Since the release of the CSCO Renal Cancer Diagnosis and Treatment Guidelines in 2013, the guidelines have undergone eight updates, significantly advancing the standardization of renal cancer management in China. Over the past year, significant progress has been made globally and domestically in renal cancer treatment, particularly in medical therapies that have influenced clinical practice. In light of this, the CSCO Renal Cancer Expert Committee discussed and revised the 2024 edition of the guidelines. At the recent 14th Shanghai Urological Oncology Academic Conference and Annual Meeting of the Chinese Anti-Cancer Association Male Reproductive System Oncology Committee (CACA-GO), Dr. Guohai Shi from Fudan University Shanghai Cancer Center provided an in-depth interpretation of the updated guidelines. Below is a summary of his insights.

Strategies for First-Line Treatment of ccRCC

The guidelines emphasize stratifying treatment for patients with advanced clear cell renal cell carcinoma (ccRCC) based on risk categories. Prognostic assessment models, such as the International Metastatic RCC Database Consortium (IMDC), are recommended to comprehensively evaluate tumor pathology, clinical characteristics, and laboratory data. This approach aids in determining prognosis and guiding treatment selection.

First-Line Treatment for Low-Risk mccRCC

For patients with low-risk metastatic or unresectable ccRCC (mccRCC), monotherapy with tyrosine kinase inhibitors (TKIs) remains the primary option. Level I recommendations include sunitinib (1A), pazopanib (1A), and sorafenib (2A). Clinical studies such as Sternberg, COMPARZ, and SPAZO have provided substantial evidence supporting the efficacy and survival benefits of pazopanib in this patient group.

Conversely, combination therapies with immunotherapy and targeted therapy have not shown survival advantages over monotherapies in several Phase III clinical trials. The 5-year analysis of the KEYNOTE-426 study demonstrated no difference in overall survival (OS) between pembrolizumab plus axitinib and sunitinib in IMDC low-risk patients (HR 1.10, 95% CI: 0.79–1.54). Similarly, the 4-year follow-up of the CLEAR trial revealed comparable OS outcomes between lenvatinib plus pembrolizumab and sunitinib in low-risk patients (HR 0.94, 95% CI: 0.58–1.52). The 55-month follow-up of the CheckMate 9ER trial also showed no improvement in OS with nivolumab plus cabozantinib compared to sunitinib (HR 1.10, 95% CI: 0.69–1.75).

First-Line Treatment for Intermediate/High-Risk mccRCC

For intermediate- or high-risk metastatic or unresectable ccRCC, the updated guidelines prioritize immune-targeted combination therapies as Level I recommendations, while dual immunotherapy combinations have been elevated to Level II recommendations.

These updates are based on evidence from several recent studies.

• The RENOTORCH study, presented at ESMO 2023, reported that in intermediate- and high-risk populations, toripalimab plus axitinib reduced the risk of disease progression or death by 35% compared to sunitinib (HR 0.65, 95% CI: 0.49–0.86, P = 0.0028), with a trend toward improved OS (HR 0.61, 95% CI: 0.40–0.92).
• The 5-year analysis of the KEYNOTE-426 study, presented at ASCO 2023, showed OS (HR 0.76, 95% CI: 0.62–0.93) and progression-free survival (PFS) (HR 0.68, 95% CI: 0.56–0.82) benefits with pembrolizumab plus axitinib compared to sunitinib in intermediate/high-risk patients.
• The 4-year follow-up of the CLEAR trial also demonstrated PFS (HR 0.43, 95% CI: 0.34–0.55) and OS (HR 0.74, 95% CI: 0.57–0.96) advantages for lenvatinib plus pembrolizumab over sunitinib in intermediate/high-risk patients.
• The CheckMate 9ER study, presented at ASCO GU 2024, confirmed that nivolumab plus cabozantinib improved PFS (HR 0.56, 95% CI: 0.45–0.68) and OS (HR 0.73, 95% CI: 0.58–0.91) in intermediate/high-risk patients compared to sunitinib.
• Meanwhile, the CheckMate 214 study, with a median follow-up of 80 months, revealed that nivolumab plus ipilimumab improved PFS (HR 0.73, 95% CI: 0.61–0.87) and OS (HR 0.69, 95% CI: 0.59–0.81) compared to sunitinib in this population.

Additionally, novel bispecific antibodies, such as the anti-PD-1 antibody epalurimab combined with the anti-CTLA-4 antibody toripalimab, are expected to offer more effective treatment options in the future.

ccRCC Second-Line Treatment Strategies

The updated CSCO guidelines encourage all patients undergoing second-line treatment to actively participate in clinical trials. Stratified treatment recommendations are made based on prior therapies.

For patients who experience failure with first-line targeted therapy, sequential use of other unused treatments is suggested. Studies have demonstrated the efficacy of axitinib, cabozantinib, sorafenib, everolimus, pazopanib, or nivolumab as single-agent therapies for those who fail targeted treatments. In China, the CONCEPT study investigated famitinib combined with everolimus as a dual-target second-line therapy. The results showed significant improvements in objective response rate (ORR) (24.8% vs. 8.3%; P = 0.0003) and median progression-free survival (PFS) (10.0 vs. 6.4 months; HR 0.70, 95% CI: 0.52–0.94; P = 0.0171) compared to everolimus alone.

After failure of first-line immunotherapy or immune-targeted combination therapy, sequential use of other treatment options remains effective, though robust evidence is still limited. Reported studies include LITESPARK-005, which showed that nivolumab brought a PFS of 5.6 months, overall survival (OS) of 21.4 months, and an ORR of 22.7%. In the KEYNOTE-146 study, lenvatinib combined with pembrolizumab achieved a median PFS of 12.2 months and an ORR of 55.8% in patients who failed immunotherapy. However, the randomized controlled CONTACT-03 study indicated that cabozantinib combined with atezolizumab did not outperform cabozantinib alone, showing no difference in ORR (41% vs. 41%) or PFS (10.6 vs. 10.8 months) in patients with prior immunotherapy failure.

Systemic Treatment Strategies for nccRCC

Non-clear cell renal cell carcinoma (nccRCC) is a rare and heterogeneous group of renal cancers with limited large-scale randomized controlled trials. The guidelines recommend that patients with metastatic or unresectable nccRCC primarily enroll in clinical studies, with current treatment strategies generally referencing ccRCC therapies.

Evidence for nccRCC remains limited. The ASPEN Phase II study in 2016 reported that sunitinib significantly prolonged PFS compared to everolimus in nccRCC patients (8.3 vs. 5.6 months, HR 1.41, 80% CI: 1.03–1.92, P = 0.16), particularly in low-risk MSKCC patients (14.0 vs. 5.7 months, HR 0.29). At ASCO 2020, a Phase II study showed that erlotinib combined with bevacizumab achieved an ORR of 72.1% and a median PFS of 21.1 months in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) patients. In 2021, the SWOG1500 Phase II study showed cabozantinib significantly extended PFS (9.0 vs. 5.6 months, HR 0.60, 95% CI: 0.37–0.97, P = 0.019) and improved ORR (23% vs. 4%, P = 0.010) compared to sunitinib in advanced papillary RCC patients.

The same year, lenvatinib plus everolimus dual-target therapy achieved an ORR of 26%, median PFS of 9.2 months, and OS of 15.6 months in advanced nccRCC patients. The KEYNOTE-427 study found pembrolizumab as a first-line treatment for metastatic nccRCC had an ORR of 26.7%, median PFS of 4.2 months, and OS of 28.9 months. In 2022, a Phase II investigator-initiated trial reported cabozantinib plus nivolumab achieved an ORR of 47.5%, median PFS of 12.5 months, and OS of 28 months in nccRCC patients. In 2023, the KEYNOTE-B61 study showed that lenvatinib plus pembrolizumab as a first-line treatment for advanced nccRCC achieved an ORR of 49% and a median PFS of 18 months. At ASCO 2024, a single-arm Phase II study found axitinib combined with sintilimab achieved an ORR of 60.5%, a disease control rate of 86.8%, and a median PFS of 19.83 months in advanced or metastatic fumarate hydratase-deficient RCC patients.

For collecting duct carcinoma, the GETUG study demonstrated that the GC regimen (gemcitabine combined with cisplatin) achieved an ORR of 26%, median PFS of 7.1 months, and OS of 10.5 months. In 2018, a single-arm Phase II study reported that adding sorafenib to the GC regimen achieved an ORR of 30.8%, median PFS of 8.8 months, and OS of 12.5 months. More recently, the BONSAI Phase II study reported cabozantinib as first-line treatment for collecting duct carcinoma, achieving an ORR of 35%, median PFS of 4 months, and OS of 7 months.

Conclusion

The 2024 CSCO guidelines for renal cancer provide updated references to further standardize diagnosis and treatment in China. The updated guidelines emphasize stratified treatment decisions for advanced renal cancer. For low-risk metastatic or unresectable ccRCC, TKI monotherapy such as pazopanib or sunitinib remains the preferred first-line treatment. For intermediate- and high-risk patients, first-line options include immune-targeted or dual-immunotherapy regimens.

For second-line treatment of metastatic or unresectable ccRCC, sequential therapy is recommended based on the first-line strategy, with clinical trial participation encouraged. After failure of TKI monotherapy, second-line options include other unused monotherapy or combination therapies. After failure of immune combination therapy, sequential use of targeted monotherapy or immune-targeted combinations is advised. For nccRCC, given the limited high-quality evidence, clinical trial participation is prioritized, with treatment referencing ccRCC therapies and considering targeted or immune-targeted combination options.

Guohai Shi

Associate Professor, MD

Chief Physician, Department of Urology, Fudan University Cancer Hospital

Dr. Guohai Shi specializes in the diagnosis, surgical treatment, minimally invasive therapies, and systemic treatment of advanced urological cancers. He performs over 400 urological cancer surgeries annually, including more than 200 kidney cancer cases. He participates in over 50 multidisciplinary discussions on urological cancers each year.

Education:

• 1996–2001: Bachelor of Medicine, Harbin Medical University
• 2001–2007: Doctorate in Urology, Shanghai Jiao Tong University School of Medicine
• 2007: National GCP Clinical Training
• 2010: European-Chinese Urology Training
• 2011: Visiting Scholar, General Hospital of Vienna, Austria
• 2012: Participated in the International Society of Cryosurgery Annual Meeting and academic exchanges on minimally invasive cryosurgery for urological cancers

Academic Affiliations:

• International Member, American Urological Association (AUA)
• Member, Chinese Anti-Cancer Association
• Reviewer for Chemistry Medical Research and Journal of Cancer and Clinical Oncology
• Member, Shanghai Urological Surgery Minimally Invasive Working Group
• Judge, Pudong Science and Technology Development Fund
• Chief Examiner, Shanghai Resident Standardized Training Program