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Original Investigation
June 26, 2018

Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal CancerThe FRESCO Randomized Clinical Trial

Author Affiliations
  • 1Department of Medical Oncology, Tongji University Shanghai East Hospital, Shanghai, China
  • 2Department of Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
  • 3Department of Medical Oncology, Nanjing Chinese Medicine University–Affiliated Bayi Hospital, Nanjing, China
  • 4Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
  • 5Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
  • 6Department of Medical Oncology, Beijing University Cancer Center, Beijing, China
  • 7Department of Medical Oncology, 307th Hospital of Chinese People's Liberation Army, The Affiliated Hospital of Military Medical Sciences, Beijing, China
  • 8Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
  • 9Department of Medical Oncology, Nantong Cancer Hospital, Nantong, China
  • 10Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
  • 11Department of Medical Oncology, The Second Hospital of Anhui Medical University, Hefei, China
  • 12Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China
  • 13Department of Medical Oncology, Sir RunRun Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
  • 14Department of Medical Oncology, Jiangsu Provincial Hospital, Nanjing, China
  • 15Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
  • 16Department of Medical Oncology, Peking Union Medical College Hospital, Beijing, China
  • 17Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
  • 18Department of Medical Oncology, Fudan University Zhongshan Hospital, Shanghai Medical College, Shanghai, China
  • 19Department of Medical Oncology, Guangdong General Hospital, Guangzhou, China
  • 20Department of Medical Oncology, The First People's Hospital of Changzhou, Changzhou, China
  • 21Department of Medical Oncology, Jilin Province Cancer Hospital, Changchun, China
  • 22Department of Medical Oncology, Shanghai Jiaotong University Affiliated First People’s Hospital, Shanghai, China
  • 23Department of Medical Oncology, The First Hospital of Jilin University, Changchun, China
  • 24Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou, China
  • 25Department of Medical Oncology, The Affiliated Hospital of Medical College Qingdao University, Qingdao, China
  • 26Department of Medical Oncology, The Third Xiangya Hospital of Central South University, Changsha, China
  • 27Department of Medical Oncology, Liuzhou Worker's Hospital, Liuzhou, China
  • 28Department of Medical Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China
  • 29Department of Medical Oncology, Peking University Shenzhen Hospital, Beijing University, Shenzhen, China
  • 30Department of Medical Oncology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou Medical College, Xuzhou, China
  • 31Hutchison MediPharma Ltd, Shanghai, China
JAMA. 2018;319(24):2486-2496. doi:10.1001/jama.2018.7855
Key Points

Question  Does fruquintinib prolong overall survival in patients with metastatic colorectal cancer (CRC) who have tumor progression following at least 2 lines of chemotherapy, targeted treatment, or both?

Findings  In this randomized clinical trial involving 416 patients in China with metastatic CRC who had tumor progression following at least 2 lines of chemotherapy, treatment with fruquintinib resulted in a statistically significant increase in overall survival compared with placebo (median survival time, 9.3 vs 6.6 months).

Meaning  Fruquintinib may prolong survival in patients with metastatic colorectal cancer who had tumor progression after previous treatment, although the efficacy of this therapy remains to be assessed outside of China.


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), objectiveresponse rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stabledisease 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