Editor's Note: In recent years, with the advancements in targeted therapy and immunotherapy, significant progress has been made in the treatment of advanced renal cell carcinoma (RCC). Several large-scale phase III clinical trials involving targeted and immunotherapy combinations have been successful, marking the beginning of a new era in first-line treatment for advanced RCC. Following the successful 2024 Annual Meeting of the Urology Physicians Branch of the Chinese Medical Doctor Association in Xi'an, Urology Frontier invited Dr. Hao Zeng from West China Hospital, Sichuan University, to share insights on unmet needs in advanced RCC, strategies for combining targeted and immunotherapy, management of adverse events, and future directions in treatment.01
Urology Frontier: What is the current status of diagnosis and treatment for advanced RCC in China? What unmet clinical needs still exist?
Dr. Hao Zeng: The treatment of advanced RCC has been evolving, progressing through three major phases: cytokine therapy, targeted therapy, and immunotherapy. However, compared to patients in developed countries such as the United States and Europe, Chinese patients with advanced metastatic RCC have lower treatment rates and five-year survival rates. This gap is due to various subjective and objective factors. Firstly, some patients might still receive older, less effective cytokine treatments like interleukin-2 and interferon-α2a. Secondly, although patients with intermediate to high-risk metastatic RCC can achieve longer survival times with combination therapy of targeted and immunotherapy or dual immunotherapy, the only approved immunotherapy drug available in China is the domestically produced PD-1 inhibitor, toripalimab. The high cost and limited accessibility of other non-approved and non-reimbursed treatments further exacerbate this issue. In current clinical practice, many patients rely on monotherapy with targeted drugs, which may not provide the same efficacy as combination strategies. The challenge of getting new treatment strategies, like immunotherapy, approved and covered by insurance in China is a pressing concern shared by both doctors and patients, as it would significantly improve the overall survival of patients with advanced metastatic RCC.
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Urology Frontier: First-line treatment for advanced RCC has now entered the era of combination targeted and immunotherapy. How does this combination improve patient outcomes?
Dr. Hao Zeng: Combination therapy with targeted and immunotherapy is currently one of the standard treatment strategies. Both domestic and international guidelines strongly recommend this approach for first-line treatment of advanced metastatic RCC, supported by high-level evidence. However, not all patients benefit equally from combination therapy. By analyzing clinical trials and real-world data using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score, it was found that patients with low or very low risk do not gain significant survival benefits from combination therapy. In such cases, these patients may opt for targeted therapy as the initial approach, with anti-angiogenic therapy being tailored based on treatment response to optimize outcomes.
For intermediate to high-risk patients, clinical trials and real-world data suggest that intermediate-risk patients may gain more benefits from combination therapy, while high-risk patients may have a lower likelihood of benefit. Nevertheless, compared to previous treatments like targeted therapy or cytokine therapy alone, combination strategies still improve survival for high-risk patients, extending median progression-free survival (PFS) from 8-10 months with targeted monotherapy to nearly 20 months with combination therapy. To better meet the clinical needs of high-risk patients, further exploration of additional treatment strategies is necessary. For intermediate-risk patients, more research is needed to determine the optimal choice between immunotherapy and combination therapy.
Of course, there may be differences in efficacy between combination therapy with targeted and immunotherapy versus dual immunotherapy. Special attention should be given to subsequent treatment options after first-line combination therapy failure. If dual immunotherapy fails in the first line, targeted therapy in the second line may offer greater benefits. However, if combination therapy with targeted and immunotherapy is chosen as the first line, subsequent treatment options may be more limited. Future research should continue to explore post-progression treatment strategies for patients who experience disease progression after combination therapy, with the goal of further extending survival.
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Urology Frontier: How should treatment-related adverse events be managed in your opinion?
Dr. Hao Zeng: Adverse events related to RCC treatment are relatively common. Whether during the cytokine therapy era, the targeted therapy era, or the immunotherapy era, the occurrence of toxic side effects during treatment can, to some extent, indicate the efficacy of the treatment strategy. Of course, neither patients nor doctors want to encounter unmanageable or irreversible toxic side effects. Effective communication between doctors and patients can help better balance treatment efficacy with the management of adverse events.
At West China Hospital, Sichuan University, we have established detailed protocols for managing adverse events. Before deciding on a treatment plan, we ensure thorough communication between doctors and patients to clarify the precautions for drug use, potential side effects, and corresponding management strategies. We also establish communication groups with patients who require them, allowing for timely and thorough communication to facilitate early detection and management of toxic side effects. During the targeted therapy era, toxic side effects ranging from grades 1 to 3, such as hypertension, hypothyroidism, and rash, can be effectively managed. Notably, the presence of these side effects may also indicate a greater likelihood of benefit from targeted therapy.
In the immunotherapy era, our team conducted a meta-analysis on the correlation between efficacy and toxic side effects in RCC patients undergoing combination therapy with targeted and immunotherapy or dual immunotherapy. The recently published results revealed that patients with grade 2 or lower toxic side effects, or those experiencing skin and/or thyroid-related toxicity, were more likely to benefit from immunotherapy. However, the occurrence of cardiac and/or pulmonary toxicity, especially at grade 3 or higher, was associated with a significantly reduced likelihood of benefit from immunotherapy. In clinical practice, dynamic monitoring and analysis of patients’ benefit profiles may help determine whether patients are likely to benefit from their current treatment regimen.
Additionally, there is some overlap in toxic side effects associated with targeted therapy, immunotherapy, and combination therapy, such as hepatotoxicity, gastrointestinal reactions, hypothyroidism, and rash. When two different drugs potentially cause similar adverse reactions, clinical physicians need to carefully differentiate and manage these effects: immunotherapy-related toxic reactions typically require steroid treatment, while targeted therapy-related toxic reactions often resolve with symptomatic treatment or drug discontinuation. All clinical physicians must pay close attention to these treatment-related adverse events.
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Urology Frontier: Treatment strategies have evolved from monotherapy to combination targeted and immunotherapy. What new treatment strategies do you see being applied in clinical practice in the near future?
Dr. Hao Zeng: Currently, there are several ongoing research efforts focused on new therapeutic targets. Hypoxia-inducible factor-2α (HIF-2α) inhibitors have already entered clinical practice for advanced RCC abroad and are expected to be approved in China soon. Both Merck’s belzutifan abroad and domestically developed HIF-2α inhibitors provide effective treatment alternatives for RCC. For patients with low-risk metastatic RCC, the efficacy of combination targeted and immunotherapy is similar to that of targeted monotherapy. However, using a combination of HIF-2α inhibitors with tyrosine kinase inhibitors (TKI) could achieve an objective response rate of over 70%, with studies showing a median PFS exceeding 30 months. This suggests that for metastatic RCC patients whose main signaling pathway is angiogenesis, combining HIF-2α inhibitors with TKI could improve survival. Additionally, research is ongoing into other therapeutic targets.
For RCC patients, there is also research exploring antibody-drug conjugate (ADC) treatment strategies and radionuclide therapies targeting prostate-specific membrane antigen (PSMA). Our team at West China Hospital, Sichuan University, analyzed PSMA expression in some non-clear cell renal cell carcinoma (nccRCC) cases, finding promising results in animal studies of radionuclide therapy. Although no such drugs are currently available, future development of novel radionuclide therapies for RCC could further validate their clinical efficacy and ultimately improve patient outcomes.
In immunotherapy, most current drugs are PD-1/PD-L1 checkpoint inhibitors. However, there are many immune checkpoints in the human body, such as LAG-3, TIM-3, TIGIT, and BTLA. Whether drugs targeting these immune checkpoints can be used in first-line or later-line treatment of RCC is a current area of exploration. These drugs may produce unexpected results in patients with specific molecular subtypes of RCC. Furthermore, treatment strategies like CAR-T therapy are also being explored in the RCC field. These novel treatment approaches offer new hope for RCC patients.
Dr. Hao Zeng:
- Position: Secretary, Professor, and Doctoral Supervisor of the Department of Urology, West China Hospital, Sichuan University.
- Leadership Roles: Member and Secretary-General of the Youth Committee of the Urology Branch of the Chinese Medical Association. Member of the Oncology Group of the Urology Branch of the Chinese Medical Association. Member of the Youth Committee of the Urology and Male Reproductive Tumors Special Committee of the Chinese Anti-Cancer Association. Member and Deputy Secretary-General/Vice-Chairman of the Youth Committee of the Urological Health Promotion Branch of the Chinese Medical Doctor Association. Member of the Prostate Cancer, Urothelial Cancer, and Kidney Cancer Expert Committees of the Chinese Society of Clinical Oncology (CSCO). Standing Member of the Urology Special Committee of Sichuan Province. Deputy Head of the Oncology Group of the Urology Special Committee of Sichuan Province. Chairman of the Urogenital Oncology Special Committee of the Sichuan Provincial Tumor (Precision Treatment) Society. Vice-Chairman of the Urology and Male Reproductive Tumors Special Committee of the Sichuan Anti-Cancer Association.
