Ghassan K. Abou-Alfa, MD

Question

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

Answer

Regarding systemic therapy, there have been major changes since the 1970s, when initial clinical trials assessing doxorubicin chemotherapy failed to show an improvement in outcome. After a long hiatus, the US Food and Drug Administration (FDA) approved sorafenib.

Since then, and especially within the past decade, there have been more major changes, including in the field of kinases, where we have seen the advent of lenvatinib and regorafenib. While we are waiting for the findings of clinical trials evaluating the c-Met inhibitor, cabozantinib, other novel drugs for HCC, it is important to recognize the major advances in immunotherapy. Also of note, FOLFOX (a combination of 5-fluorouracil, leucovorin, and oxaliplatin) has been proven to be effective in HCC, and the addition of biologics to this regimen is underway.

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

Yes. To date, the immune checkpoint inhibitors PD-1, PD-L1, and CTLA-4 have been studied and have all shown efficacy in HCC!

In early phase 1/2 trials, these agents showed antitumor effects, with evidence of an impact on response, and suggested an improvement in survival, which led to the approval of nivolumab in this space as a second-line agent. We are now awaiting the results of several ongoing phase 3 clinical trials that are evaluating the checkpoint inhibitors as single agents or in combination with other treatments for HCC. The inflammatory nature of HCC helps set the stage for their activity. Further analyses to help us better understand the effects of checkpoint inhibitors are underway.

Question

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

Answer

For my patients with metastatic HCC, I recommend the FDA-approved standards of care, which includes sorafenib for first-line treatment and regorafenib after disease progression on sorafenib.

Eventually, other novel drugs, such as lenvatinib, are expected to be approved by the FDA for metastatic HCC. Lenvantinib is an angiogenesis inhibitor that targets multiple tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors, RET, and KIT. It is imperative to also consider nivolumab as a second-line therapy now that it is approved by the FDA.

Most importantly, it is imperative for patients with metastatic HCC to seek the care of specialists so they can be considered for participation in clinical trials.

Question

Are there any current clinical trials you would recommend for patients with relapsed or refractory HCC? Do you expect any of these trials to change clinical care?

Answer

For those patients who have relapsed HCC or HCC that is refractory to approved treatments, I suggest that they consider participating in any study that is available to them, when indicated.

With the advent of approved therapies for HCC within different classes of drugs, it is expected that clinical trials will also evolve for those different classes of drugs and that new trials will potentially be added that include other novel drugs like chimeric antigen receptor T (CAR-T) cell therapies.

It is very hard to predict or anticipate which trial may be successful. From the perspectives of caring doctors and patients, trials need to be recognized as an opportunity to expose patients to novel therapies and help contribute to the advancement of the science of caring for HCC patients.

Question

Do you foresee treatment vaccines being used for HCC?

Answer

Clinical trials of different immunotherapeutic approaches for advanced HCC, including vaccines, are underway. The primary objective of such efforts would be to demonstrate the safety and efficacy of such novel vaccine approaches.

This will, of course, depend on identifying relevant antigens for HCC. Among antigens being studied is alpha-fetoprotein, but a more novel approach could depend on more particular antigens, like gypican-3.

Vaccine immunotherapy is a very novel approach being studied for the treatment of solid tumors, and it is very encouraging to see robust multiple efforts of this nature for HCC.