Jin Li1,2, Shukui Qin3, Rui-Hua Xu4,5, Lin Shen6, Jianming Xu7, Yuxian Bai8, Lei Yang9, Yanhong Deng10, Zhen-Dong Chen11, Haijun Zhong12, Hongming Pan13, Weijian Guo2, Yongqian Shu14, Ying Yuan15, Jianfeng Zhou16, Nong Xu17, Tianshu Liu18, Dong Ma19, Changping Wu20, Ying Cheng21, Donghui Chen22, Wei Li23, Sanyuan Sun24, Zhuang Yu25, Peiguo Cao26, Haihui Chen27, Jiejun Wang28, Shubin Wang29, Hongbing Wang30, Songhua Fan31, Ye Hua31, Weiguo Su31. 1. Department of Medical Oncology, Tongji University Shanghai East Hospital, Shanghai, China. 2. Department of Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China. 3. Department of Medical Oncology, Nanjing Chinese Medicine University-Affiliated Bayi Hospital, Nanjing, China. 4. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China. 5. Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. 6. Department of Medical Oncology, Beijing University Cancer Center, Beijing, China. 7. Department of Medical Oncology, 307th Hospital of Chinese People's Liberation Army, The Affiliated Hospital of Military Medical Sciences, Beijing, China. 8. Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China. 9. Department of Medical Oncology, Nantong Cancer Hospital, Nantong, China. 10. Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. 11. Department of Medical Oncology, The Second Hospital of Anhui Medical University, Hefei, China. 12. Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China. 13. Department of Medical Oncology, Sir RunRun Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China. 14. Department of Medical Oncology, Jiangsu Provincial Hospital, Nanjing, China. 15. Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. 16. Department of Medical Oncology, Peking Union Medical College Hospital, Beijing, China. 17. Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. 18. Department of Medical Oncology, Fudan University Zhongshan Hospital, Shanghai Medical College, Shanghai, China. 19. Department of Medical Oncology, Guangdong General Hospital, Guangzhou, China. 20. Department of Medical Oncology, The First People's Hospital of Changzhou, Changzhou, China. 21. Department of Medical Oncology, Jilin Province Cancer Hospital, Changchun, China. 22. Department of Medical Oncology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, China. 23. Department of Medical Oncology, The First Hospital of Jilin University, Changchun, China. 24. Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou, China. 25. Department of Medical Oncology, The Affiliated Hospital of Medical College Qingdao University, Qingdao, China. 26. Department of Medical Oncology, The Third Xiangya Hospital of Central South University, Changsha, China. 27. Department of Medical Oncology, Liuzhou Worker's Hospital, Liuzhou, China. 28. Department of Medical Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China. 29. Department of Medical Oncology, Peking University Shenzhen Hospital, Beijing University, Shenzhen, China. 30. Department of Medical Oncology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou Medical College, Xuzhou, China. 31. Hutchison MediPharma Ltd, Shanghai, China.
Abstract
Importance: Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options. Objective: To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. Design, Setting, and Participants: FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017. Interventions: Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. Main Outcomes and Measures: The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. Results: Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization. Conclusions and Relevance: Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China. Trial Registration: ClinicalTrials.gov Identifier: NCT02314819.
Importance: Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options. Objective: To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. Design, Setting, and Participants: FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017. Interventions: Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. Main Outcomes and Measures: The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. Results: Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization. Conclusions and Relevance: Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China. Trial Registration: ClinicalTrials.gov Identifier: NCT02314819.
Authors: Jean-Yves Douillard; Salvatore Siena; James Cassidy; Josep Tabernero; Ronald Burkes; Mario Barugel; Yves Humblet; György Bodoky; David Cunningham; Jacek Jassem; Fernando Rivera; Ilona Kocákova; Paul Ruff; Maria Błasińska-Morawiec; Martin Šmakal; Jean-Luc Canon; Mark Rother; Kelly S Oliner; Michael Wolf; Jennifer Gansert Journal: J Clin Oncol Date: 2010-10-04 Impact factor: 44.544
Authors: J Y Douillard; D Cunningham; A D Roth; M Navarro; R D James; P Karasek; P Jandik; T Iveson; J Carmichael; M Alakl; G Gruia; L Awad; P Rougier Journal: Lancet Date: 2000-03-25 Impact factor: 79.321
Authors: A de Gramont; A Figer; M Seymour; M Homerin; A Hmissi; J Cassidy; C Boni; H Cortes-Funes; A Cervantes; G Freyer; D Papamichael; N Le Bail; C Louvet; D Hendler; F de Braud; C Wilson; F Morvan; A Bonetti Journal: J Clin Oncol Date: 2000-08 Impact factor: 44.544
Authors: Leonard B Saltz; Stephen Clarke; Eduardo Díaz-Rubio; Werner Scheithauer; Arie Figer; Ralph Wong; Sheryl Koski; Mikhail Lichinitser; Tsai-Shen Yang; Fernando Rivera; Felix Couture; Florin Sirzén; Jim Cassidy Journal: J Clin Oncol Date: 2008-04-20 Impact factor: 44.544
Authors: Herbert Hurwitz; Louis Fehrenbacher; William Novotny; Thomas Cartwright; John Hainsworth; William Heim; Jordan Berlin; Ari Baron; Susan Griffing; Eric Holmgren; Napoleone Ferrara; Gwen Fyfe; Beth Rogers; Robert Ross; Fairooz Kabbinavar Journal: N Engl J Med Date: 2004-06-03 Impact factor: 91.245
Authors: Axel Grothey; Eric Van Cutsem; Alberto Sobrero; Salvatore Siena; Alfredo Falcone; Marc Ychou; Yves Humblet; Olivier Bouché; Laurent Mineur; Carlo Barone; Antoine Adenis; Josep Tabernero; Takayuki Yoshino; Heinz-Josef Lenz; Richard M Goldberg; Daniel J Sargent; Frank Cihon; Lisa Cupit; Andrea Wagner; Dirk Laurent Journal: Lancet Date: 2012-11-22 Impact factor: 79.321
Authors: Eric Van Cutsem; Josep Tabernero; Radek Lakomy; Hans Prenen; Jana Prausová; Teresa Macarulla; Paul Ruff; Guy A van Hazel; Vladimir Moiseyenko; David Ferry; Joe McKendrick; Jonathan Polikoff; Alexia Tellier; Rémi Castan; Carmen Allegra Journal: J Clin Oncol Date: 2012-09-04 Impact factor: 44.544