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Role of regorafenib as second-line therapy and landscape of investigational treatment options in advanced hepatocellular carcinoma

View Article: PubMed Central - PubMed

ABSTRACT

Sorafenib is still the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). In recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development due to either toxicity or lack of benefit. Recently, data of the RESORCE trial, a placebo-controlled Phase III study that evaluated the efficacy and safety of regorafenib in patients with HCC and documented disease progression after systemic first-line treatment with sorafenib, were presented at the ESMO World Congress on Gastrointestinal Cancer, 2016. Regorafenib treatment resulted in a 2.8-month survival benefit compared to placebo (10.6 months vs 7.8 months). Side effects were consistent with the known profile of regorafenib. The approval of regorafenib for this indication is expected in 2017. Further candidate agents in Phase III evaluation for second-line treatment of patients with HCC are the MET inhibitors tivantinib and cabozantinib, the vascular endothelial growth factor receptor-2 antibody ramucirumab, and the programmed death receptor-1 (PD-1) blocking antibody pembrolizumab. Furthermore, results from two first-line trials with either the tyrosine kinase inhibitor lenvatinib or the PD-1 antibody nivolumabin in comparison to sorafenib are awaited in the near future and might further change the treatment sequence of advanced HCC.

No MeSH data available.


Chemical structure of sorafenib: 4-(4-[{(4-chloro-3-[trifluoromethyl] phenyl)carbamoyl}amino]-3-phenoxy)-N-methylpyridine-2-carboxamide.Note: Regorafenib differs from sorafenib by addition of a fluorine atom in the central phenyl ring as indicated in red, resulting in different target inhibition.
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f1-jhc-3-031: Chemical structure of sorafenib: 4-(4-[{(4-chloro-3-[trifluoromethyl] phenyl)carbamoyl}amino]-3-phenoxy)-N-methylpyridine-2-carboxamide.Note: Regorafenib differs from sorafenib by addition of a fluorine atom in the central phenyl ring as indicated in red, resulting in different target inhibition.

Mentions: Regorafenib is a novel diphenylurea multikinase inhibitor of VEGFR1-3, c-KIT, TIE-2, PDGFR-β, FGFR-1, RET, c-RAF, BRAF, and p38 MAP kinase.10 Although it is structurally related to sorafenib (Figure 1), the addition of a fluorine atom in the central phenyl ring might result in a higher potency. It has been approved for the treatment of metastatic colorectal cancer after failure of oxaliplatin- and irinotecan-based systemic chemotherapy and shows a significant prolongation of OS compared to placebo.11 Moreover, it is approved for the treatment of metastatic gastrointestinal stroma tumors after failure of imatinib and sunitinib.12 A small single-arm Phase II study in HCC patients who progressed on sorafenib (n=36) was reported that showed a signal for activity.13 In this Phase II trial, the median OS was 13.8 months, and the efficacy was mainly based on disease stabilization with a disease control rate of 72%. In this trial, the side effect profile of regorafenib seemed quite similar to sorafenib, such as hypertension, hand–foot skin reaction, fatigue, and diarrhea. Of note, none of the deaths including two patients who died due to liver failure were deemed to be related to regorafenib.


Role of regorafenib as second-line therapy and landscape of investigational treatment options in advanced hepatocellular carcinoma
Chemical structure of sorafenib: 4-(4-[{(4-chloro-3-[trifluoromethyl] phenyl)carbamoyl}amino]-3-phenoxy)-N-methylpyridine-2-carboxamide.Note: Regorafenib differs from sorafenib by addition of a fluorine atom in the central phenyl ring as indicated in red, resulting in different target inhibition.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5036543&req=5

f1-jhc-3-031: Chemical structure of sorafenib: 4-(4-[{(4-chloro-3-[trifluoromethyl] phenyl)carbamoyl}amino]-3-phenoxy)-N-methylpyridine-2-carboxamide.Note: Regorafenib differs from sorafenib by addition of a fluorine atom in the central phenyl ring as indicated in red, resulting in different target inhibition.
Mentions: Regorafenib is a novel diphenylurea multikinase inhibitor of VEGFR1-3, c-KIT, TIE-2, PDGFR-β, FGFR-1, RET, c-RAF, BRAF, and p38 MAP kinase.10 Although it is structurally related to sorafenib (Figure 1), the addition of a fluorine atom in the central phenyl ring might result in a higher potency. It has been approved for the treatment of metastatic colorectal cancer after failure of oxaliplatin- and irinotecan-based systemic chemotherapy and shows a significant prolongation of OS compared to placebo.11 Moreover, it is approved for the treatment of metastatic gastrointestinal stroma tumors after failure of imatinib and sunitinib.12 A small single-arm Phase II study in HCC patients who progressed on sorafenib (n=36) was reported that showed a signal for activity.13 In this Phase II trial, the median OS was 13.8 months, and the efficacy was mainly based on disease stabilization with a disease control rate of 72%. In this trial, the side effect profile of regorafenib seemed quite similar to sorafenib, such as hypertension, hand–foot skin reaction, fatigue, and diarrhea. Of note, none of the deaths including two patients who died due to liver failure were deemed to be related to regorafenib.

View Article: PubMed Central - PubMed

ABSTRACT

Sorafenib is still the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). In recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development due to either toxicity or lack of benefit. Recently, data of the RESORCE trial, a placebo-controlled Phase III study that evaluated the efficacy and safety of regorafenib in patients with HCC and documented disease progression after systemic first-line treatment with sorafenib, were presented at the ESMO World Congress on Gastrointestinal Cancer, 2016. Regorafenib treatment resulted in a 2.8-month survival benefit compared to placebo (10.6 months vs 7.8 months). Side effects were consistent with the known profile of regorafenib. The approval of regorafenib for this indication is expected in 2017. Further candidate agents in Phase III evaluation for second-line treatment of patients with HCC are the MET inhibitors tivantinib and cabozantinib, the vascular endothelial growth factor receptor-2 antibody ramucirumab, and the programmed death receptor-1 (PD-1) blocking antibody pembrolizumab. Furthermore, results from two first-line trials with either the tyrosine kinase inhibitor lenvatinib or the PD-1 antibody nivolumabin in comparison to sorafenib are awaited in the near future and might further change the treatment sequence of advanced HCC.

No MeSH data available.