New Pathways, Targeted Therapies Being Explored in Hepatocellular Carcinoma

Wayne Kuznar

March 2014, Vol 5, No 2 - Pathways


San Francisco, CA—Many molecularly targeted agents that inhibit different pathways of hepatocarcinogenesis are under development, and novel targets are being assessed in hepatocellular carcinoma (HCC), said Andrew X. Zhu, MD, PhD, Director, Liver Cancer Research, Massachusetts General Hospital, Boston, at the 2014 Gastro­intestinal Cancers Symposium.

Sorafenib (Nexavar) remains the only systemic agent that improves the survival of patients with advanced HCC. It improves median overall survival (OS) in HCC, but median survival is still only approximately 10 months. Many more potent or selective antiangiogenic agents have failed to improve on this outcome.

“While we develop new therapies, a concerted and parallel effort must be made to identify and validate biomarkers of response, resistance, and toxicity to better match patients with safe, effective therapies,” said Dr Zhu.

Surpassing sorafenib may require a combination of antiangiogenic agents with cytotoxic chemotherapy or with other molecularly targeted therapies to allow for synergy or additive effects. “Alternatively, it might require moving beyond the antiangiogenesis approach and targeting cell autonomous pathways involved in hepatocarcinogenesis, such as the hepatocyte growth factor [HGF]/c-MET, PI3K/AKT/mTOR, or FGF [fibroblast growth factor]/FGF receptor pathways,” Dr Zhu said.

Antiangiogenic Strategies
Antiangiogenic agents, including pazopanib (Votrient), lenvatinib, axit­inib (Inlyta), and ramucirumab, are in development for the treatment of patients with HCC. Based on phase 2 clinical data, lenvatinib and ramucirumab have advanced to phase 3 trials.

Although HCCs are highly vascular tumors with increased levels of vascular endothelial growth factor (VEGF), several VEGF receptor (VEGFR) inhibitors have failed to improve OS in HCC. This failure has prompted reconsideration of targeting VEGFR in HCC, said Dr Zhu. Future efforts should focus on developing surrogate and predictive markers to identify patients likely to benefit from antiangiogenic treatment.

Antiangiogenics are being combined with chemotherapy (sorafenib plus doxorubicin [Doxil]) in late-stage clinical trials, and with targeted therapies (ie, bevacizumab [Avastin]) in early-phase trials.

mTOR Inhibitors
mTOR regulates protein translation, angiogenesis, and cell-cycle progression in patients with HCC. mTOR inhibitors have been shown to inhibit cell growth and tumor vascularity in HCC cell lines and HCC tumor models. The mTOR inhibitor everolimus (Afinitor) failed to extend OS compared with best supportive care in the multicenter EVOLVE-1 trial of 546 patients with advanced HCC. Nevertheless, the preclinical promise of inhibiting the mTOR pathway has led to the development of other mTOR inhibitors, such as temsirolimus (Torisel), sirolimus (Rapamune), and CC-223, which is a dual inhibitor of TORC1/TORC2.

Immune-Based Therapy
In the realm of immune-based therapy for HCC, “perhaps the most excitement comes from the inhibitors targeting the checkpoint pathway,” said Dr Zhu.

A phase 1 trial has been conducted with tremelimumab, a fully human immunoglobulin G2 monoclonal antibody that blocks cytotoxic T-lymphocyte–associated antigen 4, in patients with HCC associated with hepatitis C virus infection. It generated a modest response rate of 17% and a progression-free survival (PFS) of approximately 6 months in 17 evaluable patients. It also modulated hepatitis C viral load. The PD-1 inhibitor nivolu­mab is also entering clinical trials.

HGF/c-MET Inhibitors
The HGF/c-MET pathway has a significant role in promoting angiogenesis, proliferation, and metastasis in patients with HCC.

Some c-MET inhibitors have shown early evidence of modest efficacy. Compared with placebo, tivantinib, a selective, non–ATP-competitive inhibitor of c-MET, improved the time to progression, particularly in patients with tumors with a high MET signature, in a phase 2 study. The median OS in patients with MET-high tumors was 7.2 months with tivantinib versus 3.8 months with placebo. “If you enrich the right population, you may achieve the clinical benefit,” Dr Zhu told the audience.

Cabozantinib (Cometriq), an RTK inhibitor of c-MET/VEGFR2, is also in phase 3 clinical trials for patients with HCC in whom sorafenib has failed or could not be tolerated. It demonstrated antitumor activity in a randomized discontinuation phase 2 study, with a median PFS of 4.2 months.

Cancer Stem Cells
Novel approaches to targeting cancer stem cells (CSCs) are being explored in multiple cancers, including in advanced HCC. Hepatocarcinogenesis and the regulation of CSCs have both been shown to involve the Wnt pathway. OMP-54F28 targets CSCs, bulk tumor cells, and tumor stromal cells. A phase 1/2 study combining OMP-54F28 and sorafenib for the first-line treatment of advanced HCC is under way. n