Genomic Profiling and Response to Immune Checkpoint Inhibition plus Tyrosine Kinase Inhibition in FH-Deficient Renal Cell Carcinoma

Yunze Xu¹, Wen Kong¹, Ming Cao¹, Jieying Wang², Zaoyu Wang³, Liang Zheng⁴, Xiaoyu Wu⁴, Rongrong Cheng⁴, Wei He³, Bo Yang⁵, Baijun Dong¹, Jiahua Pan¹, Yonghui Chen¹, Jiwei Huang¹, Chen Jiang¹, Wei Zhai¹, Fangzhou Li¹, Ruohua Chen⁶, Xiang Zhou⁶, Guangyu Wu⁷, Xiaochuan Geng⁷, Jiasheng Chen⁸, Huimin An⁹, Yichu Yuan¹⁰, Tianyuan Xu¹¹, Dongning Chen¹², Dengqiang Lin¹³, Lieyu Xu¹⁴, Kangbo Huang¹⁵, Ling Peng¹⁶, Yanfei Yu¹⁷, Shengcheng Tai¹⁸, Honggang Qi¹⁹, Kai Luo²⁰, Xiaonan Kang²⁰, Hang Wang²¹, Yiran Huang²², Jin Zhang²³, Wei Xue²⁴

Affiliations

¹ Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Clinical Center for Investigation, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁵ Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁶ Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁷ Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁸ Department of Urology, Changzhou No. 2 People's Hospital, Changzhou, China.
⁹ Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
¹⁰ Department of Urology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
¹¹ Department of Urology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
¹² Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
¹³ Department of Urology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China.
¹⁴ Department of Urological Surgery, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, China.
¹⁵ Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
¹⁶ Department of Respiratory Disease, Zhejiang Provincial People's Hospital, Hangzhou, China.
¹⁷ Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing, China.
¹⁸ Department of Urology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China.
¹⁹ Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
²⁰ Biobank Department, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
²¹ Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
²² Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: huangyrrenji@163.com.
²³ Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: med-zhangjin@vip.sina.com.
²⁴ Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: uroxuewei@163.com.

PMID: 35715365
DOI: 10.1016/j.eururo.2022.05.029

Multicenter Study

Genomic Profiling and Response to Immune Checkpoint Inhibition plus Tyrosine Kinase Inhibition in FH-Deficient Renal Cell Carcinoma

Yunze Xu et al. Eur Urol. 2023 Feb.

. 2023 Feb;83(2):163-172.

doi: 10.1016/j.eururo.2022.05.029. Epub 2022 Jun 15.

Authors

Affiliations

¹ Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Clinical Center for Investigation, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁵ Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁶ Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁷ Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁸ Department of Urology, Changzhou No. 2 People's Hospital, Changzhou, China.
⁹ Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
¹⁰ Department of Urology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
¹¹ Department of Urology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
¹² Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
¹³ Department of Urology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China.
¹⁴ Department of Urological Surgery, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, China.
¹⁵ Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
¹⁶ Department of Respiratory Disease, Zhejiang Provincial People's Hospital, Hangzhou, China.
¹⁷ Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing, China.
¹⁸ Department of Urology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China.
¹⁹ Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
²⁰ Biobank Department, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
²¹ Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
²² Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: huangyrrenji@163.com.
²³ Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: med-zhangjin@vip.sina.com.
²⁴ Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: uroxuewei@163.com.

PMID: 35715365
DOI: 10.1016/j.eururo.2022.05.029

Abstract

Background: FH-deficient renal cell carcinoma (RCC) is a rare and exceptionally aggressive RCC subtype. There is currently limited understanding of the molecular alterations, pathogenesis, survival outcomes, and systemic therapy efficacy for this cancer.

Objective: To perform a retrospective multicenter analysis of molecular profiling and clinical outcomes for patients with FH-deficient RCC, with an emphasis on treatment response to first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI/TKI) versus bevacizumab plus erlotinib (Bev/Erlo) combination therapy in patients with advanced disease.

Design, setting, and participants: The study included 77 cases of FH-deficient RCC from 15 centers across China.

Outcome measurements and statistical analysis: Clinical characteristics, molecular correlates, ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography imaging, and treatment outcomes were analyzed.

Results and limitations: A total of 77 patients were identified, including 70 cases with a germline FH alteration (hereditary leiomyomatosis RCC syndrome [HLRCC]-associated RCC) and seven patients with somatic FH loss. Recurrent pathogenic alterations were found in NF2 (six/57, 11%), CDH1 (six/57, 11%), PIK3CA (six/57, 11%), and TP53 (five/57, 8.8%). Sixty-seven patients were evaluable for response to first-line systemic therapy with Bev/Erlo (n = 12), TKI monotherapy (n = 29), or ICI/TKI (n = 26). ICI/TKI combination therapy was associated with more favorable overall survival on systemic treatment (hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.04-0.90) and progression-free survival on first-line therapy (HR 0.22, 95% CI 0.07-0.71) compared to Bev/Erlo combination therapy. The main limitation is the retrospective study design.

Conclusions: We described the genomic characteristics of FH-deficient RCC in an Asian population and observed a favorable response to ICI/TKI combinational therapy among patients with advanced disease.

Patient summary: This real-world study provides evidence supporting the antitumour activity of combining molecular targeted therapy plus immunotherapy for kidney cancer deficient in fumarate hydratase. Further studies are needed to investigate the efficacy of this combination strategy in this rare cancer.

Keywords: (18)F-fluorodeoxyglucose positron emission tomography; FH-deficient renal cell carcinoma; Fumarate hydratase; Genomic profiling; Hereditary leiomyomatosis and renal cell carcinoma; Immunotherapy; PD-L1.

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Comment in

Improving Systemic Therapy for Fumarate Hydratase-deficient Renal Cell Carcinoma.
Carlo MI. Carlo MI. Eur Urol. 2023 Apr;83(4):e113-e114. doi: 10.1016/j.eururo.2022.12.020. Epub 2023 Jan 20. Eur Urol. 2023. PMID: 36682904 No abstract available.

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Genomic Profiling and Response to Immune Checkpoint Inhibition plus Tyrosine Kinase Inhibition in FH-Deficient Renal Cell Carcinoma

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Genomic Profiling and Response to Immune Checkpoint Inhibition plus Tyrosine Kinase Inhibition in FH-Deficient Renal Cell Carcinoma

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