Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer

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+ LineColorectal 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 MEASURESThe 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 Ն8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. RESULTSOf 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.

Disease characteristics and treatment patterns of Chinese patients with metastatic colorectal cancer: a retrospective study using medical records from China

“…If patients were previously diagnosed with CRC outside the selected hospitals, the initial diagnosis dates, if available, were used as the primary diagnosis dates. As a previous phase III clinical trial suggested that the maximum period of the 3rd line treatment usage was nine months [21], in this study, patients who started third-line chemotherapy after January 1, 2016 were excluded to allow a minimum nine-month observation period for the entire third-line chemotherapy to be documented.…”

Afatinib treatment for her-2 amplified metastatic colorectal cancer based on patient-derived xenograft models and next generation sequencing

“…9 In this case, the patient experienced disease progression during the first-line FOLFIRI plus cetuximab treatment, and after taking afatinib, achieved 3-month progression free. Compared with the median PFS of other molecule-targeting drugs for mCRC third-line treatment, like regorafenib (1.9months) 22 , trifluridine-tipiracil (TAS-102, 2.0months) 23 and fruquintinib (3.7months) 24 , afatinib brought more impressive benefit for this HER2-amplified mCRC patient.…”

Third- or Later-line Therapy for Metastatic Colorectal Cancer: Reviewing Best Practice

“…104 Several other novel agents are being investigated as third-line or later-line treatment options for mCRC. 3 Tyrosine kinase inhibitors, such as famitinib (NCT02390947), fruquintinib, 105 and anlotinib (NCT02332499), are under investigation in phase III trials. The alkylating agent temozolomide showed some activity in phase II studies of patients with mCRC and O 6 -methylguanine DNA methyltransferase (MGMT) promoter methylation, 106,107 even though molecular selection might be further improved leaving the latter approach under investigation.…”