Genetic Testing and Second-Line Treatments in HCC

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The current value of genetic sequencing in hepatocellular carcinoma (HCC) is the identification of patients that are eligible for clinical trials, explains Robert G. Gish, MD, FAASLD. While it is important to understand the tumor type, there are numerous receptors and signaling pathways that are being assessed for future therapies. With 500 clinical trials and 20 emerging agents, Gish notes, it is useful to know the baseline profile of a tumor.

Unfortunately, many centers still approach liver cancer as a one-size-fits-all disease, other than staging, states Richard Finn, MD. If a patient has HCC, he will receive sorafenib. Molecular profiling studies have been done in liver cancer that parallel breast cancer, as far as defining a molecularly heterogeneous disease is concerned, he notes. One of these profiling tests, Finn explains, is actually being commercialized for patients who were resected to aid in predicting their risk of relapse. However, the HCC field is not as far along with using profiling for selecting the best patients for therapy. Treatment for HCC needs to move to a more personalized approach that takes into account molecular heterogeneity and identifies predictive markers for response.

In the first-line setting, even when compared with other agents in similar drug classes, sorafenib continues to demonstrate its efficacy. The phase III, CALGB 80802 trial is looking at first-line sorafenib versus sorafenib plus doxorubicin, says Ghassan K. Abou-Alfa, MD. Reported data has shown improvements in outcome with the combination therapy. However, Abou-Alfa warns that this approach should remain within the realm of clinical trials.

In the second line setting, other approaches are looking at different mechanism of action. Laboratory data suggest that the circulating ligand HCF may play a role in the pathogenesis or alterations in the receptor, according to Finn. The most provocative data, he notes, came from a randomized phase II study with second-line tivantinib. Patients who were progressing on sorafenib were randomized to tivantinib or placebo in a blinded fashion. Overall, the study did not show any benefit.

A planned retrospective analysis of the phase II tivantinib study tested patients' tissue for c-Met expression by immunohistochemistry. This analysis showed 2 things: first, c-Met high was associated with a bad prognosis in the placebo group; and second, in the group that was c-Met low, those who received tivantinib had a significant improvement in overall survival. This latter result led to one of the first phase III, biomarker-selected studies in HCC.

Cabozantinib is another c-Met inhibitor that was analyzed in a randomized discontinuation study. This agent has moved to the next phase of testing in the second-line setting, but without selecting for c-Met high tumors. Other second-line therapies that are being tested include, ramucirumab, mTOR inhibition, and ADI-PEG20, an arginine deiminase inhibition approach.