Efficacy and safety of vorolanib plus everolimus in metastatic renal cell carcinoma: A three-arm, randomised, double-blind, multicentre phase III study (CONCEPT)

Xinan Sheng; Dingwei Ye; Aiping Zhou; Xin Yao; Hong Luo; Zhisong He; Zengjun Wang; Yingchao Zhao; Zhigang Ji; Qing Zou; Chaohong He; Jianming Guo; Xinhua Tu; Ziling Liu; Benkang Shi; Ben Liu; Peng Chen; Qiang Wei; Zhiquan Hu; Yanqiao Zhang; Kui Jiang; Fangjian Zhou; Dapeng Wu; Cheng Fu; Xingya Li; Bin Wu; Lijie Wang; Shukui Qin; Gang Li; Yunpeng Liu; Hongqian Guo; Kehe Chen; Dahong Zhang; Gongxian Wang; Lieming Ding; Yang Wang; Xiaobin Yuan; Jun Guo

doi:10.1016/j.ejca.2022.10.025

Efficacy and safety of vorolanib plus everolimus in metastatic renal cell carcinoma: A three-arm, randomised, double-blind, multicentre phase III study (CONCEPT)

Eur J Cancer. 2023 Jan:178:205-215. doi: 10.1016/j.ejca.2022.10.025. Epub 2022 Nov 1.

Authors

Xinan Sheng¹, Dingwei Ye², Aiping Zhou³, Xin Yao⁴, Hong Luo⁵, Zhisong He⁶, Zengjun Wang⁷, Yingchao Zhao⁸, Zhigang Ji⁹, Qing Zou¹⁰, Chaohong He¹¹, Jianming Guo¹², Xinhua Tu¹³, Ziling Liu¹⁴, Benkang Shi¹⁵, Ben Liu¹⁶, Peng Chen¹⁷, Qiang Wei¹⁸, Zhiquan Hu¹⁹, Yanqiao Zhang²⁰, Kui Jiang²¹, Fangjian Zhou²², Dapeng Wu²³, Cheng Fu²⁴, Xingya Li²⁵, Bin Wu²⁶, Lijie Wang²⁷, Shukui Qin²⁸, Gang Li²⁹, Yunpeng Liu³⁰, Hongqian Guo³¹, Kehe Chen³², Dahong Zhang³³, Gongxian Wang³⁴, Lieming Ding³⁵, Yang Wang³⁵, Xiaobin Yuan³⁵, Jun Guo³⁶

Affiliations

¹ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, China. Electronic address: doctor_sheng@126.com.
² Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
³ Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁴ Department of Genitourinary Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
⁵ Department of Urologic Oncology, Chongqing University Cancer Hospital, Chongqing, China.
⁶ Department of Urology, Peking University First Hospital, Beijing, China.
⁷ Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
⁸ Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁹ Urology Department, Peking Union Medical College Hospital, Beijing, China.
¹⁰ Department of Urology, Jiangsu Cancer Hospital, Nanjing, China.
¹¹ Department of Urology, Cancer Hospital of Henan Province, Zhengzhou, China.
¹² Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
¹³ Department of Urology, Jiangxi Province Tumor Hospital, Nanchang, China.
¹⁴ Department of Oncology, The First Hospital of Jilin University, Changchun, China.
¹⁵ Department of Urology, Qilu Hospital of Shandong University, Jinan, China.
¹⁶ Department of Urology, The First Affiliated Hospital, School of Medical, Zhejiang University, Hangzhou, China.
¹⁷ Department of Urology, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China.
¹⁸ Department of Urology, West China Hospital Sichuan University, Chengdu, China.
¹⁹ Department of Urology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
²⁰ Gastroenterology Department II, Harbin Medical University Cancer Hospital, Harbin, China.
²¹ Department of Gynecological and Genitourinary Medical Oncology, The Second Hospital of Dalian Medical University, Dalian, China.
²² Urology, Cancer Center, Sun Yat-sen University, Guangzhou, China.
²³ Department of Urology, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.
²⁴ Department of Urology, Liaoning Cancer Hospital & Institute, Shenyang, China.
²⁵ Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
²⁶ Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China.
²⁷ Department of Oncology, Chinese PLA General Hospital, Beijing, China.
²⁸ Department of Oncology, Qinhuai Medical Area, Theater General Hospital of PLA, Nanjing, China.
²⁹ Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
³⁰ Department of Oncology, The First Hospital of China Medical University, Shenyang, China.
³¹ Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
³² Department of Medical Oncology II, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
³³ Department of Urology, Zhejiang Provincial People's Hospital, Hangzhou, China.
³⁴ Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
³⁵ Betta Pharmaceuticals Co., Ltd., Hangzhou, China.
³⁶ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, China. Electronic address: guoj307@126.com.

PMID: 36459768
DOI: 10.1016/j.ejca.2022.10.025

Abstract

Background: Vorolanib is a highly potent tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor. This three-arm, randomised, registered study aimed to assess the combination of vorolanib and everolimus or vorolanib alone versus a control arm of everolimus as second-line treatment in patients with metastatic renal cell carcinoma (RCC).

Patients and methods: Patients with advanced or metastatic RCC who had received one prior VEGFR-TKI were randomised (1:1:1) to receive the combination of vorolanib and everolimus or either monotherapy. Patients with brain metastases were excluded. The primary end-point was progression-free survival (PFS) assessed by the independent review committee per Response Evaluation Criteria in Solid Tumours v1.1.

Results: Between 10th March 2017 and 30th May 2019, 399 patients (133 in each group) were enrolled. By the cutoff date (30th April 2020), a significant improvement in PFS was detected in the combination group compared with the everolimus group (10.0 versus 6.4 months; hazard ratio, 0.70; P = 0.0171). PFS was similar between the vorolanib group and the everolimus group (median: 6.4 versus 6.4 months; hazard ratio, 0.94; P = 0.6856). A significantly higher objective response rate was observed in the combination group than in the everolimus group (24.8% versus 8.3%; P = 0.0003), whereas there was no significant difference between the vorolanib group and the everolimus group (10.5% versus 8.3%; P = 0.5278). The overall survival data were immature. A total of 96 (72.2%), 52 (39.1%) and 71 (53.4%) grade 3 or higher treatment-related adverse events occurred in the combination group, vorolanib group and everolimus group, respectively.

Conclusions: The addition of vorolanib to everolimus as 2nd-line treatment for patients with advanced or metastatic RCC who have experienced cancer progression after VEGFR-TKI therapy provided a better objective response rate and PFS than everolimus alone with a manageable safety profile.

Trial registration: ClinicalTrials.gov, NCT03095040; Chinadrugtrials, CTR20160987.

Keywords: Everolimus; Renal cell carcinoma; VEGFR; Vorolanib; mTOR.

Publication types

Randomized Controlled Trial
Multicenter Study
Clinical Trial, Phase III
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Combined Chemotherapy Protocols* / adverse effects
Carcinoma, Renal Cell* / drug therapy
Everolimus / therapeutic use
Humans
Kidney Neoplasms* / drug therapy
Protein Kinase Inhibitors / therapeutic use
Receptors, Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor A

Substances

Everolimus
Protein Kinase Inhibitors
Receptors, Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor A
vorolanib

Associated data

ClinicalTrials.gov/NCT03095040