preface
Venous system invasion is one of the clinical features of locally advanced renal cell carcinoma (RCC), and radical nephrectomy combined with cancer embolectomy is the preferred treatment for patients with localized renal cancer thrombus. However, even with open surgery, serious complications such as massive bleeding and pulmonary embolism may occur during the removal of the cancer thrombus and reconstruction of the inferior vena cava. Studies have shown that patients with renal cancer and venous thrombosis have a perioperative mortality rate of 5% to 15%1, and the higher the thrombus grade, the higher the risk of perioperative complications. Therefore, preoperative neoadjuvant therapy to reduce the height and grade of cancer thrombus is of great significance to reduce perioperative risk. The NEOTAX study of toripalimab combined with axitinib neoadjuvant therapy for renal cancer with inferior vena cava cancer thrombosis led by the team of Academician Zhang Xu, Professor Ma Xin and Professor Gu Liangyou of the General Hospital of the People's Liberation Army of Chinese People's Liberation Army was selected for the 2024 ESMO Annual Meeting and the results were announced in the form of a poster2. On this occasion, Yimaitong invited Professor Gu Liangyou, the first author of the study, to share the cutting-edge progress of target-free combination therapy for kidney cancer, and to discuss the impact of the results of this NEOTAX study on the treatment pattern 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).
Figure 2A Cancer thrombus degradement
Figure 2B Change in thrombus height
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 results
● 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).
Figure 2C
Figure 2D
● Security
Treatment-related adverse events (TRAEs) occurred in all patients (100.0%), and most of them were grade 1 or 2. Grade 3 TRAEs occurred in 7 patients (28.0%), mainly hypertension (8.0%) and proteinuria (8.0%).
● 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 non-responders.
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