Sequencing Strategies, Combinations Mark Next Steps in HCC

Josep M. Llovet, MD, PhD

The recent addition of multikinase inhibitors and immunotherapies has moved the needle in the right direction for hepatocellular carcinoma (HCC), but the next steps involve sequencing these agents and incorporating combination regimens.

According to Josep M. Llovet, MD, PhD, there are several promising approaches with checkpoint inhibitors being tested in phase III studies. For example, the frontline combination of the PD-L1 inhibitor atezolizumab (Tecentriq) and bevacizumab (Avastin) was granted a breakthrough therapy designation for patients with advanced or metastatic HCC.

A phase Ib study presented at the 2018 ESMO Congress showed that atezolizumab plus bevacizumab induced a confirmed investigator-assessed objective response rate of 32% per RECIST v1.1 criteria in patients with advanced HCC, with more than half of responders maintaining their response for at least 6 months and about one-fourth for at least 12 months.

Moreover, the CheckMate-459 trial (NCT02576509) is comparing nivolumab (Opdivo) with sorafenib (Nexavar) in the frontline setting. If the study is positive, Llovet said, he expects that nivolumab will become the frontline standard of care. Nivolumab is currently approved in the second-line setting following progression on sorafenib.

In the space of kinase inhibitors, sorafenib was the only FDA-approved agent in HCC for more than a decade. However, in August 2018, the FDA approved lenvatinib (Lenvima) as a first-line treatment for patients with unresectable disease, based on data from the phase III REFLECT trial. REFLECT results showed that lenvatinib was noninferior to sorafenib in the frontline setting. Median overall survival was 13.6 months on the lenvatinib arm compared with 12.3 months for those who received sorafenib.

The multikinase inhibitor regorafenib (Stivarga) is also approved for patients with HCC who have progressed on sorafenib.

OncLive: How have you seen the HCC paradigm evolve recently?

In an interview with OncLive^®, Llovet, founder and director of the Liver Cancer Program at Mount Sinai School of Medicine and a professor at the University of Barcelona, discussed the rapidly evolving treatment landscape for HCC and the work that lies ahead.Llovet: During the last 12 years, we had only 1 drug that was effective. This was sorafenib. For 10 years, we had several trials testing all types of drugs, and all these trials were negative. The last 3 years have been a revolution. In the second-line setting, we now have regorafenib and nivolumab. These have been shown to be effective compared with placebo.

What would you say are the next steps?

Even in the frontline setting, we have lenvatinib, which was shown to be similar to sorafenib in a noninferiority design. Suddenly, we now have a lot of drugs. Therefore, the question now is, "Where are we going, and what are the next steps?"What we are seeing now is that we have established frontline and second-line treatment for patients with HCC. In the beginning, we thought there would be the design of completely new drugs for third-line treatment. However, this is not going to happen. At least, that is my view.

What will happen is that new combinations will come out from agents we already have. They will try to challenge the frontline treatments. Right now, there is a head-to-head trial that is finished of nivolumab versus sorafenib. We will know the results very soon. If nivolumab is superior, we imagine it will become the standard of care.

What other ongoing research do you want to mention?

Another thing that is emerging and will probably be the future of this paradigm are combination therapies. Thus far, the data are showing that checkpoint inhibitors are good for a certain percentage of patients—let's say 20% to 30%. In those patients, they achieve durable response and long-lasting outcomes. In the other 70% or 80% of patients, the impact of immunotherapy is irrelevant. We'll see what happens with the nivolumab trial. We are seeing that immunotherapy in combination with tyrosine kinase inhibitors could move the field to a different dimension. [There are] data on a trial of atezolizumab and bevacizumab in combination. It led to unheard of response rates for this disease. We also saw a trial of lenvatinib and pembrolizumab (Keytruda).In the realm of precision medicine, this is an area we need to get better. This is specifically identified as 1 driver that creates what we call oncogenic addiction, meaning the tumor is addicted to that driver. You are able to unplug this addiction with TKIs or monoclonal antibodies and improve outcomes. We don't have this in HCC.

What is the current state of biomarkers in HCC?

Why don't we have this? There are 2 main reasons. The most important thing is that these drivers are not targetable. TERT, p53, and all the other prominent mutations are not targetable. Looking at other diseases, HER2 amplification can be targeted with trastuzumab (Herceptin) in breast cancer and BRAF mutations can be targeted in melanoma. These are drivers that have a specific, working drug. This isn't the case in HCC. We have a couple ongoing studies looking at this.In terms of biomarkers, it will be critical to further understand responders to checkpoint inhibitors. We could also try to figure out why tumors become resistant to immunotherapy. I say this because when immunotherapy works, it's fantastic. The outcomes are impressive, and sometimes it doesn't depend on the stage of the disease. It provides a lot of hope, but only to a small proportion of patients. It would be very nice to identify better biomarkers in HCC.

Pishvaian MJ, Less MS, Ryoo B-Y, et al. Updated safety and clinical activity results from a Phase Ib study of atezolizumab + bevacizumab in hepatocellular carcinoma (HCC). Presented at: ESMO 2018; October 19-12; Munich, Germany. LBA26.