Editor’s Note: Renal cancer is one of the three major tumors of the urinary system. Several large phase III studies on combined targeted and immunotherapy have been successful, and the 2024 update of the CSCO renal cancer diagnosis and treatment guidelines has officially brought first-line treatment for advanced renal cancer into the era of combined targeted and immunotherapy in China. But what are the remaining unmet needs for patients with special types of renal cancer? During the 31st Urology Academic Conference held in Tianjin, Urology Frontier invited Dr. Hao Zeng from West China Hospital, Sichuan University to share his insights on the evolving treatment concepts for advanced renal cancer, the value of combined targeted and immunotherapy, and the West China Hospital team’s exploration into treating special types of renal cancer.

01

Urology Frontier: How has the treatment philosophy for advanced renal cancer changed in recent years?

Dr. Hao Zeng: Renal cancer treatment has undergone significant changes over the past two or three decades. Before the 21st century, the systemic treatment options for renal cancer were relatively limited, mainly relying on cytokine therapies such as interferon or interleukin-2, which showed poor efficacy with a five-year survival rate of less than 10%. However, with the in-depth understanding of the molecular mechanisms of renal cancer, particularly clear cell renal cell carcinoma, the advent of anti-angiogenic drugs in 2005 marked the beginning of the targeted therapy era for renal cancer. This shift rapidly extended the median survival time from 10–12 months to over two years, but it still did not fully meet patients’ needs.

Since 2010, immune checkpoint inhibitors have achieved breakthroughs in various cancers, including melanoma and lung cancer, bringing immunotherapy back to the forefront of cancer treatment. In 2015, immune checkpoint inhibitors also succeeded in second-line treatment for renal cancer. Subsequently, phase III clinical trials combining targeted and immunotherapy, as well as dual immunotherapy, in first-line treatment for renal cancer demonstrated excellent clinical efficacy, marking the true arrival of the combined targeted and immunotherapy era. This shift not only changed the treatment philosophy for renal cancer but also highlighted the positive impact of restoring patients’ complete immune response in tumor treatment. With the synergistic effect of these two drugs, the five-year survival rate now exceeds 50%, and with the continued development of immune-based treatment regimens, patient survival times could be further extended.

Despite significant progress, extending overall survival and improving treatment efficacy for advanced renal cancer remains a key challenge. Clinical trials show that the overall survival of patients treated with combined therapies has not yet exceeded 50 months. Therefore, exploring new immunotherapy approaches, such as CAR-T cell therapy, could offer new hope for renal cancer patients. In addition, radionuclide therapy has shown promising clinical applications in various solid tumors and is becoming an important focus of research in renal cancer. By analyzing potential therapeutic targets such as membrane proteins and target proteins, we can explore the application of radionuclide drugs in renal cancer treatment, which may bring effective and lasting therapeutic effects to patients.

02

Urology Frontier: The latest renal cancer guidelines have listed axitinib combined with toripalimab as a first-line recommendation, ushering advanced renal cancer into the era of combined targeted and immunotherapy. How do you view the value of this combined approach?

Dr. Hao Zeng: The combination of axitinib and toripalimab has been approved as a first-line treatment for patients with intermediate to high-risk unresectable or metastatic renal cell carcinoma, marking the official approval of China’s first combined targeted and immunotherapy regimen for advanced metastatic renal cancer. This milestone achievement undoubtedly brings great hope to renal cancer patients in China, and we hope it will soon be included in medical insurance to greatly enhance the accessibility of the drug, allowing more patients to benefit from and adopt this innovative treatment.

03

Urology Frontier: Clinical trials provide more evidence-based support for clinical decision-making and identifying the optimal patient population. How should clinical researchers further drive innovation in this field?

Dr. Hao Zeng: Clinical trials provide a solid foundation for clinical decision-making, especially when selecting the best treatment regimen for specific patient populations. As clinical researchers, how can we promote more effective innovation in this field? Taking renal cancer as an example, although only the axitinib and toripalimab combination is currently approved in China, multiple combinations have been approved abroad. In particular, the treatment options for clear cell renal cell carcinoma have become increasingly diverse, but there are still many unknowns to explore for non-clear cell renal cell carcinoma or patients with specific driver gene mutations.

Therefore, the successful experiences in clinical trials for clear cell renal cell carcinoma provide valuable clues and insights for conducting trials on non-clear cell renal cell carcinoma. Clinicians can refer to the process of discovering VHL as the major driver gene in clear cell carcinoma to explore more definitive driver genes in non-clear cell carcinoma. Once these driver genes are identified, targeted drugs can be developed and tested in clinical trials to validate the potential of these new treatments, ultimately improving outcomes for patients with more aggressive subtypes of renal cancer. Through continuous exploration and innovation, we hope to bring more effective and personalized treatment regimens to more renal cancer patients.

04

Urology Frontier: What research has your team conducted in the field of renal cancer, and how has it impacted clinical practice?

Dr. Hao Zeng: Our team focuses on clinical and translational research of special types of renal cancer, primarily targeting renal cancer subtypes with specific genetic alterations, such as fumarate hydratase-deficient renal cell carcinoma, TFE3-rearranged renal cell carcinoma, SMARCB1-deficient renal medullary carcinoma, BAP1-mutant renal cell carcinoma, and NF2-mutant renal cell carcinoma. These renal cancer subtypes tend to be highly aggressive, and the affected patients are often younger, even adolescents, which creates an urgent need for effective treatment options in clinical practice.

To address these challenges, our team has completed a phase II prospective clinical trial on fumarate hydratase-deficient renal cell carcinoma, achieving good clinical outcomes. This treatment regimen was also explored in suitable patient populations, and results showed a significant extension of overall survival from the previous 8–13 months to over two years.

Additionally, we have conducted molecular profiling on various renal cell carcinomas, including fumarate hydratase-deficient and TFE3-rearranged subtypes. This achievement provides strong support for physicians to develop personalized treatment strategies based on patients’ molecular characteristics and has also accelerated the drug development process for these special types of renal cancer. Research on TFE3-rearranged renal cell carcinoma is ongoing. Given the strong heterogeneity of this tumor type, further scientific research and clinical trials are necessary to identify more effective treatment methods.

Here, we would like to extend our special thanks to our colleagues in urology across China for their support and collaboration. We have initiated three clinical trials for special types of renal cell carcinoma, and these trials have relied not only on our ability to find patients but also on the recommendations of experts and colleagues from multiple medical centers across China. This has allowed us to complete patient enrollment in a relatively short time and smoothly advance the clinical trials with the active cooperation of patients and doctors from multiple centers. Moving forward, we need to strengthen collaboration between multiple centers in China to efficiently advance clinical exploration in urologic oncology and bring more benefits to patients.

Dr. Hao Zeng West China Hospital, Sichuan University Professor, Ph.D. Supervisor, and Secretary of Urology at West China Hospital Secretary-General and Member of the Youth Committee, Chinese Urological Association Member of the Oncology Group, Chinese Urological Association Member of the Youth Committee, Chinese Anti-Cancer Association, Urologic Oncology Branch Vice Secretary-General and Deputy Director of the Youth Committee, Urological Health Promotion Branch, China International Exchange and Promotive Association for Medical and Health Care Member of the CSCO Prostate Cancer, CSCO Urothelial Cancer, and CSCO Renal Cancer Expert Committees Standing Member of the Sichuan Urological Association Deputy Leader of the Oncology Group, Sichuan Urological Association Chairman of the Urogenital Oncology Committee, Sichuan Precision Medicine Society Vice Chairman of the Urologic Oncology Committee, Sichuan Anti-Cancer Association