Artikel
Targeting metastatic colorectal cancer with the multikinase inhibitor regorafenib [invited speaker]
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Veröffentlicht: | 25. September 2014 |
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Gliederung
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Metastatic colorectal cancer (CRC) is still a significant cause of morbidity and mortality worldwide with a median survival of approximately 24 months. Besides current standard of care chemotherapeutic regimens, recent improvement in outcome was obtained by introduction of molecularly targeted agents. These agents that have improved efficacy of chemotherapeutic regiments in CRC target the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). In particular, both the humanized monoclonal antibody bevacizumab and aflibercept that are directed against VEGF have been approved for the treatment of metastatic CRC. In addition, the two monoclonal antibodies cetuximab and panitumumab that target the EGFR are therapeutic options for patients with KRAS wild-type tumors.
Recently, the oral multikinase inhibitor regorafenib (Stivarga®) has been approved for patients with heavily pretreated metastatic CRC. Regorafenib blocks the activity of several protein kinases involved in the regulation of tumor angiogenesis (VEGFR1-3, angiopoetin-1 receptor), oncogenesis (stem cell growth factor receptor, RET, BRAF including BRAFV600E mutants), and tumor microenvironment (PDGFR-β and FGFR). Therefore, regorafenib is a novel, additional treatment option after progression on standard treatments, and its multi-targeted effect potentially provides antiproliferative activity in tumors after progression on previous therapies.
The most common regorafenib-related toxicities are hoarseness, hand–foot skin reaction, rash, mucositis, diarrhea, hypertension and fatigue. Pharmacokinetic analysis showed a dose-dependent increase in exposure up to 160 mg, when it reaches a plateau. The two active metabolites, M2 and M5, also showed dose-dependent increases in exposure up to 220 mg. Pharmacodynamic markers like soluble VEGFR-2 plasma levels and Gd-DTPA uptake at DCE-MRI decreased and correlated with drug exposure. The recommended dose for regorafenib is 160 mg daily using a 21 days on/7 days off treatment schedule.
Open questions and challenges address the identification of predictive biomarkers of efficacy and its role in the treatment algorithm.