Molecular Therapy Beyond Sorafenib in HCC: New Pathways, Targets Being Explored

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Many molecularly targeted agents that inhibit different pathways of hepatocarcinogenesis are under clinical development, and novel targets are being assessed in hepatocellular carcinoma (HCC). These efforts were described by Andrew X. Zhu, MD, PhD.

Sorafenib remains the only systemic agent to improve survival in advanced HCC. It improves median overall survival (OS), but median survival is still only about 10 months. Unfortunately, multiple 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 Zhu, director of liver cancer research at Massachusetts General Hospital, Boston, MA.

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 HGF/c-MET, PI3K/AKT/mTOR, or FGF/FGFR pathways,” he said.

Antiangiogenic Strategies
Antiangiogenic agents including pazopanib, lenvatinib, axitinib, and ramucirumab are in clinical development for treating HCC. Based on phase 2 data, lenvatinib and ramucirumab have advanced to phase 3 evaluation.

Although HCCs are highly vascular tumors with increased levels of vascular endothelial growth factor (VEGF), multiple VEGF receptor (VEGFR) inhibitors have failed to improve OS in HCC. This failure has prompted reconsideration of targeting VEGFR in HCC, said 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) in late-stage clinical trials, and with targeted therapies (ie, bevacizu­mab) in early-phase trials.

mTOR Inhibitors
mTOR regulates protein translation, angiogenesis, and cell cycle progression in 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 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 and sirolimus, 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 Zhu.

A phase 1 trial has been conducted with tremelimumab, a fully human IgG2 monoclonal antibody that blocks cytotoxic CTLA-4 in hepatitis C virus–related HCC. It generated a modest response rate of 17% and a progression-free survival 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 HCC.

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

Cabozantinib, a receptor tyrosine kinase inhibitor of c-MET/VEGFR2, is also in phase 3 evaluation in patients in whom sorafenib has failed or could not be tolerated. It demonstrated antitumor activity in a randomized discontinuation phase 2 study, with a median progression-free survival of 4.2 months.

Cancer Stem Cells
Novel approaches to targeting cancer stem cells (CSCs) are being explored in multiple cancers, including advanced HCC. Hepatocarcinogenesis and the regulation of CSCs have both been shown to involve the Wnt pathways. OMP-54F28, a fusion protein, 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.

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