Jin Li¹, Ruihua Xu², Junning Cao³, Yuxian Bai⁴, Jianming Xu⁵, Tianshu Liu⁶,Lin Shen⁷, Liwei Wang⁸, Hongming Pan⁹

¹Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, ²Medical Oncology, Sun Yat-sen University Cancer Center, ³Shanghai Medical College, Fudan University Shanghai Cancer Center, ⁴Medical Oncology, Harbin Medical University Cancer Hospital, ⁵the affiliated hospital of Military Medical Sciences, 307th hospital of Chinese PLA, ⁶Shanghai Medical College, Fudan University Zhongshan Hospital, ⁷Medical Oncology, Beijing University Cancer Center, ⁸Shanghai General Hospital, ⁹College of Medicine, SIR RUN RUN SHAW Hospital

Objective:Fruquintinib is a novel oral small molecule compound selectively inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 with potent inhibitory effects on multiple human tumor xenografts. In the first-in-human phase I study (AACR 2013 Abs#2413), fruquintinib demonstrated good tolerability and impressive antitumor activity in patients with various heavily pre-treated solid tumors including colorectal cancer (CRC). 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 as recommended dose and regimen in mCRC for phase II/III study. The phase 1b and phase 2 studies further verified the PFS and safety profile of fruquintinib as 3+line therapy in mCRC. Method:Phase 1b study was designed as two-site, single arm study; and phase 2 was a randomized (2:1 randomization), double-blind, placebo-controlled, multicenter Phase II clinical trial to compare the efficacy of fruquintinib vs BSC in mCRC patients who failed at least 2 prior therapies, including fluorouracil, oxaliplatin and irinotecan. 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 was Progression Free Survival (PFS). Secondary endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR), Overall Survival (OS), and safety. Data were analyzed up to 11 February 2015, approximately 6 months post last patient enrolled. Result: During Dec 2012 to Oct 2014, Forty-two patients were enrolled in phase 1b study to received Fruquintinib 5mg 3 weeks on /1 week off. The median PFS and median OS were 5.3 months and 8.8 months, respectively. In ITT ORR = 9.5%; DCR =76.2%.In the Phase 2 mCRC trial, a total of 71 patients were randomized, with 47 in the fruquintinib arm and 24 in the placebo arm, respectively. Patient baseline characteristics were similar between the two treatment arms. Median PFS was 4.7 months in the fruquitinib arm whereas PFS was 1.0 month in the placebo arm (Hazard Ratio (HR) =0.30 (P<0.001)). There was one tumor response reported in the fruquintinib arm. The Disease Control Rate (DCR) in the fruquintinib arm was 68.1%, as compared with 20.8% DCR in the placebo arm (P<0.001). Twenty-two and 15 patients died in the fruquintinib and placebo arm up to the data cut-off date, respectively. The median OS was 7.6 months and 5.5 months in the fruquintinib and placebo arm, respectively. The most commonly reported fruquintinib treatment-related adverse events (AE) were hand-foot syndrome and hypertension, dysphonia, proteinuria and TSH increased. Grade 3/4 AEs were relatively uncommon, G3/4 (≥10%): HFS and hypertension. Dose interruption and dose reduction due to AE was reported to 51.3% in the fruquintinib arm patients. Conclusion: Fruquintinib 5mg 3/1 wk treatment demonstrated superior PFS benefit in patients with metastatic CRC as compared with placebo. Fruquintinib was well tolerated and the safety profile appeared to be consistent with other TKI drugs in the same class. A phase 3 confirmatory study in mCRC is ongoing.

Key Words: Fruquintinib  mCRC  PFS