Editor's Note: From July 5-7, 2024, the 2024 Chinese Clinical Oncology Annual Progress Seminar (BOC) and Beast of ASCO® 2024 China were grandly held in Guangzhou. On the 6th, a special session on urinary system tumors convened, gathering significant progress from ASCO. In the field of kidney cancer treatment, besides international advancements, China has made significant strides in first-line and second-line treatments involving immunotherapy combinations and HIF-2α inhibitors, showcasing China’s cutting-edge scientific strength on the international stage. At this conference, "Oncology Frontier" invited Professor Xinan Sheng from Peking University Cancer Hospital to discuss the unmet clinical needs and cutting-edge developments in kidney cancer treatment domestically and internationally, and to grasp the trends in combination therapy for kidney cancer.Capturing Global Progress and Strategizing Kidney Cancer Diagnosis and Treatment
Oncology Frontier: What unmet patient needs currently exist in kidney cancer treatment?
Professor Xinan Sheng: Targeted-immunotherapy has become the main first-line treatment for advanced kidney cancer, significantly changing the treatment landscape. The primary challenge we face is the treatment options for patients after targeted-immunotherapy failure. Last year, the CONTACT-03 study explored the continuation of targeted therapy or targeted-immunotherapy in the second line, and the KEYMAKER-U03B study initially showed better efficacy with HIF-2α inhibitors combined with TKI, but more phase III clinical trials are needed to establish standard treatment choices.
With the increasing number of treatment options for kidney cancer, the best combination of different targeted drugs and immunotherapy drugs for first-line treatment of advanced clear cell renal carcinoma needs exploration. We also observe better efficacy of targeted-immunotherapy in intermediate to high-risk patient groups. For low-risk groups, targeted therapy is effective, and how to further enhance efficacy is worth considering. This year’s ASCO also introduced the concept of extremely low risk, raising questions about whether extremely low-risk patients are more suitable for targeted therapy and whether ordinary low-risk patients still benefit from targeted-immunotherapy, which are important research hotspots.
Significant breakthroughs in drug therapy for non-clear cell renal carcinoma have not yet been achieved due to the variety of subtypes, limited biological understanding of these subtypes, and the small number of patients hindering large-scale clinical research on non-clear cell renal carcinoma.
These clinical needs require our active attention and exploration through corresponding clinical research to address each unmet need.
Oncology Frontier: Peking University Cancer Hospital has also announced several kidney cancer research advancements at recent domestic and international conferences. Could you share the main research results and discuss strategies for fostering new productivity in clinical research?
Professor Xinan Sheng: In the field of drug treatment for advanced kidney cancer, we reported the RENOTORCH study at the 2023 ESMO. This study, led by Professor Jun Guo from our hospital and Professor Huang Yiran from Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, is the eighth randomized, controlled, multicenter phase III clinical study globally in the field of kidney cancer and the largest phase III clinical study in the history of kidney cancer treatment in China. The study confirmed the efficacy advantage of axitinib combined with toripalimab over sunitinib in intermediate to high-risk advanced kidney cancer. Previous studies proving the benefits of immunotherapy in kidney cancer were mostly from subgroup analyses, and this study’s significance lies in providing direct evidence for targeted-immunotherapy in intermediate to high-risk patients. Based on this study, China’s National Medical Products Administration (NMPA) approved the indication of toripalimab combined with axitinib for first-line treatment of intermediate to high-risk renal cell carcinoma. This truly signifies the entry of advanced kidney cancer treatment in China into the era of targeted-immunotherapy, opening a new chapter.
For low-risk clear cell renal carcinoma, we are also exploring new approaches and will soon initiate a clinical study on VEGF combined with PD-L1 monoclonal antibodies to explore the benefits of immunotherapy combinations for low-risk patients. At the 2024 ASCO meeting, our team reported a phase I clinical study on the combination of belzutifan (a HIF-2α inhibitor) and lenvatinib for Chinese patients with multi-line treatment-refractory kidney cancer, showing an ORR of 50% and a median PFS of 13.7 months, providing preliminary data for the domestic approval of HIF-2α inhibitors. HIF-2α inhibitors have been successfully marketed abroad for second-line treatment of advanced kidney cancer, and two domestically developed HIF-2α inhibitors are currently being studied under the leadership of Professor Jun Guo. We hope these HIF-2α inhibitors will soon be available for clinical practice in China.
In advanced kidney cancer clinical research, any innovative drugs, treatments that change the treatment landscape, and strategies that bring clinical efficacy to patients represent new productivity.
Oncology Frontier: With the boost in confidence from the RENOTORCH study, the rapid rise of HIF-2α inhibitors, and the vigorous development of combination therapy research, how do you view the strategy for advanced kidney cancer?
Professor Xinan Sheng: Domestic and international guidelines recommend first-line treatments for advanced kidney cancer based on evidence from clinical studies, with risk stratification being a crucial factor. Based on current domestic availability, the first-line choice for intermediate to high-risk patients is axitinib combined with toripalimab, while targeted therapy drugs remain an option for low-risk patients. For low-risk patients with poor biological behavior, such as those with liver or brain metastases, targeted-immunotherapy can be actively tried.
For second-line treatment, if only targeted therapy was used previously, targeted-immunotherapy will undoubtedly be considered for the second line. For patients with second-line failure of targeted-immunotherapy, the strongest evidence is from the phase III study of the HIF-2α inhibitor belzutifan in advanced clear cell renal carcinoma, with a median PFS of only 5.6 months. Although statistically positive, the results did not differ much from everolimus numerically, so further exploration of combination therapy efficacy may be needed.
The era of monotherapy for kidney cancer is quickly coming to an end, with combination therapy on the horizon, such as HIF-2α inhibitors combined with TKIs, lenvatinib, or vorolanib combined with everolimus. While monotherapy may suffice for some special patients, the trend for second-line treatment is still towards combination therapy. To summarize second-line treatment in one sentence: combination is the main strategy, whether it is targeted-immunotherapy or combinations of different targeted therapies.
The treatment options for kidney cancer are increasing, as are survival and treatment times, but there is still insufficient evidence for second-line, third-line, fourth-line, and beyond treatments. Conventionally, drugs not previously used are theoretically considered for subsequent lines, but with improved treatment efficacy, our understanding of unmet clinical needs remains limited. For instance, due to uncertainties in previous third-line treatments, we removed third-line treatment recommendations in this year’s guidelines. Therefore, more exploration is needed to address unmet clinical needs.
Professor Xinan Sheng
Chief Physician, Professor, Doctoral Supervisor Deputy Director of the Department of Urological Oncology, Peking University Cancer Hospital Vice Chairman of the Uro-Genital Tumor Integrated Rehabilitation Professional Committee of the Chinese Anti-Cancer Association Standing Committee Member of the Urological Tumor Professional Committee of the Chinese Anti-Cancer Association Director of the Chinese Society of Clinical Oncology (CSCO) Secretary General of the CSCO Renal Cancer Expert Committee Standing Committee Member of the CSCO Urothelial Cancer Expert Committee Committee Member of the Bladder Cancer Quality Control Expert Committee of the National Tumor Quality Control Center President-Elect of the Urological Tumor Branch of the Beijing Cancer Prevention and Treatment Research Association Chairman of the Youth Committee of the Uro-Genital Tumor Professional Committee of the Beijing Anti-Cancer Association Standing Committee Member of the Tumor Branch of the Beijing Medical Association
