Regorafenib (STIVARGA®)

Agent Description

Regorafenib is an approved oral multi-kinase (MK) inhibitor with distinct kinase inhibition profile which includes (receptor tyrosine) kinases involved in:

Angiogenesis through inhibition of vascular endothelial growth factor receptor (VEGFR) 1-3, tyrosine kinase with immunoglobulin-like and epidermal growth factor (EGF)-like domains 2 (TIE2),
Oncogenesis by blocking KIT stem cell factor receptor, RET, and BRAF,
Metastasis by inhibition of VEGFR3, platelet-derived growth factor receptor (PDGFR)-β, fibroblast growth factor receptor (FGFR), and
Tumor immunity by the inhibition of colony-stimulating factor 1 receptor (CSF1R).

Mechanism of Action

Regorafenib is a multi-kinase inhibitor which targets tumor cells and the tumor microenvironment. It inhibits tumor growth, progression and metastasis by inhibiting the proliferation of tumor cells, the formation of new tumor vasculature and stromal signaling in the microenvironment of the tumor. The compound was selected based on its kinase-inhibition profile which includes angiogenic (VEGFR 1/2/3, TIE2), stromal (PDGFR-β, FGFR), oncogenic (KIT, RET, and BRAF) receptor tyrosine kinases and tumor immunity (CSF1R).

Classification

L01XE21

Molecular Targets

VEGFR1, VEGFR2, VEGFR3, TIE2, PDGFRB, FGFR1, KIT, RET, RAF1, BRAF

Monograph

In multiple murine and human tumor models, regorafenib, alone or in combination with drugs representing current or emerging standard of care, inhibits tumor growth and the formation of metastases. The non-clinical antitumor activity in vivo was mediated by inhibition of tumor cell proliferation and neovascularization and by induction of apoptosis.

Regorafenib has two major metabolites: M-2 (BAY 75-7495) and M-5 (BAY 81-8752). In human plasma, M-2 and M-5 were shown to have similar pharmacological activities compared to regorafenib in biochemical and cell-based assays in vitro and in tumor growth inhibition (TGI) and vascular effect studies in vivo.

In the pivotal CORRECT phase 3 study, metastatic colorectal cancer (CRC) patients who failed available therapies (fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab and anti-EGFR if Ras wt) had a significant increase of their median Overall Survival (mOS) by 1.4 mo. In a confirmatory Phase 3 study, CONCUR performed in Asian patients with CRC, the addition of regorafenib to BSC significantly prolonged OS compared with placebo (median OS 8.8 vs. 6.3 days).

In the GRID Phase 3 trial, GIST patients who failed imatinib and sunitinib had a significantly longer median progression-free survival (PFS) for patients treated in the regorafenib + BSC group (4.8 mo) than in placebo + BSC group (0.9 mo). After failure of the placebo arm, patients were allowed to cross-over to regorafenib. At final OS analysis, the median OS time in the regorafenib arm was longer (17.4 mo) compared to the placebo arm (11.1 mo).

The RESORCE phase 3 trial enrolled patients with HCC with Child-Pugh A score who failed and tolerated prior first line systemic therapy with sorafenib therapy. The median OS time was 10.6 months in the regorafenib arm compared with 7.8 months in the placebo arm.

These 3 trials led to the subsequent approvals for patients with mCRC, GRID and HCC by regulatory agencies worldwide.

Regorafenib safety profile was consistent across all the trials, independently of the indication. Its use is associated with hand-foot skin reaction, hypertension, diarrhea and fatigue.

Several phase 3 trials in collaboration with collaborative groups are ongoing: INTEGRATE-2 (AGITG): regorafenib + BSC vs BSC in patients with gastric cancer after failure of ≥ 3 lines of therapies and regoragenib in 1st or 2nd line glioblastoma in the basket trial sponsored by AGILE.

Studies of Interest

N/A

Information collaborator would like included in investigator proposals

N/A