《美国医学会杂志》(The Journal of the American Medical Association)2018年6月26日选登

8/20/2018

2268

8/20/2018 12:00:00 AM

June 26, 2018
        由和记黄埔公司申办、国内著名肿瘤学专家李进教授、秦叔逵教授、徐瑞华教授等担纲、国内二十多家肿瘤研究中心参与的呋喹替尼三期临床试验FRESCO的结果被国际顶尖刊物JAMA接纳并于6月26日公开发表,这个中国抗肿瘤新药领域属于“前无古人”创举。
        全文指出FRESCO研究回答了“呋喹替尼可否延长既往曾接受至少两线化疗或/和靶向治疗的晚期转移性结直肠癌患者的总生存期”这一重要问题,同时肯定了呋喹替尼相比安慰剂,用于既往至少接受两线治疗的中国416例转移性结直肠癌,极大延长了总生存期(中位生存期,9.3 比 6.6个月),其重要意义不言而喻,也意味着呋喹替尼有可能成为晚期或转移性结直肠癌(CRC)患者新的标准三线治疗方案。

Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer
The FRESCO Randomized Clinical Trial
Jin Li, MD1,2; Shukui Qin, MD3; Rui-Hua Xu, MD, PhD4,5; et al Lin Shen, MD, PhD6; Jianming Xu, MD7; Yuxian Bai, MD8; Lei Yang, MD, PhD9; Yanhong Deng, MD, PhD10; Zhen-dong Chen, MD11; Haijun Zhong, MD12; Hongming Pan, MD, PhD13; Weijian Guo, MD2; Yongqian Shu, MD14; Ying Yuan, MD, PhD15; Jianfeng Zhou, MD16; Nong Xu, MD17; Tianshu Liu, MD18; Dong Ma, MD19; Changping Wu, MD20; Ying Cheng, MD21; Donghui Chen, MD22; Wei Li, MD23; Sanyuan Sun, MD24; Zhuang Yu, MD25; Peiguo Cao, MD26; Haihui Chen, MD27; Jiejun Wang, MD28; Shubin Wang, MD29; Hongbing Wang, MD30; Songhua Fan, MD31; Ye Hua, MD, MPH31; Weiguo Su, PhD31
Author Affiliations
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.
 
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), 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.

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