Editor’s Note: Renal cell carcinoma (RCC) is one of the three major tumors of the urinary system. In recent years, the development of targeted and immunotherapy drugs—particularly the success of several large-scale Phase III trials of combination therapies—has ushered in a new era of targeted and immunotherapy combinations for advanced RCC. At this year’s ESMO ASIA Congress, several studies on treatments for advanced RCC were presented. Urology Frontier invited Dr. Guohai Shi from Fudan University Shanghai Cancer Center to share insights into these advancements.

LBA2 Efficacy of Belzutifan Versus Everolimus in Treated Advanced Clear Cell Renal Cell Carcinoma (ccRCC): Latest Follow-Up of the East Asian Subgroup in the Phase III LITESPARK-005 Study

Dr. Guohai Shi：The mTOR pathway, targeted by everolimus, is a downstream signaling pathway in tumors, and everolimus, though approved for second-line and beyond treatment of advanced RCC, offers limited clinical benefits. However, everolimus is generally well-tolerated, with common side effects like oral ulcers and hyperlipidemia.

In contrast, belzutifan, a HIF-2α inhibitor, has a more limited effect when used alone and is associated with notable side effects, such as anemia. In this study, treatment-related grade 3–5 AEs occurred in 53% of patients receiving belzutifan versus 33% for everolimus, reflecting real-world clinical practice where single-agent targeted therapies in late-line settings are chosen carefully due to toxicity and tolerability concerns.

Despite its side effect profile, belzutifan achieving a PFS of 7.5 months demonstrates promising efficacy, making it a treatment worth considering for patients with advanced RCC.

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Determinants of Response to Immune Checkpoint Inhibitor Combined with Tyrosine Kinase Inhibitor Neoadjuvant Therapy in Renal Cell Carcinoma

Dr. Guohai Shi：The extent of tumor thrombus significantly affects surgical complexity—even a 2 cm increase can dramatically change surgical outcomes. In this study, the 44.0% tumor thrombus downstaging rate with neoadjuvant immunotherapy-targeted therapy (NCT) is notably higher than the 29% downstaging rate previously reported with preoperative sunitinib alone.

Primary renal tumors may exhibit immune evasion, which could explain why combined therapy does not show a major advantage over monotherapy in the primary tumor (44% vs. 29%). However, for tumor thrombi and metastatic lesions, the combination therapy appears to be more effective, possibly due to differing biological characteristics, such as unique cell clones and distinct immune microenvironments.

This study also identified high SAA expression as a marker of poor response to NCT and worse prognosis. For this specific tumor type, targeted therapies might yield surprising outcomes, similar to how HER2-targeted antibody-drug conjugates have significantly improved outcomes in HER2-positive urothelial carcinoma, despite its traditionally poor prognosis.

Challenges often present new opportunities, and further research into SAA-targeted therapies could offer promising solutions for this difficult-to-treat cancer type.

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Efficacy and Safety of Fruquintinib Combined with Sintilimab as First-Line Treatment for Advanced Non-Clear Cell Renal Cell Carcinoma (nccRCC): A Multicenter Single-Arm Clinical Trial

Dr. Guohai Shi：Conducting clinical research in metastatic non-clear cell RCC is particularly challenging due to the diverse subtypes and wide variations in prognosis. Diagnosing these subtypes can also be complex. Fruquintinib, both as a monotherapy and in combination with everolimus, has previously shown favorable outcomes in second-line treatment for advanced RCC. In this study, the combination of targeted therapy and immunotherapy, now the standard of care for metastatic RCC, yielded an ORR of 33% and a DCR of 66.7%. Although these results are encouraging, it is important to note that most patients in this study had lymph node and lung metastases, which generally predict a better prognosis than other metastatic sites.

Adverse events were primarily grade 1 or 2 and were easily manageable, suggesting that this regimen has strong potential for clinical application. However, the rapid disease progression observed in two papillary RCC and one chromophobe RCC patient highlights a significant challenge in treating aggressive disease subtypes and warrants further investigation.

Dr. Guohai shi

• Associate Professor, MD, Chief Physician
• Department of Urology, Fudan University Shanghai Cancer Center

Expertise:

• Diagnosis, surgical treatment, minimally invasive procedures, and systemic therapy for urologic cancers
• Performs over 400 urologic tumor surgeries annually, including 200+ kidney cancer surgeries
• Regularly participates in multidisciplinary discussions on urologic oncology

Education:

• 1996–2001: Bachelor of Medicine, Harbin Medical University
• 2001–2007: Ph.D. in Urologic Surgery, Shanghai Jiao Tong University School of Medicine
• 2007: National GCP Clinical Training
• 2010: Sino-European Urology Training
• 2011: Visiting Scholar, Medical University of Vienna, Austria
• 2012: Participated in the International Cryosurgery Conference and academic exchange on cryoablation for urologic cancers

Professional Memberships:

• 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 Urologic Minimally Invasive Surgery Group
• Reviewer, Pudong Science and Technology Development Fund
• Examiner for Shanghai standardized residency training in urology