Many novel therapeutic agents for HCC have been evaluated in phase I and II studies. Sorafenib (Nexavar), erlotinib (Tarceva), bevacizumab (Avastin), and flavopiridol will be discussed herein. Sorafenib is a Raf kinase inhibitor with anti-vascular endothelial growth factor (VEGF) and –platelet-derived growth factor (PDGF) activity.18
VEGF and PDGF have been implicated in tumor angiogenesis of highly vascular HCC.19,20
A phase II study evaluating sorafenib in patients with HCC has been completed.21
The primary endpoint was response. Of 137 patients accrued, 5% showed a partial response. However, 43% of patients had stable disease for at least 4 months. Interestingly, some of these patients who had progression of disease by radiologic criteria had a decrease in alpha-fetoprotein, and on closer inspection of the radiologic evaluations, were shown to have an increase in tumor necrosis. This suggests a response to therapy despite progression by routine radiologic criteria. In addition, patients whose tumors expressed higher baseline staining intensity of pERK (n = 33), downstream from Raf (2–4+; n = 18), had a significantly longer time to progression (TTP) than those with a lower staining intensity (0–1+; n = 15) (P
= .00034), suggesting the validity of the target and its response to sorafenib. Sorafenib is being further evaluated in two international randomized studies in HCC; one is a phase III placebo-controlled trial, and the other is a randomized phase II comparison of doxorubicin plus sorafenib versus doxorubicin plus placebo. The latter study emanates from the concept that antiangiogenic agents have limited single-agent activity and are likely more active in combination with cytotoxic therapy, perhaps by facilitating improved chemotherapy delivery to the tumor.
Erlotinib, an oral tyrosine kinase inhibitor, has also been evaluated in a phase II trial in patients with HCC and those with cholangiocarcinoma. Twelve of 38 (32%) evaluable patients had progression-free survival at 6 months, the primary objective of the study.22
Similarly, in a phase II trial23
evaluating the VEGF inhibitor bevacizumab in patients with HCC, stable disease was observed in 18 of 25 (72%) evaluable patients. The latter trial is ongoing.
Several other targets further along the signal transduction pathway have been explored, including the cyclin-dependant kinase inhibitor, flavopiridol.24
In the laboratory, flavopiridol, when given seven hours after SN38 (the active metabolite of irinotecan [Camptosar, CPT-11]), caused cleavage of the poly (ADP-ribose) polymerase (PARP) and caspase-3 cleavage (), resulting in enhanced apoptosis.25
Additional data suggest that patients with wild-type p53 and stable post-treatment p21 levels are most likely to respond to an irinotecan and flavopiridol combination.26
Sequential apoptotic activation. Flavopiridol was given 7 hours after SN38, the active metabolite of irinotecan, resulting in cleavage of the Poly (ADP-ribose) polymerase (PARP) and caspase-3 activation.
This concept has evolved from the laboratory to the bedside in a phase II trial of irinotecan followed by flavopiridol in patients with advanced HCC.27
Of 16 patients on this study, one patient had stable disease for more than 1 year. This patient had a wild-type p53 tumor; however, p21 expression before and after therapy was not known, as its evaluation was not part of the study design.
Thus far, none of the novel therapeutics discussed above has shown any tangible disease regression against HCC, however, they are good illustrations of the targets that are currently being studied in this disease. An understanding of how these novel therapeutic agents may work will hopefully lead to a better understanding of the molecular pathogenesis of hepatocellular carcinoma.