Safety and efficacy of fruquintinib in patients with previously treated metastatic colorectal cancer: a phase Ib study and a randomized double-blind phase II study

Abstract

BackgroundTo assess the efficacy and safety of fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, in metastatic colorectal cancer (mCRC) patients.MethodsA phase Ib open-label study and phase II randomized, placebo-controlled trial compared the efficacy of fruquintinib plus best supportive care (BSC) with placebo plus BSC in mCRC patients with ≥2 lines of prior therapies. The primary endpoint was progression-free survival (PFS).ResultsIn the phase Ib study, 42 patients took fruquintinib 5 mg for 3 weeks on/1 week off. The median PFS was 5.80 months, and the median overall survival (OS) was 8.88 months. In the phase II study, 71 patients were randomized (47 to fruquintinib, 24 to placebo). PFS was significantly improved with fruquintinib plus BSC (4.73 months; 95% confidence interval [CI] 2.86–5.59) versus placebo plus BSC (0.99 months; 95% CI 0.95–1.58); (hazard ratio [HR] 0.30; 95% CI 0.15–0.59; P < 0.001). The median OS was 7.72 versus 5.52 months (HR 0.71; 95% CI 0.38–1.34). The most common grade 3–4 adverse events were hypertension and hand-foot skin reaction.ConclusionsFruquintinib showed a significant PFS benefit of 3.7 months in patients with treatment-refractory mCRC. The safety profile was consistent with that of VEGFR tyrosine kinase inhibitors. A randomized phase III confirmatory study in mCRC is underway.Trial registration NCT01975077 and NCT02196688 Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0384-9) contains supplementary material, which is available to authorized users.

Activation of the VEGFC/VEGFR3 Pathway Induces Tumor Immune Escape in Colorectal Cancer

“…Furthermore, several small-molecule protein kinase inhibitors (PKI) targeting various kinases, including VEGFR3, are now available and some of them have been approved for the treatment of colorectal cancer. For example regorafenib (43,44), nintedanib (45), fruquintinib (46) and famitinib (47) progressed to phase II and III clinical trial, showing benefit without significant toxicity. These clinical data indicate that blocking VEGFR3 could provide a safe therapeutic approach also in nonmetastatic colorectal cancer.…”

The current status of treatment for colorectal cancer in China

“…With new breakthroughs achieved in precision medical treatment, the prognosis can be further improved by chemotherapy combined with targeted therapy, such as bevacizumab plus chemotherapy in right-sided colon cancer, [ 61 ] vemurafenib, [ 50 ] fruquintinib. [ 49 ] Meanwhile, immunization therapy is expected to make great strides in treatment of CRC, such as anti-programmed death 1(PD-1) antibody and cytotoxic T-lymphocyte antigen 4 (CTLA-4) immunotherapy for advanced colorectal cancer. [ 57 , 62 ]…”

“…Several trials have compared the safety and efficacy of fruquintinib in mCRC patients. [ 49 ] In the phase Ib study, the median PFS was 5.8 months, and the median OS was 8.88 months. In the phase II study, the median PFS was 4.73 months in the fruquintinib group versus 0.99 months in the placebo group ( P < .001)…”

Famitinib versus placebo in the treatment of refractory metastatic colorectal cancer: a multicenter, randomized, double-blinded, placebo-controlled, phase II clinical trial

“…Regorafenib has been approved to treat mCRC based on the results of two phase III studies CORRECT [ 10 ] and CONCUR [ 11 ]. Another clinical study involving fruquintinib also demonstrated promising anticancer effect on mCRC [ 12 ].…”