Clinical Outcomes and Safety Profile of Neoadjuvant PD-1 Inhibitors Combined With VEGFR-TKI versus VEGFR-TKI in Nonmetastatic Renal Cell Carcinoma

Our nationwide collaboration involving 29 Chinese medical centers has generated compelling real-world evidence for neoadjuvant PD-1/VEGFR-TKI combination therapy in nonmetastatic renal cell carcinoma (RCC), especially for tumor thrombus (TT) cases. While the abstract highlights key findings (improved objective response ratio [ORR], pathological complete response [pCR] rates, recurrence-free survival (RFS benefit in TT patients, and reduced surgical blood loss), several nuances and implications warrant further discussion.

1. Methodological Considerations

1.1 Design Limitations
The retrospective design inherently introduces selection bias and heterogeneity in study protocols (e.g., varied TKIs and PD-1 inhibitors used, non-strict TNM selection criteria). Although multivariate analysis and subgroup analysis could have mitigated confounding, we still acknowledge this limitation and advocate for prospective validation. Notably, the inclusion of 29 centers across China strengthens generalizability within Asian populations but leaves open questions about applicability to other ethnic groups.

1.2 TT as a High-Risk Subgroup
The focus on TT patients is clinically significant, as this subgroup represents a surgical challenge with poor prognosis. The observed RFS benefit (HR 0.52, P = 0.047) and pCR rate of 18.2% in TT patients suggest that combination therapy may reverse the potential micro-metastatic scenario. However, the lack of overall survival (OS) benefit (P = 0.247) raises questions about long-term durability. Especially for TT, whether the RFS benefit brought by combination therapy can be translated into OS benefit needs further exploration.

2. Unanswered Questions and Future Directions

2.1 Mechanistic Insights
Our study does not elucidate why combination therapy outperforms monotherapy. Preclinical data suggest VEGF inhibition may enhance T-cell infiltration,¹ but biomarker analyses (e.g., PD-L1 expression, tumor mutational burden) are missing. Such data could identify patients most likely to benefit. Strictly designed clinical studies accompanied by multi-omics analysis are necessary

2.2 Optimal Duration and Sequencing
The median combined treatment duration was 3 months, but the range (1–18 months) underscores variability. Prospective trials should standardize neoadjuvant duration and explore adjuvant ICI continuation post-surgery.

3. Clinical Implications

The reduced intraoperative blood loss (200 vs. 300 mL, P = 0.004) is a pragmatic advantage, likely due to tumor downsizing and vascular normalization. This could translate to fewer transfusions and shorter hospital stays, though the study did not capture these metrics. For surgeons, these findings support neoadjuvant combination therapy as a strategy to simplify complex resections, especially for TT extending into the vena cava.

4. Conclusion

While this study advances neoadjuvant paradigms in RCC, its retrospective nature and lack of mechanistic data caution against overgeneralization. The results align with the emerging trend but highlight the need for further trials to confirm RFS/OS benefits and define predictive biomarkers.^2-4 For now, the combination approach appears viable for high-risk localized RCC, particularly in TT patients, but shared decision-making should weigh efficacy against potential toxicity.

Written by: Cheoklong Ng,¹ Cheng Peng,² Shangqian Wang,³ Lei Zheng,⁴ Le Qu,⁵ Pei Dong,⁶ Changwei Ji,⁷ Jun Xiao,⁸ Minfeng Chen,⁹ Zhankui Jia,¹⁰ Tao Zhang,¹¹ Xiaoyi Hu,¹² Taile Jing,¹³ Wei Xiong,¹⁴ Jianping Wu,¹⁵ Xiongjun Ye,¹⁶ Fan Li,¹⁷ Qing Yang,¹⁸ Qi Tang,¹⁹ Juping Zhao,²⁰ Xuedong Wei,²¹ Jitao Wu,²² Wen Cai,²³ Guodong Zhu,²⁴ Zhixian Yu,²⁵ Zejun Yan,²⁶ Chancan Li,²⁷ Zhiyang Huang,²⁸ Zhenyu Wang,²⁹ Yonghui Chen,¹ Jin Zhang,¹ Wei Xue,¹ Yige Bao,³⁰ Chao Qin,³ Gang Guo,² Jiwei Huang¹

Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Urology, The Third Medical Centre, Chinese PLA General Hospital, Beijing, China.
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Urology, Jinling Hospital, Clinical School of Medical College, Nanjing University; Nanjing, China.
Department of Urology Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Department of Urology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Department of Urology, Xiangya Hospital Central South University, Changsha, Hunan, China.
The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, PR China.
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Urology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Department of Urology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.
Affiliated Zhongda Hospital of Southeast University, Nanjing, China.
Department of Urology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, PR China.
Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Urology, Peking University First Hospital, Peking University, National Urological Cancer Center, Beijing, China.
Department of Urology, Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China.
The First Affiliated Hospital of Soochow University, Suzhou, China.
Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China.
Department of Urology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China.
Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Urology, the First Affiliated Hospital of Ningbo University, Ningbo,China.
Department of Urology, Anhui No.2 Provincial People's Hospital, Hefei, Anhui, China.
Department of Urology, Quanzhou First Hospital affiliated to Fujian Medical University, Quanzhou, China.
Department of Urology, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
Department of Urology, West China Hospital, Sichuan University, Chengdu, China.

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