Editor’s Note: Renal cancer is a common malignancy of the urinary system. For localized and locally advanced renal cancer without distant or extraregional lymph node metastases, surgical removal of the tumor or the affected kidney remains the primary treatment. Recent advances in targeted therapy and immunotherapy have expanded the options for perioperative treatment of renal cancer. In 2024, this field saw significant breakthroughs, and Dr. Liangyou Gu from the Chinese PLA General Hospital shared the latest research developments.

Surgical resection continues to be the cornerstone of treatment for localized renal cell carcinoma (RCC). For early-stage RCC (Stages I–II), guidelines from both domestic and international bodies recommend surgery as the primary treatment, including radical nephrectomy and partial nephrectomy. The choice of surgical method depends on factors such as the surgeon’s expertise, the resources of the medical institution, and the patient’s physical condition to balance the risks and benefits.

For advanced RCC, radical nephrectomy remains the primary treatment for locally advanced RCC (Stage III). In contrast, systemic therapy is the main approach for metastatic RCC (Stage IV), complemented by palliative surgeries, such as cytoreductive nephrectomy and removal of oligometastatic lesions.

Neoadjuvant Therapy for Partial Nephrectomy

Previous research has demonstrated that neoadjuvant treatments, including pazopanib, axitinib, and sunitinib, can allow some patients to transition from radical nephrectomy to partial nephrectomy. This shift has made partial nephrectomy an increasingly preferred approach in many medical centers for localized RCC.

In 2024, the PADRES study, a single-arm Phase II clinical trial, explored the effectiveness of axitinib as neoadjuvant therapy for patients with complex renal tumors who were candidates for partial nephrectomy. The study included patients with localized RCC (cT1b-cT3M0) and RENAL scores between 10 and 12. After axitinib treatment, patients underwent partial nephrectomy. The primary endpoint was the proportion of patients who successfully underwent surgery.

The study enrolled 27 patients with a median age of 69 years. Among them, 74% had tumors staged at T3a or higher before treatment. Results showed that axitinib significantly reduced tumor diameter (from 7.5 cm to 6.2 cm) and lowered RENAL scores (from 11 to 10). According to RECIST criteria, 33.3% of patients achieved partial remission, and 33.3% experienced clinical downstaging. A total of 74% of patients underwent partial nephrectomy, and 96.2% achieved negative surgical margins. These findings confirm that neoadjuvant therapy enables safe and effective partial nephrectomy in patients with complex renal tumors.

Neoadjuvant Therapy for Locally Advanced Renal Cancer

Around 30% of renal cancer patients present with locally advanced disease at diagnosis. Despite radical surgery, recurrence rates for these patients can reach up to 40%. Although no high-level evidence currently supports neoadjuvant therapy for non-metastatic locally advanced RCC (M0), adjuvant therapy has shown benefits in progression-free survival (PFS) and overall survival (OS) for high-risk patients. This has sparked interest in exploring preoperative neoadjuvant therapies as a potential strategy to improve outcomes.

In 2024, several important studies examined the role of neoadjuvant therapy in this context. A team from Nanjing Drum Tower Hospital conducted a clinical trial presented at the ASCO-GU conference, investigating the combination of tislelizumab and axitinib as neoadjuvant therapy for clear cell RCC (ccRCC). Among 13 patients enrolled, 9 completed surgery as planned, and the objective response rate (ORR) was 50%, demonstrating promising efficacy and manageable safety for the combination therapy.

Similarly, Renji Hospital conducted a Phase II clinical trial on toripalimab combined with axitinib for non-metastatic ccRCC patients (T2-3N0-1M0). After 12 weeks of treatment, the ORR reached 45%, with a median tumor reduction of 26.7%. Notably, four patients achieved pathological complete remission (pCR), demonstrating that this preoperative regimen effectively reduces tumor size and facilitates surgery.

A systematic review led by Professor Xu Zhang from the Chinese PLA General Hospital, published in Critical Reviews in Oncology/Hematology, analyzed 204 cases of RCC with venous tumor thrombus treated with neoadjuvant therapy. Results showed that most patients experienced reduced thrombus height (66.1%), although the overall thrombus downstaging rate was only 29.4%. Targeted therapies, particularly sunitinib and axitinib, were the most commonly used treatments, emphasizing their potential in optimizing surgical conditions.

The NEOTAX study, also led by Professor Xu Zhang and presented at ESMO 2024, explored the efficacy of toripalimab combined with axitinib for RCC patients with inferior vena cava (IVC) thrombus. Among the 25 patients enrolled, 44% achieved thrombus downstaging, with a median reduction in thrombus height of 2.3 cm. This adjustment simplified surgical strategies for 61.9% of patients, and the one-year PFS rate was 89.1%, highlighting the potential of neoadjuvant therapy in improving short-term outcomes for locally advanced RCC.

Tackling Resistance to Neoadjuvant Therapy

While neoadjuvant therapies have shown promising results, resistance remains a challenge for some patients. At the 2024 ESMO Asia conference, the NEOTAX team presented insights into resistance mechanisms based on single-cell sequencing analyses of pre- and post-treatment samples. The findings revealed an increased presence of SAA+ tumor cells and LDHA+ neutrophils, along with a decrease in CCL5+CD8+ T cells. These unique cellular populations were found to mediate resistance through metabolic remodeling, ultimately leading to the irreversible exhaustion of CCL5+CD8+ T cells.

Animal studies further demonstrated that targeting SAA can enhance the effectiveness of combination therapies in renal cancer models, suggesting that SAA may be a promising target for overcoming resistance to neoadjuvant treatments in RCC with venous tumor thrombus.

Adjuvant Therapy for Locally Advanced Renal Cancer

Following the success of targeted therapies in metastatic renal cancer, VEGF-targeted adjuvant treatments have been actively explored. However, with the exception of the S-TRAC trial, none of these studies have achieved the primary endpoint of improved disease-free survival (DFS). In contrast, immunotherapy-based approaches have shown promise, with the KEYNOTE-564 study emerging as the first randomized Phase III trial to report positive outcomes for adjuvant immunotherapy in renal cancer.

The KEYNOTE-564 study evaluated the efficacy and safety of pembrolizumab as adjuvant therapy in patients with intermediate-high or high-risk renal cell carcinoma (RCC) following surgery. In 2021, based on its demonstrated DFS benefit (28% reduction in recurrence risk, HR = 0.72), pembrolizumab received FDA approval for adjuvant treatment of RCC patients who underwent nephrectomy or resection of metastatic lesions. The third interim analysis, presented at the 2024 ASCO GU conference and published in the New England Journal of Medicine (NEJM), confirmed these findings.

This double-blind, placebo-controlled Phase III trial enrolled 994 patients aged 18 years or older, all of whom had undergone nephrectomy and/or metastasectomy within 12 weeks prior to randomization. Patients had increased risk of recurrence and an ECOG performance status of 0 or 1. The primary endpoint was DFS, with overall survival (OS) as a key secondary endpoint. Consistent with earlier results, pembrolizumab reduced the risk of death by 38% (HR = 0.62, P = 0.005), with a 48-month OS rate of 91.2% compared to 86.0% in the placebo group. All major subgroups benefited similarly, establishing pembrolizumab as a new option for adjuvant therapy in intermediate-high-risk RCC patients.

For patients with extremely high-risk clear cell RCC, the Chinese PLA General Hospital conducted a study on the efficacy and safety of adjuvant treatment with penpulimab. By October 24, 2024, a total of 81 patients with extremely high recurrence risk (e.g., pT3a G3-4 N0M0 or pT3b N0M0) were enrolled. The treatment group included 42 patients, while 39 received standard care. Penpulimab showed a significant benefit, reducing the risk of disease progression by 68.8% (HR = 0.312, P = 0.046), although the median DFS was not reached in the treatment group. Adverse events were manageable, with the most common being mild rash (30.95%), proteinuria (16.67%), and fatigue (11.9%). These results confirmed penpulimab as an effective and well-tolerated adjuvant therapy for extremely high-risk RCC.

Conversion Therapy for Unresectable or Metastatic Renal Cancer

For patients with unresectable or metastatic renal cancer, preoperative targeted therapy can offer survival benefits. The SURTIME trial demonstrated that delaying cytoreductive nephrectomy after initial treatment with sunitinib resulted in improved overall survival compared to immediate surgery followed by sunitinib. Additionally, real-world studies have confirmed that first-line dual immunotherapy provides better DFS outcomes for patients with metastatic RCC (mRCC).

At the 2024 ESMO conference, findings from three ongoing prospective studies were presented, providing new evidence on the combination of cytoreductive nephrectomy and immunotherapy. These studies aim to clarify the timing, sequence, patient selection criteria, and post-treatment management strategies for this combination approach, offering valuable guidance for clinical practice.

About Dr. Liangyou Gu

• Current Positions: Deputy Chief Physician and Associate Professor, Department of Urology, Chinese PLA General Hospital Master’s Supervisor
• Professional Affiliations: Secretary, Clinical Research Office, Chinese Urological Association Member, Basic and Translational Medicine Group, Beijing Urological Society Member, Renal Cancer Specialty Committee, Chinese Anti-Cancer Association
• Research Contributions: Selected as part of the Beijing Science and Technology Star Program in 2023 Principal Investigator for two National Natural Science Foundation projects and two institutional research projects Published 35 papers as the first or corresponding author in journals such as Science Translational Medicine, Innovation, European Urology, Cancer Treatment Reviews, Journal of Urology, and Cancer Five publications with an impact factor exceeding 10 Research findings presented at international conferences, including ESMO, EAU, SIU, and UAA
• Editorial and Peer Review Roles: Editorial Board Member for BMC Urology and Frontiers in Oncology Reviewer for journals including Cancer Letters and Surgery
• Awards and Recognition: First-Class Chinese Medical Science and Technology Award First-Class Medical Achievement Award and Second-Class Scientific Progress Award from the Chinese PLA General Hospital