A randomised, double-blind, placebo controlled, multicenter Phase II clinical trial of fruquintinib in patients with metastatic colorectal cancer (ESMO 2015)

Click here to view the poster presented at the 2015 European Cancer Congress.

J. Li, R. Xu, Y. Bai, J. Xu, T. Liu, L. Shen, L. Wang, H. Pan, S. Fan, Y. Hua, W. Su, C. Hogg

Background: Fruquintinib is a novel, potent and highly selective oral small molecule VEGF receptor inhibitor. In a Phase 1b study (ASCO 2014 #126686), fruquintinib administered at 5mg once daily in cycles of three weeks on and one week off (3/1 wk) was well tolerated and demonstrated encouraging preliminary clinical efficacy in mCRC patients.

Methods: This is a randomized, double-blind, placebo-controlled, multicenter Phase II clinical trial to compare the efficacy of fruquintinib plus best supportive care (BSC) vs. placebo plus BSC in mCRC patients who failed at least 2 prior therapies, including fluorouracil, oxaliplatin and irinotecan. Patients were randomized to receive fruquintinib 5mg orally 3/1 wk or placebo at 2:1 ratio. Treatment was given in 28-day cycles until disease progression or non-tolerable toxicity occurs. Tumor assessments were conducted using RECIST 1.1 criteria. Primary efficacy endpoint for the trial was Progression Free Survival (PFS). Secondary efficacy endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR), and Overall Survival (OS).Safety endpoints included Adverse Event (AE), laboratory tests, vital signs and ECG. Data were analyzed up to February 11, 2015, approximately 6 months post last patient enrolled.

Results: A total of 71 patients were enrolled in the Phase 2mCRC trial,47 in the fruquintinib arm and 24 in the placebo arm, respectively. Patient baseline characteristics were similar between the two treatment arms. The median fruquintinib exposure was 84 (range: 13–188) days whereas the median was 21(range: 19,191) days in the placebo arm. Median PFS was 4.7 months in the fruquintinib arm compared with 1.0 month in the placebo arm (Hazard Ratio of PFS=0.30 (p<0.001)). The Disease Control Rate (DCR) in the fruquintinib arm is 68.1%, compared with 20.8% DCR in the placebo arm (p<0.001). Twenty-two and 15 patients died in the fruquintinib and placebo arm, respectively, by the time of data cut-off, with a median OS of 7.6 months and 5.5 months in the fruquintinib and placebo arm, respectively.

The 5 most common fruquintinib treatment-related adverse events (AE) were hand-foot syndrome (61.7%), hypertension (51.4%), dysphonia (46.8%), proteinuria (44.7%) and AST elevation (27.7%). Dose interruption and dose reduction due to AE was reported in 29.8% and 27.7%, respectively, in the fruquintinib arm patients.

Conclusions: Fruquintinib 5mg 3/1 wk treatment demonstrated superior PFS in patients with metastatic CRC as compared with placebo. Fruquintinib was well tolerated and the safety profile appeared to be consistent with that of the TKI class. Further confirmatory clinical studies are warranted.