Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial

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), 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.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr R. Xu reported receipt of personal fees and nonfinancial support from Roche and Merck; and personal fees from Bristol-Myers Squibb and Bayer. Drs Fan, Hua, and Su reported receipt of personal fees as employees of Hutchison MediPharma during the conduct of the study but outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Flow of Patients With Metastatic Colorectal Cancer Receiving Fruquintinib vs Placebo

aInclusion criteria are detailed in eTable 1 in Supplement 2. bMore detailed information regarding the 71 patients who met the exclusion criteria is provided in eTable 6 in Supplement 2. cIndicates patients who met the end of treatment criteria but were still receiving the study treatment at the cutoff date (January 17, 2017). dIncludes patients who died or were still alive at the study cutoff date.

Figure 2.. Kaplan-Meier Estimates for Overall Survival and Progression-Free Survival in Patients With Metastatic Colorectal Cancer Receiving Fruquintinib vs Placebo (Intent-to-Treat Population)

All eligible patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (0 indicates fully active, able to carry on all predisease activities without restriction; 1 indicates restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature [eg, light housework, office work]). The median follow-up time was 13.3 months (95% CI, 12.1-14.7) for the fruquintinib group and 13.2 months (95% CI, 10.6-19.6) for the placebo group. Tick marks on the curves denote the last known follow-up time for patients with no death date reported. A, The hazard ratio (HR) for death and corresponding 95% CI for overall population were estimated from a stratified Cox proportional hazards model. Stratified factors included use of vascular endothelial growth factor (VEGF) inhibitor (yes vs no) and K-ras gene state (wild type vs mutated). At the planned cutoff date (January 17, 2017), after 297 deaths, the median overall survival was 9.3 (95% CI, 8.2-10.5) months in the fruquintinib group and 6.6 (95% CI, 5.9-8.1) months in the placebo group (HR for death, 0.65 [95% CI, 0.51-0.83]; log-rank P < .001). B, The HR for progression-free survival and corresponding 95% CI were estimated from stratified Cox proportional hazards model with treatment as the only covariate. Stratified factors included use of VEGF inhibitors and K-ras gene status. Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 [95% CI, 1.8-1.8] months with placebo; HR for progression or death, 0.26 [95% CI, 0.21-0.34]; P < .001).

Figure 3.. Subgroup Analyses for Overall Survival (Primary Outcome) in Patients With Metastatic Colorectal Cancer Receiving Fruquintinib vs Placebo (Intent-to-Treat Population)

ECOG PS indicates Eastern Cooperative Oncology Group performance status; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor. The hazard ratio for death and corresponding 95% CI for each subgroup were estimated from unstratified Cox proportional hazards model with treatment as the only covariate. P values were calculated from the Cox model including treatment, subgroup factor, and subgroup factor × treatment interaction term.

Figure 4.. Subgroup Analyses for Progression-Free Survival (Secondary Outcome) in Patients With Metastatic Colorectal Cancer Receiving Fruquintinib vs Placebo (Intent-to-Treat Population)

ECOG PS indicates Eastern Cooperative Oncology Group Performance Status; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor. The hazard ratio for progression or death and corresponding 95% CI for each subgroup were estimated from unstratified Cox proportional hazards model with treatment as the only covariate. P values were calculated from the Cox model including treatment, subgroup factor, and subgroup factor × treatment interaction term.