease; long-term survival data confirming the durability of first-line immunotherapy-based regimens; innovative later-line strategies overcoming therapeutic resistance; and biomarker-driven approaches enabling molecularly guided treatment for rare non–clear cell subtypes.Oncology Frontier – Urology Stream invited Prof. Xinan Sheng from Peking University Cancer Hospital to provide an in-depth review of the pivotal breakthroughs in RCC during 2025 and to outline future directions at the forefront of global research.
Advances in Perioperative Therapy for RCC
1. Neoadjuvant Therapy
In 2025, multiple studies explored targeted therapy combined with immunotherapy, as well as dual immunotherapy, in high-risk localized or locally advanced RCC. The aim was to achieve tumor downstaging prior to surgery, optimize surgical strategies, and improve long-term outcomes.
The earlier NEOAVAX study evaluated neoadjuvant avelumab plus axitinib in high-risk localized clear cell RCC (ccRCC). Among 40 enrolled patients, 30% achieved partial response after 12 weeks of treatment, with a mean tumor reduction of 20%. With a median follow-up of 52.9 months, median disease-free survival (DFS) reached 25.1 months. Exploratory analyses revealed that high densities of CD8+CD39+ T-cell infiltration in postoperative specimens were strongly associated with prolonged DFS, and patients achieving major pathological response (MPR) experienced superior outcomes. These findings underscore the importance of the tumor immune microenvironment as a predictive biomarker.
For locally advanced ccRCC with inferior vena cava tumor thrombus, several Chinese studies investigated neoadjuvant immunotherapy plus targeted therapy. In the phase II NEOTAX trial evaluating toripalimab plus axitinib, 90% of patients experienced thrombus shrinkage, with 45% achieving thrombus downstaging. The objective response rate (ORR) was 37.5%, and over half of patients were able to undergo optimized surgical planning. One-year progression-free survival (PFS) reached 87.5%, highlighting the transformative potential of neoadjuvant therapy.
Dual immunotherapy strategies were also examined. The NESCIO study presented at ESMO 2025 compared nivolumab monotherapy, nivolumab plus ipilimumab, and nivolumab plus relatlimab in localized intermediate- to high-risk RCC. Dual immunotherapy arms achieved the predefined primary endpoint, with 14.3% of patients reaching near-pathologic complete response (pCR) or pCR, whereas nivolumab monotherapy did not. These results suggest enhanced pathological response induction with combination immunotherapy.
Collectively, these data demonstrate that neoadjuvant targeted–immunotherapy and dual immunotherapy regimens can induce meaningful radiologic and pathologic responses, modulate the tumor microenvironment, and expand surgical opportunities in selected patients.
2. Adjuvant Therapy
For patients at high risk of recurrence after surgery, adjuvant immunotherapy has become an important strategy.
Long-term follow-up from the KEYNOTE-564 trial reinforced the standard role of pembrolizumab. With a median follow-up of nearly six years, adjuvant pembrolizumab reduced the risk of death by 34% compared with placebo (OS HR 0.66), and sustained DFS benefit was observed. No new safety signals emerged.
The phase III RAMPART trial evaluated durvalumab alone or combined with tremelimumab versus active surveillance. After three years of follow-up, the combination arm demonstrated DFS benefit, particularly among high-risk patients, while no significant advantage was observed in intermediate-risk patients. These findings suggest that combination immunotherapy may offer deeper disease control in selected high-risk populations.
Together, KEYNOTE-564 and RAMPART confirm the value of adjuvant immunotherapy, while highlighting the importance of risk stratification in tailoring postoperative strategies.
Systemic Therapy for Metastatic RCC
1. First-Line Treatment of Advanced Clear Cell RCC
First-line treatment of metastatic ccRCC is now dominated by immunotherapy-based combinations, including dual checkpoint inhibition, immunotherapy plus VEGF-targeted therapy, and novel triplet regimens.
Long-term data from CheckMate 214 (median follow-up 108 months) demonstrated durable survival benefit of nivolumab plus ipilimumab compared with sunitinib. Eight-year overall survival (OS) rates reached 31% in the intention-to-treat population, confirming sustained benefit, particularly among PD-L1–positive patients.
Immunotherapy plus VEGF-TKI combinations—including pembrolizumab plus axitinib (KEYNOTE-426), nivolumab plus cabozantinib (CheckMate 9ER), and pembrolizumab plus lenvatinib (CLEAR)—continued to demonstrate superior PFS and OS compared with sunitinib. Notably, pembrolizumab plus lenvatinib achieved a median PFS of 23.1 months and ORR of 71%. Domestic regimens such as toripalimab plus axitinib and TQB2450 plus anlotinib further expanded treatment options.
Triplet regimens were investigated to enhance efficacy. However, final results from COSMIC-313 showed that adding cabozantinib to nivolumab plus ipilimumab did not improve OS and increased toxicity. Adaptive strategies such as PDIGREE, which tailor subsequent therapy based on initial response, aim to balance efficacy and safety.
Emerging regimens incorporating HIF-2α inhibitors have shown promise. In KEYMAKER-U03 sub-study 03A, adding belzutifan to pembrolizumab plus lenvatinib yielded an ORR of 77.5%, suggesting synergistic potential. Belzutifan also demonstrated strong activity in von Hippel–Lindau–associated RCC.
2. Second-Line and Later-Line Therapy
With widespread use of first-line immunotherapy combinations, optimizing subsequent therapy has become critical.
In KEYMAKER-U03 sub-study 03B, lenvatinib plus belzutifan showed encouraging activity after PD-1/PD-L1 inhibitor progression (ORR 46.9%; median PFS 12.5 months). By contrast, pembrolizumab plus belzutifan demonstrated more modest activity.
The phase III FRUSICA-2 trial reported that fruquintinib plus sintilimab significantly improved PFS compared with axitinib or everolimus after VEGF-TKI failure.
The phase II LenCabo trial provided head-to-head evidence that lenvatinib plus everolimus achieved superior ORR and PFS compared with cabozantinib following immune checkpoint inhibitor progression.
Belzutifan combined with cabozantinib also demonstrated meaningful activity in later-line settings, while showing particularly strong efficacy in treatment-naïve patients.
3. Treatment of Metastatic Non–Clear Cell RCC
Non–clear cell RCC (nccRCC) remains highly heterogeneous. Immunotherapy combinations have demonstrated activity across subtypes. The phase II SUNNIFORECAST trial showed improved ORR and 12-month OS with nivolumab plus ipilimumab compared with standard therapy.
For papillary RCC (pRCC), the CALYPSO study demonstrated that savolitinib plus durvalumab achieved improved outcomes in MET-driven disease. Circulating tumor DNA (ctDNA) status correlated strongly with prognosis.
Hereditary leiomyomatosis and RCC (HLRCC), driven by FH mutations, responded favorably to erlotinib plus bevacizumab. Similarly, FH-deficient RCC showed promising responses to sintilimab plus axitinib, particularly in germline mutation carriers.
These findings highlight the growing importance of molecular stratification in rare RCC subtypes.
Conclusion
The year 2025 marked comprehensive progress in RCC management. Perioperative targeted–immunotherapy strategies enhanced surgical outcomes; durable survival data reinforced immunotherapy-based first-line regimens; novel agents such as HIF-2α inhibitors expanded therapeutic boundaries; effective later-line combinations addressed resistance; and biomarker-driven strategies brought precision treatment to rare subtypes.
Looking ahead, deeper biomarker exploration, refinement of perioperative strategies, development of next-generation immunotherapies—including bispecific antibodies and antibody–drug conjugates—and global collaboration in rare subtypes will continue to shape the evolving treatment landscape of renal cell carcinoma.
Prof. Xinan Sheng
