Efficacy and Safety of Vorolanib plus Everolimus in Metastatic Renal Cell Carcinoma: A Three-Arm, Randomised, Double-Blind, Multicentre Phase III Study (CONCEPT) - Beyond the Abstract
Optimal second-line therapies in mRCC in the current era of ICI-ICI and ICI-TKI combinations are challenging. Overall, there are no head-to-head comparisons between different treatment options for second and subsequent lines of therapy. After primary or acquired progression on ICI-TKI combination, non-ICI VEGF inhibition strategies with a different VEFGR TKI should be employed. In the absence of strong evidence to support continued ICIs after progression on first-line ICI-based therapy, if disease control was achieved on ipilimumab plus nivolumab prior to progression, consideration could be given to ICI-TKI combinations for second line, particularly lenvatinib plus pembrolizumab. If long-term disease control was previously achieved on first-line single-agent VEGFR TKI (i.e., pazopanib), patients could either continue TKI alone (cabozantinib, axitinib or tivozanib), or in combination with an mTOR inhibitor (lenvatinib and everolimus), or receive ICI monotherapy (nivolumab) according to NCCN guidelines; active second-line regimens also include other TKIs (sunitinib), ICI-TKI combinations or dual ICIs.
Until present, therapeutic decisions in second-line setting are mostly guided by strength of evidence for each drug, its toxicity profile, disease aggressiveness, mechanism of action, and pattern of responses during prior lines of therapy, patient comorbidities, availability of clinical trials, patient and physician preferences, and financial concerns. The ICI-based combinations as first-line treatment for mRCC are only approved in some countries only, and VEGFR-TKIs remain a recommended option as first-line therapy in China. Therefore, in this phase 3 CONCEPT study, VEGFR-TKIs were selected as first-line treatments and the combination of mTOR- and VEGF-targeting agents (everolimus + vorolanib) was employed as second-line treatments for mRCC. Although across-trial comparisons are difficult and should be made with caution, to our best knowledge, this is the first phase 3 study as the second-line setting that demonstrated the longest OS duration (30.4 months) in patients with RCC, which was longer than that reported in other pivotal phase 3 trials of sorafenib (17.8 months), everolimus (14.8 months), axitinib (20.1 months), nivolumab (25.8 months) and cabozantinib (21.4 months). This study provides a new option for previously TKI-treated patients with mRCC.
Written by: 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
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, China., Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China., 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., Department of Genitourinary Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China., Department of Urologic Oncology, Chongqing University Cancer Hospital, Chongqing, China., Department of Urology, Peking University First Hospital, Beijing, China., Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Urology Department, Peking Union Medical College Hospital, Beijing, China., Department of Urology, Jiangsu Cancer Hospital, Nanjing, China., Department of Urology, Cancer Hospital of Henan Province, Zhengzhou, China., Urology, Zhongshan Hospital, Fudan University, Shanghai, China., Department of Urology, Jiangxi Province Tumor Hospital, Nanchang, China., Department of Oncology, The First Hospital of Jilin University, Changchun, China., Department of Urology, Qilu Hospital of Shandong University, Jinan, China., Department of Urology, The First Affiliated Hospital, School of Medical, Zhejiang University, Hangzhou, China., Department of Urology, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China., Department of Urology, West China Hospital Sichuan University, Chengdu, China., Department of Urology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China., Gastroenterology Department II, Harbin Medical University Cancer Hospital, Harbin, China., Department of Gynecological and Genitourinary Medical Oncology, The Second Hospital of Dalian Medical University, Dalian, China., Urology, Cancer Center, Sun Yat-sen University, Guangzhou, China., Department of Urology, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China., Department of Urology, Liaoning Cancer Hospital & Institute, Shenyang, China., Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China., Department of Oncology, Chinese PLA General Hospital, Beijing, China., Department of Oncology, Qinhuai Medical Area, Theater General Hospital of PLA, Nanjing, China., Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China., Department of Oncology, The First Hospital of China Medical University, Shenyang, China., Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China., Department of Medical Oncology II, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China., Department of Urology, Zhejiang Provincial People's Hospital, Hangzhou, China., Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China., Betta Pharmaceuticals Co., Ltd., Hangzhou, China., Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, China.
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