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A randomized, double-blind, placebo-controlled, multi-centered phase 3 trial comparing fruquintinib versus placebo plus best supportive care in Chinese patients with metastatic colorectal cancer (FRESCO)

Jin Li, Shukui Qin, Yuxian Bai, Yanhong Deng, Lei Yang, Rui-hua Xu, et al.


Background: Treatment options for third-line metastatic colorectal cancer (mCRC) patients remain limited in China. Fruquintinib, an oral kinase inhibitor selectively targeting vascular endothelial growth factor receptors, in a phase II study was found to significantly improve progression free survival (“PFS”) in patients with mCRC as compared to placebo (ESMO abs#2111). Based on these results, a Phase III registration trial, FRESCO, was carried out to confirm fruquintinib’s efficacy and safety in third-line mCRC patients ( # NCT02314819).

Methods: This is a randomized, double-blind, placebo-controlled, multi-center phase III trial. Patients with mCRC who have failed at least 2 lines of systemic chemotherapy were enrolled from 28 centers in China. Patients were stratified based on prior anti-VEGF therapy and K-ras status and randomized to a fruquintinib or placebo arm in a 2:1 ratio. The primary endpoint was overall survival (“OS”) which was analyzed in the intent-to-treat population.

Results: Between December 12, 2014 and May 13, 2016, 416 patients were randomized. Protocol predefined number of OS events for final analysis was reached on January 17, 2017. Fruquintinib significantly improved OS comparing to placebo with a hazard ratio of 0.65 (95% CI: 0.51-0.83; two sided p<0.001). Median OS was 9.30 months [95% CI 8.18-10.45] in the fruquintinib group versus 6.57 months [95% CI 5.88-8.11] in the placebo group. Statistically significant benefits were also seen with fruquintinib in all secondary endpoints, such as PFS, objective response rate and disease control rate. The most frequent fruquintinib-related ≥ Grade 3 treatment emerged adverse events included hypertension (21.6%), hand-foot skin reaction (10.8%), proteinuria (3.2%) and diarrhea (3.2%).

Conclusion: In this phase III confirmatory trial, fruquintinib demonstrated a statistically significant and clinically meaningful OS benefit as compared with placebo in mCRC patients in China. Fruquintinib was well tolerated with a safety profile that is consistent with what was reported previously. 

Clinical trial information: NCT02314819.

All content © 2017 American Society of Clinical Oncology. All rights reserved.

Editorial comment from Prof Ducreux:
The data presented here are very interesting mimicking with a new compound the data already obtained with two drugs: regorafenib and trifluridine/tipiracil.  Fruquintinib is an oral kinase inhibitor selectively targeting vascular endothelial growth factor receptors, thus this drug should be considered as quite similar to regorafenib even if it does not work on the same targets…  The hazard ratio observed in this study was even better than the one observed in the CORRECT study evaluating the role of regorafenib in refractory metastatic colorectal cancer (0.77, median survival: 6.4 versus 5.0 months)). However, it was less favorable that the hazard ratio observed in the Concur trial evaluating regorafenib versus placebo in Asian population (0.55, median survival: 8.8 versus 6.3 months), with a better effect in patients who did not receive targeted therapies before administration of regorafenib. Trifluridine/tipiracil is a completely different agent, combining a cytototoxic drug and a molecule inhibiting the degradation of this drug. In a very similar population of refractory metastatic patients, this compound showed an efficacy in terms of overall survival with a hazard ratio of 0.68, (median overall survival: 7.1 versus 5.3 months in the placebo group). The toxicity profile of this agent is neutropenia, contrasting with the toxicity of the tyrosine kinase inhibitors. Thus we will have in the future more and more compounds to treat the patients with late stage refractory metastatic colorectal cancer. However nobody knows if patients who have received and failed to regorafenib could be treated with fruquintinib. As it has been reported in the Concur trial it is clearly possible that resistance to any drug targeting angiogenesis have been developed during the first treatment with an agent of this therapeutic class. The competition could thus be imagined more between fruquintinib and regorafenib than with trifluridine/tipiracil… Finally, the availability of a Chinese drug on the occidental market is clearly not guaranteed. 

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