Latest Study on Targeted Therapy for HCC

Targeted therapies have become a valuable therapeutic option for HCC. Professor Massimo Colombo, from Fondazione IRCCS Maggiore Hospital, Mangiagalli and Regina Elena and University of Milan, Italy, presented a report on targeted therapy for HCC. More than 50% of patients who present at most centers with a hepatocellular carcinoma (HCC) have an advanced disease, i.e. multiple tumor nodes or a single greater than 5 cm tumor with portal vein invasion and symptoms. Until 2006, no effective systemic therapy existed for these patients, probably because HCC retains active drug-metabolizing systems that contribute to an intrinsic resistance to chemotherapeutic drugs, while the use of many anticancer drugs was limited by their intrinsic hepatotoxicity that may exacerbate the underlying liver disease. Since HCC is a complex tumor characterized by the aberrant activation of several signaling cascades, including multiple receptor tyrosine kinase pathways involved in growth and angiogenic signaling pathways, targeted therapies have become an important therapeutic option.

Professor Colombo noted that in the SHARP study conducted in 602 patients with advanced HCC in Europe and USA, the bisaryl urea Sorafenib, which simultaneously inhibits molecular components of the Raf-MEK-ERK signaling pathway involved in tumor growth and VEGF and PDGR receptors involved in neoangiogenesis, was shown to delay the time of radiological progression by 42% and cancer-related death by 31%. More recently, the beneficial effects of Sorafenib on patients with advanced HCC were confirmed in a phase III study conducted in Asian patients, enrolling patients with more advanced HCC compared to the SHARP study. Due to the low incidence of objective responses, the clinical effectiveness of Sorafenib has created a new paradigm in cancer therapeutics, different from the paradigm of tumor involution and radiological remission typical of the cytotoxic chemotherapies. Interestingly, the beneficial effects of Sorafenib on HCC compares well with other treatments such as Trastuzumab in breast cancer, Bevacizumab in colorectal cancer or Erlotinib in NSC lung cancer (25%~35%).

He continued that as these studies opened the era of targeted therapy for HCC, other molecules were being evaluated in phase II studies like Erlotinib alone or in combination with Bevacizumab (monoclonal antibody against VEGF), Lapotinib, an EGFR and Her2 receptor blocker, Rapamycin an mTOR inhibitor and Sunitinib a VEGF and PDGF inhibitor, as potential therapies for patients with advanced HCC. To overcome the complexity of genomic aberrations in HCC, combination therapies likely need to be implemented, though current phase II studies have provided disappointing results for combination therapies with drugs blocking EGFR, VEGF and PDGF receptors and mTOR signaling. Unfortunately, the implementation of targeted therapies is hampered by costs, since HCC is prevalent in resources-poor countries where access to these drugs is limited. In resources-rich countries, adjuvant therapy with Sorafenib after resection or local ablation has been advocated to improve the outcome of patients with an early HCC. This hypothesis is being tested in a multinational phase III study.

Finally, he concluded that since novel drugs needed to be tested in a common frame, a multidisciplinary panel of EASL and AASLD experts proposed survival and time to recurrence as primary end-points for phase III trials assessing primary and adjuvant therapies, respectively. The paradigm of phase II trials was also changed following the advent of targeted therapies, i.e. discouraging the response rate while endorsing time to progression as a reliable end-point to capture clinical benefits.