Oral multikinase inhibitor against endothelial receptor kinases active in colon cancer.

A multi-kinase inhibitor of the VEGF receptors, C-kit,Ret, and FGF receptor and targets various pathways important for angiogenesis, oncogenesis, and tumor microenvironment.

Structurally similar to sorafenib.

Metabolized into M-2 and M-5 metabolites which are clinically active.

Stivarga trade name.

Approved for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.

Improves overall survival in patients with metastatic colorectal cancer refractory to standard chemotherapy (CORRECT) 6.4 months vs 5 months compared to placebo.

Approved for the treatment of advanced gastrointestinal stromal tumors.

Regorafenib, and its active metabolites, inhibit multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes, including those in the RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl pathways.

Acts in a four-pronged approach against multiple tumor pathways: angiogenesis, inhibition of tumor metastases, angogenesis, and tumor immunity.

Acts an anti-angiogenesis agent by inhibiting the VEGF receptors 1,2,3.

It directly targets the tumor microenvironment, through inhibition of multiple tyrosine kinases.

It can positively interfere with the immunosuppressive state, increasing the immunity sensitivity of the tumor or the tumor microenvironment.

It affects the VEGF by inhibition as VEGF induces angiogenesis with abnormal tumor vascular production, leading to hypoxic related events creating an immuno suppressive tumor environment.

Improves progression free survival in GIST.

The approval was based on the results of an international, randomized (2:1), double-blind, placebo-controlled trial enrolling 760 patients with previously treated mCRC (Grothey A et al).

All patients had received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and with bevacizumab.

In the above study patients in the regorafenib arm received 160 mg regorafenib orally once daily for the first 21 days of each 28-day cycle plus best supportive care, while those in the control group received matching placebo with best supportive care (CORRECT trial).

The median survival time was 6.4 months in the regorafenib arm and 5.0 months in the placebo arm.

The median progression-free survival was 2.0 months in the regorafenib arm and 1.7 months in the placebo arm.

No difference in overall response rate was observed.

Only 1% of patients had an objective response.

The median duration of treatment was only 2.8 months for the regorafenib group and 1.8 months for the placebo group.

Regorafenib as a third line therapy for CRC demonstrated overall survival benefit compared to placebo, but it is largely attributed to durable stable disease rather than tumor response (CORRECT trial).

Patients with rectal carcinoma derived no benefit.

The most frequently observed adverse drug reactions greater than or equal to 30%, are asthenia/fatigue, decreased appetite and food intake, hand-foot skin reaction, diarrhea, mucositis, weight loss, infection, hypertension and dysphonia.

The two most common adverse events are hand foot skin reaction and fatigue, similar to other tyrosine kinase inhibitors.

The most serious adverse drug reactions are hepatotoxicity, hemorrhage, and gastrointestinal perforation.

Higher incidence of hand foot syndrome in Asian patients.

Up to 80-90% of patients experience some degree of hand-foot skin reaction, and their reaction is severe and about 10-15% of patients.

The recommended dose and schedule for regorafenib is 160 mg (four 40 mg tablets) orally once daily for the first 21 days of each 28-day cycle.

In a phase 3 GRID trial this agent reduce the risk of disease progression by 73% in patients with GIST tumors that exhausted all other treatment options(Demetrius GD et al).

90% of patients with GIST tumors treaty with Imatinib or sunitinib become refractory, but this agent still allows the drug to inhibit the KIT and PDGFR-alpha mutations that drive the tumor.

A choice for second line therapy for advanced hepatocellular carcinoma.

The approval of regorafenib was based on results of a randomized multicenter trial that included 573 HCC patients whose disease had progressed on sorafenib.

Patients receiving regorafenib had an improvement in progression-free survival based on modified RECIST, with a median progression-free survival of 3.1 vs 1.5 months with placebo.

Overall survival was also improved in patients on regorafenib with a median overall survival of 10.6 months vs 7.8 months with placebo in hepatoma.

The overall response rate based on modified RECIST was 11% vs 4% in favor of regorafenib.

The most common adverse events (> 20%) associated with the drug were asthenia, decreased appetite, diarrhea, dysphonia, elevated bilirubin, fever, hand-foot skin reaction, hypertension, infection, mucositis, nausea, pain, rash, and weight loss.

The recommended dose for regorafenib is 160 mg daily, taken in four 40-mg tablets, for the first 21 days of each 28-day cycle.

It is recommended that the drug be taken after a low-fat meal.

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