HCC Armamentarium Expands, But Sequencing and Immunotherapy Issues Remain

Ryan W. Huey, MD

The field of hepatocellular carcinoma (HCC) is rapidly evolving with the emergence of novel options after years of stagnancy, according to Ryan W. Huey, MD.

In January 2020, for example, a supplemental biologics application was submitted to the FDA for the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) for the treatment of patients with unresectable HCC who have not received prior systemic therapy. The application was based on findings from the IMbrave150 study, which demonstrated that the combination led to a 42% reduction in the risk of death compared with sorafenib (Nexavar; HR, 0.58; 95% CI, 0.42-0.79; P = .0006).

“Recent data on atezolizumab and bevacizumab have shown an improvement over sorafenib in the frontline setting. That is exciting because patients are always excited to try a new therapy but we want to do it in a context that works. This [regimen] seems to have more promising results than that which we have tried [with immunotherapy in HCC] before and, in addition to that, it seems to be more tolerable,” said Huey.

He also described the growing number of options in the second-line HCC setting. “We have regorafenib (Stivarga) in the second-line setting. In addition to that, we have cabozantinib (Cabometyx) and we also have ramucirumab (Cyramza).”

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Gastrointestinal Malignancies, Huey, assistant professor, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, highlighted the evolving treatment options in the HCC paradigm and discussed challenges and next steps in the field.

OncLive: How are we navigating the landscape of HCC today?

Huey: HCC is a cancer that for a long time did not have systemic therapies that we had a lot of enthusiasm about. Over the last several years that has changed fairly rapidly. In a world that used to be inhabited by sorafenib, we have a lot of drugs that are in the second-line now, an additional drug in the first-line setting, and even a combination of drugs in the first-line setting including immunotherapy, which is very exciting for our patients and will hopefully provide new opportunities for them.

Health-related quality-of-life data are coming out as well. The struggle with that is we may be a victim of our own success and as the order of operations changes, we are not going to know how to sequence therapies. Those are questions that remain to be answered at this time because many of our second-line treatments are under the assumption that patients get sorafenib first. "What happens if they receive lenvatinib (Lenvima) or atezolizumab and bevacizumab first?" We do not know the answer to that either. These trials may not be run in the large expansive settings that they were initially, but real-world data can help to answer some of these questions that remain outstanding and are very important to ask.

If atezolizumab plus bevacizumab is approved in the frontline setting, where do you see sorafenib going?

I do not know if we know the answer to that. We have a lot of experience with sorafenib but none of that is in the second-line setting. That is a question that remains outstanding. Several other TKIs are related to sorafenib and are, in fact, very close. There is a role for TKIs because we have been sequencing them all along and so if we are using a VEGF inhibitor now and we have been using TKIs that target VEGF in addition to other things in the past then there may be some activity. But, that biological rationale does not always hold up in the clinical setting and so we do not know. Sorafenib is not going to go away because of its familiarity and long-standing use. We just do not have the answers to the questions on how patients will react in the second-line setting.

What have we learned from the negative studies that used immunotherapy?

We have learned that patient selection is going to be really important and not only in terms of the groups of patients that we are targeting, but also not all disease stages are created equal. We may have more of a signal in the early stages of disease, perhaps even more resectable disease, whereas patients who get further down the road and have deterioration of liver function may not have as much susceptibility to these agents. We do not know the answer to that.

It may be that immunotherapy by itself is not sufficient and we need to figure out a better way to harness that. One thing we struggle with in HCC is a lack of tissue, so the opportunity to find predictive biomarkers is less than it would be in other tumor types. While some of those biomarkers in other diseases leave us wanting a bit more, it can help provide a signal for the rationale for immunotherapy and that is something that we do not have in HCC.

Do you see a future for circulating tumor DNA (ctDNA) in HCC?

The theory behind ctDNA in HCC is great because it may provide us the opportunity to gather molecular information in the disease. However, we do not have the body of evidence to suggest that that could be beneficial to patients at this time. Anybody who is excited about the future of oncology is looking for opportunities to use ctDNA and those are great questions to ask as well.

Is there any area of research in HCC that you would like to see more research focused on?

So much of early-stage HCC has been focused on the role of localized treatment, whether it was a surgical option or a procedural technique. The questions that arise are, "Is there a benefit to using our systemic agents?”; “Do they work better in the metastatic setting or advanced setting?"; and "Do they work better in early-stage disease?" When you do not have things that work very well in the advanced setting, there is not a lot of enthusiasm to bring them into the early setting. We have looked at sorafenib plus [other agents] in HCC before, but questions remain as we develop agents that are more active and conceivably provide us with better disease control. "Should we be using them in an earlier setting?"

Roche submits supplemental biologics license application to the FDA for Tecentriq in combination with Avastin for the most common form of liver cancer [news release]. Roche. Published January 27, 2020. https://bit.ly/3aP84gz. Accessed January 27, 2020.