Multi-Kinase Inhibitor

MULTI-KINASE INHIBITOR:
ORAL KINASE INHIBITORS FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA: "Sorafenib therapy for advanced hepatocellular carcinoma, single center experience on 43 patients." Abstract 436-AISL, Zimmerman. Sorafenib therapy has now been approved in the United States and in many countries world-wide as an oral therapy for hepatocellular carcinoma that improves survival. It is approved for HCC in the United States for patients with "unresectable hepatocellular carcinoma" although there are more restricted indications in other countries such as Canada. In this study, a single-center experience with 43 patients was described utilizing a lower initial sorafenib starting dose of 400 mg a day compared to 400 mg b.i.d., which is the currently approved dose, in patients with advanced HCC. Dose escalation took place at four weeks of treatment to 800 mg a day, and the medication appeared to be well-tolerated in many patients at both doses. We would like to highlight that this was a heterogeneous study population, with some patients having sorafenib as the first treatment option, whereas other patients were treated with sorafenib after liver resection or ablation. Clinical response to sorafenib was seen in 19 patients, with stable disease in 14 and partial remission in 3. Treatment related side effects due to sorafenib were seen in approximately one-half of patients. This abstract further extends on our data base in terms of sorafenib therapy in clinical practice, allowing us to further refine our care and management of patients' hepatocellular carcinoma. "Tolerability and efficacy of sorafenib in recurrent hepatocellular carcinoma after liver transplantation in a case-controlled study." Abstract 3, Dharancy. The data for sorafenib as a multi-kinase inhibitor was published recently in the New England Journal of Medicine, under the title of the "SHARP Study", which highlighted the information that led to the approval in the United States, and a number of other countries, the use of sorafenib for patients with unresectable hepatocellular carcinoma. An area in question is whether we can use sorafenib after liver transplantation. In this study, using a case-controlled study analysis, the authors looked at 14 patients who underwent liver transplant compared to 14 patients in a nontransplant group who were administered sorafenib for the treatment of hepatocellular carcinoma. Patients received sorafenib 400 mg twice daily. This study highlighted that sorafenib resulted in a substantial number of adverse events in post-liver transplant patients. It was challenging in the data analysis to determine the effects on recurrent disease due to the small study size, and the important fact that there was a great heterogeneity in terms of the post-liver transplant suppression, including mTOR inhibitors in eight patients. The mTOR pathway may be involved in hepatocellular carcinogenesis and inhibitors in the mTOR pathway may inhibit HCC development or progression. Importantly there is a marked increased risk using mTOR inhibitors in combination with sorafenib, so there is a potential of marked increased risk of side-effects by inhibiting multiple pathways, including more extensive skin reactions and diarrhea. Interestingly, the liver transplant group was at a higher risk of disease progression, which also may have been influenced by the presence of immunosuppression and loss of control over hepatocellular carcinoma progression. We will need to be cautious about the use of sorafenib after liver transplantation until a larger prospective study takes place in a controlled and monitored setting. "Sorafenib inhibits STAT 3 activation in cholangiocarcinoma cells." Abstract 151-AASLD, Blechacz. Currently there is no proven effective therapy, oral or intravenous, that improves the survival of patients with cholangiocarcinoma. A phase-2 exploratory study with sorafenib was previously completed that did demonstrate an improvement in survival. From an exploratory analysis there appeared to be patients within that study that had a clinical benefit from sorafenib. To help define whether sorafenib should be further explored for the treatment of cholangiocarcinoma, an in vitro study was designed in a cell model of cholangiocarcinoma. In this in vitro study, sorafenib was found to interfere with STAT-3 signaling pathways and also reduced cellular expression of Mcl-1, both of which would enhance apoptosis. This pathway plus direct enhancement of TRIAL induced apoptosis indicates that that sorafenib may be useful alone, or in combination with other agents, for the treatment of human cholangiocarcinoma. A larger phase 2 or phase 3 study may need to be considered to elucidate the benefits of sorafenib in this important disease that affects over 6000 patients in the US each year, with a less than 5% 5-year survival rate.