Nexavar is currently FDA approved for renal cell carcinoma and hepatocellular carcinoma . Sorafenib (Nexavar) is designed to interfere with growth of new blood vessels and the growth of new cancer cells.Inhibition of KIT signaling provides a direct anti-tumor effect in most GIST tumors and inhibition of VEGF receptors and PDGFR-β provide antiangiogenesis effects (similar to Sutent). Since RAF is downstream of KIT, inhibition of RAF might also contribute an anti-tumor effect. While inhibition of PDGRF-β has been reported, inhibition of PDGFRα, an alternative target in about 5% of GISTs has NOT BEEN reported.
This mechanism of action provoked an interest is using this drug for other solid cancers, especially for pancreatic cancer, where new agents are sorely needed. A single-centre, open-label, phase I dose-escalation study was performed to investigate the safety, pharmacokinetics (PK) and efficacy of sorafeni combined with irinotecan, a cytotoxic agent, in patients with advanced, refractory solid tumours. Thirty-four patients were treated: 20 in the dose-escalation phase (common tumour types: CRC [45%], ovarian [5%], pancreatic [5%]) and 14 patients in the CRC extension. Stable disease was achieved in 12/20 (60%) evaluable patients in cohorts 1–3, and 10/13 (77%) evaluable patients in cohort 4. A further patient from cohort 4 had a partial response of >200 days. The increase of SN38 exposure might be due to inhibition of formation of the SN38 glucuronide by sorafenib. In vitro, sorafenib strongly inhibited SN38 glucuronidation in human liver microsomes as indicated by a Ki value of 2.7 μmol/l. The investigators concluded: “Sorafenib 400 mg bid can be combined with irinotecan 125 mg/m2 or 140 mg for the treatment of patients with advanced, refractory solid tumours, although monitoring for toxicity is recommended.”
Although a phase I study was promising, a phase II study of gemcitabine/sorafenib combination showed that these combination was inactive for pancreatic cancer(Wallace et al). Data from the BAYPAN study presented at the American College of Clinical Oncology’s 2011 Annual Meeting did not support the addition of sorafenib to gemcitabine therapy in the treatment of advanced pancreatic cancer (APC). Anthony Goncalves, MD, of the Institut Paoli-Calmettes, Marseilles, France, and colleagues noted that this is in contrast to an earlier Phase I study(Siu et al) that demonstrated that the gemcitabine (G) + sorafenib (S) combination was well tolerated and had activity in APC patients. Unfortunately, similar results were obtained in studies of sorafenib with other combinations of drugs, such as erlotinib , cisplatin and capecitabine.
Siu LL, Awada A, Takimoto CH, Piccart M, Schwartz B, Giannaris T et al. Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res. 2006 Jan 1;12(1):144-51.
Wallace JA, Locker G, Nattam S, Kasza K, Wade-Oliver K, Vokes EE, Kindler HL. Sorafenib (S) plus gemcitabine (G) for advanced pancreatic cancer (PC): A phase II trial of the University of Chicago Phase II Consortium. 2007 Gastrointestinal Cancers, Symposium; Abstract No: 137.
For Lay version, see here