Editor's Note: Renal cell carcinoma (RCC) is one of the most common malignancies of the urinary system. In recent years, the exploration of combined immunotherapy strategies in RCC has transformed the treatment landscape, making immuno-targeted therapy the global first-line standard for advanced renal cancer. The 2024 European Society for Medical Oncology (ESMO) Annual Meeting was held in Barcelona, Spain, from September 13 to 17. During the Urothelial Cancer (non-prostate) Short Oral Presentation session on September 15, Dr. Xinan Sheng from Peking University Cancer Hospital delivered a presentation titled "Anlotinib in combination with the anti-PD-L1 antibody Benmelstobart (TQB2450) versus sunitinib as first-line treatment for advanced renal cell carcinoma (RCC) - A randomized, open-label, phase III study (ETER100)." This was the only late-breaking abstract (LBA) study from China selected in the field of uro-oncology at this year's ESMO conference. Urology Frontier invited Professor Sheng to elaborate on the current state of advanced renal cancer treatment in China, the survival benefits and safety of combined immunotherapy in advanced RCC, and other key topics.

01

Urology Frontier: Could you share your insights on the current status of treatment for advanced renal cancer patients in China?

Dr. Xinan Sheng: In recent years, there have been significant advancements in the treatment of advanced renal cancer in China. From both domestic and international guidelines, it is clear that the era of combined immunotherapy for advanced renal cancer has arrived. However, there are still some differences between domestic and international treatment strategies.

In China, treatment decisions are made based on the CSCO renal cancer guidelines, with intermediate- and high-risk RCC patients more likely to receive combination immunotherapy, while low-risk patients are recommended targeted therapy alone. This strategy is supported by substantial clinical trial data, including subgroup analyses from the RENOTORCH study and other phase III trials, which have shown significant benefits of combination immunotherapy in intermediate- and high-risk populations. We also tailor treatment plans more precisely based on risk stratification, considering drug accessibility.

Regarding treatment for patients who fail first-line immunotherapy or targeted therapy, the recommendations are similar in China and abroad. In China, most patients have already received targeted therapy in the first-line setting. When single-agent targeted therapy fails, we recommend combination regimens like furotinib plus everolimus based on the CONCEPT study results or the use of multi-target tyrosine kinase inhibitors (TKIs) such as axitinib or lenvatinib in combination with PD-1 inhibitors.

It is worth noting that most patients abroad have already undergone first-line combination immunotherapy, a trend that is gradually increasing in China. However, there is a lack of high-level evidence-based recommendations for subsequent treatments in these patients, both domestically and internationally. While the HIF-2α inhibitor belzutifan is already available abroad, it is not yet accessible in China. With the publication of studies like CONTACT-03, we see a growing preference for single-agent TKI therapy for patients who fail combination immunotherapy. While novel TKIs like cabozantinib are the preferred options abroad, in China, we tend to use combination targeted therapies like furotinib plus everolimus or lenvatinib plus everolimus.

Overall, the treatment landscape for advanced renal cancer in China is continuously improving, but there are still unmet needs. For instance, there is no standard recommendation for third- and fourth-line treatments, and while drug accessibility has increased, so has the complexity of treatment selection. Moreover, non-drug and localized treatment options are expanding, providing more choices for advanced RCC patients. Domestic research is also focusing on new drug development for advanced renal cancer, including anti-angiogenic TKIs, HIF-2α inhibitors, and cellular immunotherapy, which could bring better treatment outcomes for patients in the future. With ongoing medical advancements and increasing attention to advanced renal cancer, we have reason to believe that significant progress will be achieved in this field.

02

Urology Frontier: With new research data emerging, advanced renal cancer has entered the era of combination immunotherapy. At the ESMO conference, you presented the ETER100 study data at the LBA session. How does this combination therapy improve survival for patients with advanced RCC?

Dr. Xinan Sheng: In my presentation, I shared the interim analysis results from the ETER100 study, a randomized, open-label, phase III trial that compared the combination of anlotinib and the PD-L1 inhibitor Benmelstobart (TQB2450) against sunitinib as first-line treatment for patients with advanced RCC. Participants were randomly assigned in a 1:1 ratio to receive either Benmelstobart (1200 mg) intravenously every three weeks in combination with anlotinib (12 mg) orally once daily (two weeks on, one week off), or sunitinib (50 mg) orally once daily (four weeks on, two weeks off). The primary endpoint was progression-free survival (PFS), assessed by blinded independent central review using RECIST 1.1 criteria.

A total of 531 patients were randomized, with 266 receiving the combination of anlotinib and Benmelstobart, and 265 receiving sunitinib. As of January 31, 2024, after a median follow-up of 19.52 months, the combination group showed a significant improvement in PFS (HR 0.53 [95% CI 0.42-0.67]; P<0.0001; median PFS 18.96 months vs. 9.76 months) and a higher overall response rate (ORR) (71.59% vs. 25.10%; P<0.0001). These results are consistent with the conclusions of similar studies conducted both domestically and internationally. Although the interim data are not yet fully mature, they generally favor the combination immunotherapy group.

In this clinical trial, we observed survival benefits from the combination of immunotherapy and anti-angiogenic targeted agents. Notably, multiple studies worldwide have shown that this type of combination therapy can improve overall survival (OS). As a PD-L1 inhibitor, Benmelstobart is comparable to internationally studied combinations of atezolizumab and TKIs. While OS data from PD-L1 inhibitor-based combinations may not be as remarkable as those from PD-1 inhibitor-based combinations, there is still great anticipation for the final OS results of PD-L1 plus TKI therapy.

The current study findings clearly demonstrate that immunotherapy combined with TKI significantly extends OS for patients with advanced RCC, underscoring the importance of this approach in the treatment of advanced renal cancer. However, it is also essential to recognize that a holistic improvement in outcomes for advanced RCC patients requires more than just first-line therapy. Sequential treatment strategies and the appropriate application of multidisciplinary approaches are equally crucial. The combined effects of these comprehensive measures can more effectively improve overall survival for patients with advanced RCC.

03

Urology Frontier: How was the safety profile of the combination therapy in the ETER100 study? Could you share your experience in managing the potential toxicities associated with this therapy?

Dr. Xinan Sheng: In the ETER100 study, we employed a combination therapy of anlotinib and the PD-L1 inhibitor Benmelstobart. There is already substantial clinical experience with anti-angiogenic TKI agents, such as axitinib and lenvatinib, which provides a good understanding of the safety profile when used alone.

Regarding immune-related adverse events caused by PD-1/PD-L1 inhibitors, clinicians are equally experienced in their management. In the context of the combination of Benmelstobart and anlotinib, preliminary clinical data suggest that the main adverse effects are consistent with those reported in previous studies, primarily involving hypertension, hand-foot skin reactions, proteinuria, and diarrhea. There were also some immune-related adverse events, such as immune thyroiditis, myositis, and hepatitis.

Although this combination therapy may seem novel, clinicians have already accumulated considerable experience in managing these drugs’ adverse effects. Therefore, we anticipate being well-equipped to handle these safety concerns.

04

Urology Frontier: What are the future directions your team is exploring to further improve outcomes for advanced RCC patients?

Dr. Xinan Sheng: Despite the availability of various treatment options for advanced RCC, many unmet clinical needs remain. Our efforts focus on the following areas:

1. Optimizing First-Line Treatment Strategies: For first-line treatment of advanced RCC, intermediate- and high-risk patients are more inclined toward combination immunotherapy, while low-risk patients typically receive targeted therapy. We plan to explore more potent anti-angiogenic combination regimens in low-risk patients to evaluate whether this approach can deliver better outcomes for this group. Under the leadership of Professor Jun Guo at Peking University Cancer Hospital, we have initiated studies on bispecific antibodies such as AK112 and PM8002. We hope these novel agents will show promising efficacy data in low-risk populations, providing new treatment options for advanced RCC.
2. Exploring Domestic HIF-2α Inhibitors: Given that HIF-2α inhibitors have become treatment options for patients who fail multiple lines of therapy abroad, but are not yet available in China, we are actively researching similar agents to bring them into the domestic advanced RCC treatment landscape. Concurrently, we are conducting clinical trials to evaluate their efficacy and safety in Chinese patients.
3. Addressing Challenges in Non-Clear Cell RCC Treatment: The treatment of non-clear cell RCC remains a significant clinical challenge both in China and globally. To address this, we aim to further analyze the biological characteristics of non-clear cell RCC and conduct studies targeting its unique biological behavior. This will help us develop more precise treatment strategies and improve patient outcomes and quality of life.

Dr. Xinan Sheng:

Professor, Chief Physician, PhD Supervisor Deputy Director, Department of Urological Oncology, Peking University Cancer Hospital Vice Chair, Integrative Rehabilitation Committee for Urogenital Tumors, Chinese Anti-Cancer Association Standing Committee Member, Urologic Oncology Committee, Chinese Anti-Cancer Association Council Member, Chinese Society of Clinical Oncology (CSCO) Standing Committee Member and Secretary-General, CSCO Renal Cancer Expert Committee Standing Committee Member, CSCO Urothelial Cancer Expert Committee Member, Bladder Cancer Quality Control Expert Committee, National Cancer Quality Control Center Incoming Chair, Urothelial Oncology Branch, Beijing Tumor Prevention and Treatment Society Chair, Youth Committee, Urogenital Oncology Branch, Beijing Anti-Cancer Association Standing Committee Member, Oncology Branch, Beijing Medical Association