Richard Kim, MD

Question

How has the treatment of hepatocellular carcinoma (HCC) changed in the past decade?

Answer

In the past decade, novel systemic therapies and local therapies have been developed to help patients with HCC.

Sorafenib, a multi-kinase inhibitor, was the first targeted drug and was approved by the US Food and Drug Administration (FDA) in 2007 for unresectable HCC. Now we have regorafenib, a multi-kinase inhibitor, for second-line treatment and, more recently, nivolumab, a PD-1 checkpoint inhibitor, which was approved for patients who failed or who were intolerant to sorafenib. Novel local therapies such as stereotactic body radiotherapy (SBRT), radioembolization, and microwave ablation are now available as well.

Surgery and liver transplantation are, however, still the only curative options.

Question

Are PD-1, PD-L1, or CTLA-4 inhibitors effective for HCC? Are there any immunosuppressive features unique to liver cancer that make it less likely checkpoint inhibition will be effective?

Answer

Recently, nivolumab, a PD-1 checkpoint inhibitor, was approved for patients who failed or were intolerant to sorafenib based on the Checkmate 040 study (ClinicalTrials.gov Identifier: NCT01658878).

The study showed a patient response rate of 15%; nivolumab was also active regardless of the hepatitis status. Responses tended to occur early within 3 months and were durable.1

Currently nivolumab is being studied in the first line against sorafenib and hopefully we will get the final result sometime next year. Furthermore, there is a plan to study nivolumab in the adjuvant setting after liver resection or radiofrequency ablation (RFA) as well.

Another checkpoint inhibitor, pembrolizumab, along with combination durvalumab and tremelimumab is now being studied in the second line in previously treated HCC (ClinicalTrials.gov Identifiers: NCT02702401, NCT02519348).

Question

What treatment regimens do you recommend for patients who present with metastatic disease?

Answer

Currently, sorafenib is still the only drug available in the first-line setting for patients with advanced HCC.

If, however, the patient cannot tolerate sorafenib because of toxicity, then nivolumab is now available. If the patient has tumor progression on sorafenib, then we now have the options of either regorafenib or nivolumab. We now actually have a choice, whereas in the past we had nothing to offer — except for a clinical trial or best supportive care.

Question

Are there any current clinical trials you’d recommend to patients with relapsed or refractory disease? Are any of these trials likely to change clinical care?

Answer

Currently many trials are looking at combinations of immunotherapies in a refractory setting.

There are, for example, trials combining PD-1 checkpoint inhibitors with ipilimumab, an anti-CTLA-4 antibody. Other studies include combinations of local therapy such as SBRT or radioembolization with checkpoint inhibitors in order to induce an abscopal effect.

Other areas of interest include fibroblast growth factor receptor 4 (FGFR 4) inhibitors. BLU-554, for example, is a potent and highly selective inhibitor of FGFR 4. Data presented at the European Society for Medical Oncology (ESMO) 2017 Congress showed that patients with FGF19 immunohistochemistry (IHC)-positive HCC demonstrated response rate of 16%, which is comparable to nivolumab in the second-line setting.²

Question

Do you foresee treatment vaccines being used for patients with liver cancer?

Answer

One vaccine that has gotten attention as a potential HCC treatment is called Pexa-Vec.

Pexa-Vec is a live, attenuated virus with a disrupted thymidine kinase. The vaccine is directly injected into the liver tumors. Phase 2 data showed acceptable safety profile, with an improved overall survival at the highest dose.³ Based on these results, a phase 3 trial (PHOCUS; ClinicalTrials.gov Identifier: NCT02562755) is currently being conducted in which investigators are assessing the efficacy of Pexa-Vec followed by sorafenib in comparison with sorafenib alone in patients who have not received any systemic therapy.