Professors Sheng Xinan, Zeng Hao and Zhang Hailiang: Toripalimab combined with axitinib to create a 1+1>2 first-line regimen for advanced kidney cancer

Preface

In the field of cancer treatment, the continuous innovation of combination therapy regimens has promoted the improvement of clinical treatment efficacy, especially in the first-line treatment of advanced renal cell carcinoma (RCC), targeted combination immunotherapy has become a new standard. On April 7, 2024, the National Medical Products Administration (NMPA) approved toripalimab in combination with axitinib for the first-line treatment of patients with intermediate- and high-risk unresectable or distant metastatic kidney cancer. This is the first approved target-free combination protocol for advanced RCC in China, marking the official entry of a new era of late-stage RCC in mainland China. At this historic moment, Yimaitong invited Professor Sheng Xinan from Peking University Cancer Hospital, Professor Zeng Hao from West China Hospital of Sichuan University, and Professor Zhang Hailiang from Fudan University Cancer Hospital to discuss the benefits and risk balance of the first-line target-free combination regimen for advanced RCC, and to discuss the impact of the approval of toripalimab on the management pattern of patients with advanced RCC in mainland China.

The safety of target-free combination, toripalimab combined with axitinib is controllable

Yimaitong: At present, immunotherapy combined with targeted therapy has become the first-line standard treatment for advanced RCC abroad. However, there are still experts and scholars who are worried that this combination therapy model may also bring a certain degree of increase in toxicity and side effects while increasing the efficacy, what do you think about this problem?

Professor Sheng Xinan

On the one hand, we must affirm the positive significance of target-immune combination therapy. In recent years, many international multi-center clinical trials have confirmed that for patients with advanced RCC, especially those with an international metastatic kidney cancer (IMDC) score of intermediate and high risk, the effectiveness of target-immune combination therapy is better than that of targeted or immune monotherapy [1, 2], and surprising efficacy has been achieved. As a result, the National Comprehensive Cancer Network (NCCN) and the European Urological Association (EAU) guidelines for renal cell carcinoma give preference to target-immune combinations for the first-line standard of care for advanced RCC, with targeted monotherapy only as an alternative when immunotherapy is unacceptable or intolerant [3, 4].

However, efficacy and safety are inseparable sides of the same coin, so we strive to ensure the safety of treatment in the pursuit of the best efficacy. Because good safety is not only the premise of long-term survival of kidney cancer patients, but also the guarantee of quality of life of patients with long survival, and it is also convenient for doctors to manage patients. Although the target-immune combination may increase adverse drug reactions, the safety of the two when used alone has been widely validated. Evidence-based evidence is a strong endorsement, and the only approved first-line target-immune combination regimen for advanced RCC in mainland China is the toripalimab + axitinib combination, in which toripalimab combined with axitinib demonstrated a favorable safety profile in its pivotal phase III study (RENOTORCH), with a low incidence of adverse reactions during treatment [5]. In addition, as combination therapy brings more survival benefits to kidney cancer patients, the patient's physical condition gradually recovers, which will help reduce the occurrence of adverse drug reactions. Therefore, the safety of the current target-free combination therapy regimen is controllable, both from the perspective of the drug itself and the patient's physical condition.

Without increasing the safety burden, toripalimab combined with axitinib is superior to similar foreign regimens

Yimaitong: The RENOTORCH study is the first phase III study to explore the first-line target-immune combination therapy regimen in the Chinese advanced RCC population, please introduce the safety of toripalimab in combination with axitinib in the first-line treatment of advanced RCC in the RENOTORCH study?

Professor Zeng Hao

As of March 31, 2023, the median drug exposure time in the RENOTORCH study was 44.79 weeks in the Toripalimab plus Axitinib arm and 35.07 weeks in the sunitinib arm. Toripalimab plus axitinib has a favorable safety profile throughout the course of treatment, with less hematologic toxicity than in the control group, and no new safety signals have been observed[5].

In the RENOTORCH study, the ≥ grade 3 treatment-related adverse events (TRAEs) occurred in 61.5 percent, with a reduction rate of 31.3 percent and a discontinuation rate of 12.0 percent [5]. This compares with 68 percent of ≥ grade 3 TRAEs in the Pembrolizumab + Axitinib study in the Keynote-426 study [6], 81 percent in the avelumab + axitinib arm ≥ 81 percent in the JAVELIN RENAL 101 study [7], and 68 percent in the nivolumab + cabozantinib arm ≥ 68 percent in the Checkmate 9ER study [8]. Compared with similar foreign studies, the safety data of toripalimab combined with axitinib in the RENOTORCH study are not inferior.

The ORR was 56.7%, and toripalimab combined with axitinib brought long-term survival benefits to patients

Yimaitong: The good safety profile supports the success of the RENOTORCH study, could you please introduce the effectiveness of toripalimab combined with axitinib in the RENOTORCH study?

Professor Zhang Hailiang

In the intention-to-treat population (ITT), based on the results of the Independent Review Committee (IRC), the objective response rate (ORR) of patients in the toripalimab plus axitinib group was 56.7%, which was significantly higher than that in the sunitinib group (ORR 30.8%, P<0.0001）。 Further analysis of the ORR benefit of toripalimab plus axitinib based on the IMDC score at baseline showed that the ORR rates of patients at intermediate and high risk of IMDC were 56% and 59%, respectively, which were consistent with the results of the ITT set. The results confirmed that patients were treated with toripalimab in combination with axitinib with a good response, regardless of the IMDC risk level at baseline.

More importantly, the first-line regimen of toripalimab plus axitinib significantly prolonged overall survival (OS) and reduced the risk of death by 39% compared with sunitinib alone (NR vs 26.8 months, HR 0.61, P=0.0186). Overall, the favorable safety profile of toripalimab plus axitinib provides a solid foundation for long-term survival benefits, thereby helping patients better manage their disease.

In the broad world of fighting urological tumors, "Guochuang" toripalimab has made great achievements

Yimaitong: Toripalimab combined with axitinib is the first approved first-line target-free combination regimen for advanced RCC in mainland China, please talk about the significance of this for the treatment of kidney cancer in mainland China and the development of urological tumor treatment?

Professor Sheng Xinan

Internationally, target-immune combination therapy based on anti-programmed death receptor-1 (PD-1) drugs has become the first-line standard of care for advanced RCC, but no anti-PD-1 drug has been approved for the indication of advanced RCC in China. The approval of toripalimab successfully fills the gap in this field in mainland China, creating a new era of first-line target-free combination therapy for advanced RCC in mainland China, which is of milestone significance. In addition, toripalimab also has indications for the treatment of advanced urothelial carcinoma, covering two common malignant urological tumors, reflecting its far-reaching indication layout, and also vigorously promoting the development of immunotherapy in the field of urological tumors in mainland China.

Professor Zeng Hao

Previous clinical studies and experience tell us that urothelial carcinoma and kidney cancer are both diseases sensitive to immunotherapy, and toripalimab is also the only anti-PD-1 drug in mainland China that has both indications. Returning to kidney cancer, the median OS for intermediate-risk patients with IMDC is currently 14 months, compared with only 5 months for high-risk patients [9]. Therefore, the biggest beneficiary of the approval of toripalimab this time is the patient, which enables patients with advanced RCC in mainland China to use the international first-line treatment regimen and bring hope for patients to live longer.

Professor Zhang Hailiang

Since the 90s of the 20th century, the treatment of advanced RCC has gone through many epochs. From the era of cytokines to the era of targeted therapy, and then from the era of targeted therapy to the era of immunotherapy, the emergence of each treatment modality and the replacement of each treatment era represent a breakthrough in the survival of patients with advanced RCC again and again. Today, the first first-line target-immune combination regimen for advanced RCC in mainland China has been approved, which is the "key" (both the key and the key) to open a new era of target-free combination therapy for advanced RCC in mainland China, and it is also another achievement in the treatment of urological tumors in mainland China.

brief summary

The addition of toripalimab in combination with axitinib has revolutionized the treatment of advanced RCC, and the approval of this regimen is a major leap forward in the treatment of tumors in mainland China. While the significant ORR and prolonged OS brought substantial survival benefits to patients, its good safety profile revealed the therapeutic potential of the target-free combination regimen "1+1>2". Toripalimab combined with axitinib not only enhanced the therapeutic effect, but also did not significantly increase the adverse reactions, achieving a balance between therapeutic effect and safety. Toripalimab provides a more efficient and safe new option for patients with advanced RCC in mainland China, and it is expected that toripalimab can play a greater role in the treatment of urological tumors in the future and benefit a wider patient population.

-Professor Sheng Xinan-

• Chief Physician, Professor, Doctoral Supervisor
• Deputy Director of the Department of Urological Oncology, Peking University Cancer Hospital
• Vice Chairman of the Genitourinary Tumor Integrated Rehabilitation Professional Committee of the Chinese Anti-Cancer Association
• Member of the Standing Committee of the Urological Oncology Committee of the Chinese Anti-Cancer Association
• Director of the Chinese Society of Clinical Oncology (CSCO).
• Member of the Standing Committee and Secretary-General of the Renal Cancer Expert Committee of the Chinese Society of Clinical Oncology
• Member of the Standing Committee of the Urothelial Carcinoma Expert Committee of the Chinese Society of Clinical Oncology
• Member of the Bladder Cancer Quality Control Expert Committee of the National Cancer Quality Control Center
• Chairman-elect of the Urology Oncology Subcommittee of the Beijing Cancer Prevention and Treatment Research Association
• Chairman of the Youth Committee of the Genitourinary Oncology Committee of the Beijing Anti-Cancer Association
• Member of the Standing Committee of the Oncology Branch of Beijing Medical Association

- Professor Zeng Hao -

• Secretary of the Department of Urology, West China Hospital, Sichuan University, Professor, Doctoral Supervisor
• 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 Urogenital Tumor Committee of the Chinese Anti-Cancer Association
• Member and Deputy Secretary-General of the Urological Health Promotion Branch of the China Association for the Promotion of International Exchange in Health Care/Vice Chairman of the Youth Committee
• Member of the CSCO Expert Committee on Prostate Cancer/CSCO Urothelial Carcinoma/CSCO Kidney Cancer
• Member of the Standing Committee of Sichuan Provincial Urology Committee
• Deputy head of the Oncology Group of Sichuan Urology Special Committee
• Chairman of the Genitourinary Oncology Committee of Sichuan Oncology (Precision Therapy) Society
• Vice Chairman of the Urogenital Tumor Special Committee of Sichuan Anti-Cancer Association

- Professor Zhang Hailiang -

• Chief Physician of the Department of Urology, Fudan University Cancer Hospital
• Deputy Director of the Department of Urology, Fudan University Cancer Hospital
• Urologic oncology MDT expert, doctoral supervisor
• Deputy head of the Minimally Invasive Urologic Oncology Group of the Chinese Anti-Cancer Association
• Member of the Genetic Tumor Collaboration Group of the Chinese Anti-Cancer Association
• Member of China Association for the Promotion of International Exchange in Health Care
• Director of Shanghai Anti-Cancer Association
• Journal of Clinical Oncology中文版泌尿分册编委
• 近年来以第一作者或通讯作者在 Journal of Hematology & Oncology、Nature Communications、Clinical Cancer Research、Cancer Research、Journal for ImmunoTherapy of Cancer、Hypertension、International Journal of Biological Sciences、Clinical and Translational Medicine、JNCC等期刊发表SCI期刊论文120余篇，单篇最高被其他研究引用达400余次，国内权威核心期刊论文发表20余篇
• He has won the best paper at the 24th European Urology Congress, and has been invited to speak at the European Urology Congress, the American Urology Congress, and poster exchanges
• He presided over 1 sub-project of the National Major Special Fund
• He presided over 1 project of the National Science and Natural Science Foundation of China
• He has presided over 2 general projects of the Shanghai Natural Science Foundation
• He presided over 1 science popularization innovation project in Xuhui District, Shanghai
• As an academic backbone, he participated in 1 key project of basic research of Shanghai Municipal Science and Technology Commission and 1 joint research project of important diseases of Shanghai health system
• As the second completer, he won 1 first prize of Shanghai Science and Technology Progress Award
• 1 first prize of Science and Technology Progress Award of the Ministry of Education
• 1 second prize of Chinese Medical Science and Technology Award
• Participated in and won 1 first prize of the National Science and Technology Progress Award

Bibliography:

1. Renal Cancer Group, Urogenital Tumor Professional Committee, Chinese Anti-Cancer Association, et al. Journal of Clinical Urology. 2022, 37(5).

2. Guidelines Working Committee of Chinese Society of Clinical Oncology. Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Kidney Cancer. Beijing: People's Medical Publishing House. 2023.

3. European Association of Urology. Renal Cell Carcinoma 2023 [cited 2024-03-13]. Available from: https://uroweb.org/guidelines/renal-cell-carcinoma.

4. National Comprehensive Cancer Network. Kidney Cancer (Version 3.2024) 2024 [cited 2024-03-13]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf.

5. Yan X Q, et al. Annals of Oncology. 2024, 35(2): 190-199.

6. Rini B I, et al. Journal of Clinical Oncology. 2023, 41(17_suppl): LBA4501-LBA4501.

7. Haanen J B A G, et al. ESMO Open. 2023, 8(3).

8. Bourlon M T, et al. Journal of Clinical Oncology. 2024, 42(4_suppl): 362-362.

9. 中华人民共和国国家卫生健康委员会. 肾细胞癌诊疗指南（2022 年版） 2022 [cited 2024-03-26]. Available from: http://www.nhc.gov.cn/yzygj/s2911/202204/a0e67177df1f439898683e1333957c74/files/71c1a3953bcd42059e1bda2859305cef.pdf.

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