preface
Venous system invasion is one of the clinical features of locally advanced renal cell carcinoma (RCC), and radical nephrectomy combined with thrombectomy is the preferred treatment for patients with localized renal cancer with cancer thrombus. However, serious complications such as massive bleeding and pulmonary embolism may occur during the process of removing the cancer thrombus and reconstructing the inferior vena cava, and the higher the cancer thrombus grade, the higher the risk of perioperative complications. Perioperative mortality rates in patients with renal cancer and venous thrombosis have been shown to range from 5% to 15%1. In order to improve the prognosis of such patients, the team of Academician Zhang Xu, Professor Ma Xin and Professor Gu Liangyou of the General Hospital of the Chinese People's Liberation Army led the NEOTAX study of toripalimab combined with axitinib neoadjuvant treatment of renal cancer with inferior vena cava cancer thrombus, and the results showed that the program successfully achieved the "triple hit" of downgrading venous cancer thrombosis, reducing surgical difficulty and reducing perioperative risks, which has been officially published in the Nature sub-journal Signal Transduction and Targeted Therapy (Impact Factor: 40.8) 2. On this occasion, Yimaitong is honored to invite the first author, Professor Gu Liangyou, to share the research results of NEOTAX and explore the impact of the success of the neoadjuvant regimen of toripalimab combined with axitinib on the treatment landscape of locally advanced kidney cancer.
Background:
Preoperative lowering of the inferior vena cava cancer thrombosis (IVC-TT) grade reduces surgical morbidity and mortality in RCC. The RENOTORCH study is a Phase III trial evaluating the efficacy of toripalimab in combination with axitinib versus sunitinib in metastatic RCC, with progression-free survival (PFS) of 18.0 months and 9.8 months in the combination of toripalimab plus axitinib and sunitinib alone, respectively. Compared with sunitinib monotherapy, toripalimab plus axitinib was associated with a 35% reduction in the risk of disease progression or death (HR 0.65, 95% CI 0.49-0.86; P=0.0028), with an objective response rate of 56.7% in the combination group and 30.8% in the sunitinib group. This Phase II study (NEOTAX) evaluated the efficacy and safety of toripalimab in combination with axitinib in the neoadjuvant treatment of patients with RCC and IVC-TT (ChiCTR2000030405).
Research Methods:
A total of 29 patients with clear cell renal cell carcinoma (ccRCC) with grade II.-IV IVC-TT (cT3b/c), cN0/1, cM0/1, and radical nephrectomy combined with inferior vena cava cancer thrombectomy were included. The recommended dose of toripalimab is 240 mg every 3 weeks for 4 cycles. The dose of axitinib is 5 mg twice daily (Figure 1). The primary endpoint was the rate of IVC-TT de-escalation. Secondary endpoints included surgical strategy and percent change in thrombus height, response rate, surgical complication rate, PFS, safety, and biomarker analysis. The deadline for this data analysis is February 1, 2024.
Fig.1 Study design
Findings:
● Baseline characteristics
From March 2020 to October 2023, a total of 29 patients were included, of which 25 received study treatment and were included in the analysis. The median age of patients was 58 years (IQR: 51.5-67.5 years), and the majority were male (n=19, 76.0%). Ten patients (40.0%) had lymph node metastasis and 5 patients (25.0%) had distant metastases. There were 9 patients (36.0%), 7 cases (28.0%), and 9 patients (36.0%) with Mayo grades of cancer thrombus grades II., III., and IV., respectively (Table 1).
Table 1 Baseline characteristics of patients
● Efficacy
After 12 weeks of treatment, 44.0% (11/25) of patients had cancer thrombosis downgrade (2 patients were downgraded from grade IV to grade III., 1 patient was downgraded from grade IV to grade II., 1 patient was downgraded from grade IV to grade I., 5 patients were downgraded from grade III to grade II., and 2 patients were lowered from grade II to grade I) (Fig. 2A). 24/25 (96.0%) of patients had varying degrees of reduction in thrombus height (range: 5-79%), with a median change in thrombus height of -2.3 cm (range: -7.1 to 1.1 cm) (Figure 2B).
Fig. 2 (A) thrombus degradation and (B) thrombus height change
61.9% (13/21) of the patients changed their surgical strategy. The postoperative complication rate was 57.1% (12/21) (Table 2).
Table 2 Perioperative outcomes
● Follow-up
Nineteen patients (36.0%) developed tumor progression, of which 7 progressed postoperatively (Fig. 2C). The 1- and 2-year PFS rates were 89.1% (95% CI: 62.7-97.2) and 54.8% (95% CI: 27.5-75.6), respectively (Figure 2D).
Fig. 2 (C) tumor progression and (D) PFS
● Security
Treatment-related adverse events (TRAEs) occurred in all patients (100.0%), and most of them were grade 1 or 2 (Table 3). Grade 3 TRAEs occurred in 7 patients (28.0%), mainly hypertension (8.0%) and proteinuria (8.0%).
Table 3 Safety outcomes
● Conversion analysis
Biopsy samples from nonresponders show increased cytotoxic T infiltration, but these cells are predominantly PD-1 positive. Helper T cells decreased in the responder's biopsy samples, while regulatory T cell subtypes remained unchanged. In surgical samples of cancer thrombus, there was an increase in CD8T_01_GZMK_CXCR4 subset of T cells in nonresponders (Fig. 3, Fig. 4).
Figure 3. Differences in cell composition in multiplex immunofluorescence biopsy samples
Figure 4. scRNA-seq analysis was performed to analyze the differences in cell composition of the samples after treatment between patients who responded (R) and those who did not respond (NR).
Conclusions of the study
For the first time, the Phase II study of NEOTAX provides evidence for the efficacy of toripalimab in combination with axitinib in reducing the scope of surgery in a significant proportion of patients with IVC-TT downgrade.
The study is progressing well, and overall, toripalimab in combination with axitinib as a neoadjuvant treatment for patients with renal cancer and venous cancer thrombosis has demonstrated excellent efficacy and a good safety profile, bringing significant benefits to patients.
Expert commentary
Prof. Liangyou Gu
General Hospital of the Chinese People's Liberation Army
- Chinese Deputy Chief Physician, Associate Professor, Master Supervisor, Department of Urology, General Hospital of the People's Liberation Army
- Secretary of the Clinical Research Office of the Urology Branch of the Chinese Medical Association
- Member of the Basic and Translational Medicine Group of the Urology Branch of the Beijing Medical Association
- Selected for the 2023 Beijing Science and Technology Rising Star Program
- He has presided over 2 projects of the National Natural Science Foundation of China and 1 independent innovation project of the Institute, and participated in the national key research and development projects and the special key projects of health development and scientific research in the capital as the backbone of the project
- 以第一/通讯作者于Innovation、Eur Urol、Cancer Treat Rev、J Urol、BJUI等发表论文33篇
- I'm going to go "I'm going to be a
- BMC Urology、Frontiers in Oncology编委，Cancer Letters、Surgery等审稿人
- He has won 1 first prize of the Chinese Medical Science and Technology Award, 1 first prize of the Medical Achievement Award and 1 second prize of the Science and Technology Progress Award of the PLA General Hospital
Yimaitong: The drug treatment model of kidney cancer has undergone many changes in the era, and now it has entered the era of target-immune combination, and a variety of drug combination schemes have been developed internationally. As one of the NEOTAX study leaders, could you please talk about the reasons for choosing toripalimab plus axitinib?
Professor Gu Liangyou
In the treatment of advanced kidney cancer, there are many combination regimens, among which programmed death receptor 1 (PD-1) inhibitors combined with axitinib are widely used in the treatment of advanced kidney cancer in China, and are regarded as a conventional treatment option. For patients with locally advanced renal cancer with cancer thrombus, there is still no standard neoadjuvant treatment regimen in the current clinical guidelines, and there is a lack of strong evidence to support it, mainly relying on empirical therapy. If the cancer thrombus can be reduced, the surgical area can be reduced and the difficulty of surgery can be reduced.
As a PD-1 drug developed in China, toripalimab has shown good efficacy in early real-world applications. The NEOTAX study continues to be based on the Chinese population, so we chose toripalimab in the treatment regimen in order to achieve efficacy comparable to international advanced PD-1 inhibitors and further reduce the economic burden of patients. Toripalimab combined with axitinib is the first target-immune combination regimen approved for the first-line treatment of advanced RCC in mainland China, and we hope to play a "1+1>2" role to explore whether this regimen is expected to move forward to the local advanced stage, so as to provide diversified treatment options for a wider patient population and provide more effective treatment "weapons" for doctors.
Yimaitong: There is no standard perioperative treatment plan for locally advanced RCC, so the publication of the results of the NEOTAX study has attracted much attention. Could you please share with us what were the perioperative outcomes and overall prognosis of patients receiving neoadjuvant therapy with toripalimab plus axitinib in this study?
Professor Gu Liangyou
Perioperative outcomes after neoadjuvant therapy have been preliminarily evaluated, and 61.9% of patients have simplified their surgical regimen after 12 weeks of treatment with toripalimab plus axitinib, and all patients have successfully completed surgery. Compared with previous reports, the median operation time, blood loss, blood transfusion, and postoperative complications were significantly improved. Overall, the perioperative results were satisfactory.
The overall prognosis is 89.1% (95% CI: 62.7-97.2) at 1-year PFS from the current preliminary data, which is very satisfactory and many patients have been effectively controlled during the year. We will further analyse perioperative versus prognostic outcomes compared to patients who do not receive medical therapy and report them in follow-up studies.
Yimaitong: Toripalimab combined with axitinib has created the era of first-line target-immune combination for advanced kidney cancer in mainland China, and now it is in the neoadjuvant stage of locally advanced kidney cancer. Based on your clinical experience, what is the clinical significance of the positive results of the NEOTAX study for the diagnosis and treatment of locally advanced RCC, and what are your expectations for this program?
Professor Gu Liangyou
Experience with neoadjuvant therapy for kidney cancer is relatively limited. For locally advanced renal cancer, the need for drug therapy has always existed, but whether to perform preoperative neoadjuvant therapy has always been a puzzle point in clinical practice. NEOTAX is the first phase II neoadjuvant study of toripalimab combined with axitinib in patients with locally advanced thrombosis and high-risk thrombosis in patients with tumor thrombosis in China. Preliminary results showed that preoperative toripalimab combined with axitinib neoadjuvant therapy could significantly reduce the grade of cancer thrombosis, reduce the difficulty of surgery, improve the success rate of surgery, and bring significant perioperative benefits to such patients. It is expected that in the future, with the accumulation of neoadjuvant cases and the emergence of higher-level evidence, this combination regimen will become the standard protocol for patients with locally advanced kidney cancer, which will provide greater confidence and support for our application in clinical practice."
summary
The emergence of targeted therapy has changed the treatment paradigm of kidney cancer, and the combination of tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptors and immunotherapy has been widely recognized, opening a new chapter for the treatment of advanced kidney cancer. The approval of toripalimab in combination with axitinib fills the gap in the first-line target-immune combination of advanced kidney cancer in mainland China and provides clinicians with a new powerful weapon. The NEOTAX study further demonstrated the superior efficacy and safety of toripalimab in combination with axitinib as neoadjuvant therapy for clear cell renal cell carcinoma with inferior vena cava cancer thrombosis. Studies have shown that this combination can reduce the height and grade of cancer thrombus, thereby creating more favorable conditions for surgery, reducing the difficulty of surgery and improving the success rate of surgery. This discovery is expected to advance the clinical application of this treatment regimen, improve the treatment outcomes and quality of life of patients with locally advanced kidney cancer, and bring a new dawn for the treatment of such patients.
Bibliography:
1.Liangyou Gu, et al. Neoadjuvant therapy in renal cell carcinoma with tumor thrombus: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2024 Apr:196:104316.
2.Liangyou Gu, et al. Neoadjuvant toripalimab plus axitinib for clear cell renal cell carcinoma with inferior vena cava tumor thrombus: NEOTAX, a phase 2 study. Sig Transduct Target Ther. 2024,9:264.
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