Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial
Open accessAbstract
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.
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In the FRESCO trial, fruquitinib improved median overall survival versus placebo (9.3 months versus 6.6 months) and median progression-free survival (3.7 months versus 1.8 months) in patients who had progressed on at least two lines of therapy but had not received a VEGF inhibitor.
“The study demonstrated improved median overall survival with fruquitinib versus placebo (9.3 months versus 6.6 months, respectively). Median progression-free survival was also improved (3.7 months versus 1.8 months).”
From Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer (2024) · cites this paper as [61]
Fruquitinib is a kinase inhibitor targeting VEGF receptors.
“Fruquitinib is a kinase inhibitor targeting VEGF receptors, which was evaluated in the FRESCO trial [61].”
From Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer (2024) · cites this paper as [61]
In FRESCO-1, fruquintinib showed significant benefits in OS and PFS compared to placebo, with subgroup OS HR 0.56 in KRAS WT and 0.75 in KRAS-mutant patients.
“In FRESCO-1, fruquintinib showed significant benefits in both overall survival (OS) and progression-free survival (PFS) compared to placebo. Subgroup analyses reported an OS hazard ratio (HR) of 0.56 in KRAS wild-type (WT) patients and 0.75 in KRAS-mutant patients.”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [48]
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Self-citation
- Authors
- Li, J., Qin, S., Xu, R.-H., Shen, L., Xu, J., Bai, Y., Yang, L., Deng, Y., Chen, Z.-D., Zhong, H., Pan, H., Guo, W., Shu, Y., Yuan, Y., Zhou, J., Xu, N., Liu, T., Ma, D., Wu, C., Cheng, Y., Chen, D., Li, W., Sun, S., Yu, Z., Cao, P., Chen, H., Wang, J., Wang, S., Wang, H., Fan, S., Hua, Y., & Su, W.
- Affiliations
- Tongji University (CN)
- Nanjing University of Chinese Medicine (CN)
- Sun Yat-sen University Cancer Center (CN)
- Peking University (CN)
- 307th Hospital of Chinese People’s Liberation Army (CN)
- Harbin Medical University (CN)
- Nantong Tumor Hospital (CN)
- Sixth Affiliated Hospital of Sun Yat-sen University (CN)
- Second Affiliated Hospital of Anhui Medical University (CN)
- Zhejiang Cancer Hospital (CN)
- Sir Run Run Shaw Hospital (CN)
- Shanghai Medical College of Fudan University (CN)
- Jiangsu Province Hospital (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Peking Union Medical College Hospital (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Guangdong General Hospital (CN)
- The First People's Hospital of Changzhou (CN)
- Jilin Province Tumor Hospital (CN)
- Shanghai Jiao Tong University (CN)
- First Hospital of Jilin University (CN)
- Xuzhou Central Hospital (CN)
- Qingdao University (CN)
- Third Xiangya Hospital (CN)
- Fourth Affiliated Hospital of Guangxi Medical University (CN)
- Second Military Medical University (CN)
- Peking University Shenzhen Hospital (CN)
- Xuzhou Medical College (CN)
- Hutchison MediPharma Ltd, Shanghai, China
- Corresponding author
- Qin, Shukui
- ORCID
- Li, Jin
- Qin, Shukui
- Xu, Rui-Hua
- Shen, Lin
- Xu, Jianming
- Bai, Yuxian
- Yang, Lei
- Deng, Yanhong
- Zhong, Haijun
- Pan, Hongming
- Guo, Weijian
- Shu, Yongqian
- Yuan, Ying
- Zhou, Jianfeng
- Xu, Nong
- Liu, Tianshu
- Ma, Dong
- Wu, Changping
- Cheng, Ying
- Chen, Donghui
- Li, Wei
- Sun, Sanyuan
- Yu, Zhuang
- Cao, Peiguo
- Chen, Haihui
- Wang, Jiejun
- Wang, Shubin
- Wang, Hongbing
- Fan, Songhua
- Su, Weiguo
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2018-06-26
- Volume
- 319
- Issue
- 24
- Pages
- 2486
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC6583690
- OpenAlex
- W2810647922
- Cited by
- 425
- References
- 23
- Citations by year
- 2026: 55 · 2025: 82 · 2024: 87 · 2023: 69 · 2022: 42 · 2021: 38 · 2020: 31 · 2019: 16 · 2018: 5
- FWCI
- 8.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Science and Technology of the People's Republic of China
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- fruquintinib, metastatic colorectal cancer, VEGFR inhibitors, third-line therapy, overall survival, progression-free survival, anti-VEGF therapy, treatment-emergent adverse events, oral tyrosine kinase inhibitor, disease control rate, objective response rate, duration of response, safety and tolerability, KRAS wild-type
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Benzofurans, China, Combined Modality Therapy, Double-Blind Method, Female, Humans, Male, Middle Aged, Quinazolines, Colorectal Neoplasms, Survival Analysis, Vascular Endothelial Growth Factor A, Young Adult, Intention to Treat Analysis
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