Looking Beyond Atezolizumab/Bevacizumab for the Treatment of HCC

Laura Goff, MD

The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) is an FDA-approved regimen for the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior therapies for their disease. The frontline regimen is one of the only therapeutic combinations that have delivered good outcomes for patients despite several studies of agents that challenged the standard-of-care (SOC), sorafenib (Nexavar).

During a presentation given a part of the 17th Annual Meeting of the International Society of Gastrointestinal Oncology® (ISGIO), hosted by Physicians’ Education Resource, LLC (PER®), Laura Goff, MD explained how the data supporting the use of atezolizumab/bevacizumab from the phase 3 IMbrave150 clinical trial (NCT03434379) is informing research for the later-line settings in the absence of other agents. In IMbrave150, atezolizumab plus bevacizumab achieved a 42% reduction in the risk of death versus sorafenib (HR, 0.58; 95% CI, 0.42-0.79; P <.001). The combination, therefore, represents a news SOC for frontline HCC.¹

The immune checkpoint inhibitor nivolumab (Opdivo) was also compared with sorafenib in the frontline setting of HCC in the phase 3 CheckMate 459 clinical trial (NCT02576509). The study set out to show statistically significant improvement in overall survival (OS). The median OS achieved with nivolumab was longer than that of sorafenib, but the difference was not statically significant. The median OS observed with nivolumab was 16.4 months (95% CI, 14.0-18.5) versus 14.8 (95% CI,12.1-17.3) with sorafenib (HR, 0.85; 95% CI 0.72-1.00; nominal P =.0522).²

Other agents are still under active investigation in advanced HCC and the hope is that the data will answer some questions oncologists have about the second-line treatment of the disease.

In an interview with Targeted Oncology, Laura Goff, MD, associate professor of Medicine (Hematology/Oncology), medical director, Division of Hematology and Oncology, and co-chair, Data and Safety Monitoring Committee at Vanderbilt-Ingram Cancer Center, discussed the treatment of HCC in the frontline and beyond.

TARGETED ONCOLOGY: Can you give an overview of your presentation during ISGIO?

Goff: I spoke about the optimization of treatment for advanced HCC. The treatment for HCC is rapidly changing, and the impact of atezolizumab and bevacizumab in the treatment of HCC hasled us to more questions than answers. Our questions are related to what we should do, both in the first-line setting and in the advanced setting. What do we do at this point? How can we best treat patients? Is everybody eligible for atezolizumab and bevacizumab, and if not, what do we do then?

TARGETED ONCOLOGY: What therapies are showing the most promise for the treatment of advanced HCC right now?

Goff: I do think that atezolizumab plus bevacizumab is the clear winner in the first-line setting right now. And it is the standard to which we measure everything else at the moment. One of the questions I posed in my talk is what do we think the next headline is going to be in HCC? We've had lots of headlines in recent years, which is very exciting for our patients, and I made some guesses, but I don't pretend to know the answers to all the questions that we have in HCC right now. I've certainly learned even over the past year that some things that I thought were going to win didn't.

I really thought that in the comparison of nivolumab to sorafenib, nivolumab would be a clear winner and it wasn't. So, I think that some of the exciting data that I'm looking forward to seeing come out over the next months or years are the durvalumab and tremelimumab first-line comparison study. I'll be really excited to see the results of the randomized control trial of nivolumab and ipilimumab. Then I think there'll be a lot of questions asked about what are the best agents following atezolizumab and bevacizumab and what can we find out in that setting for patients refractory to that regimen?

TARGETED ONCLOGY: What novel therapies are coming down the pipeline in HCC?

Goff: There are a couple of agents for which data were presented at the 2020 ASCO Annual Meeting which were apatinib and donafenib. Those agents have demonstrated modest activity. However, they are VEGF-targeting TKIs, which is very similar to a lot of the agents that we already have in play. One of the things I’m hoping for is for some agents that don’t target either VEGF or the immune system. That’s been the focus of HCC research for a long time and I think we’re still seeking more targets for our patients.

TARGETED ONCOLOGY: Do you often refer to the NCCN guidelines to inform you on the optimal treatment approaches for HCC?

Goff: The NCCN guidelines rapidly change. They have been revised a few times over the past year. Although the recommendations are interesting and helpful, they can be difficult for oncologists to keep up with.

_Reference:

_{1. Goff L. Optimizing treatment in advanced hepatocellular carcinoma. Presented at: 17th Annual Meeting of the International Society of Gastrointestinal Oncology®, hosted by Physicians’ Education Resource, LLC (PER®). October 2-3, 2020. Virtual.}

_{2. Sangro B, Park J, Finn R, et al. CheckMate 459: Long-term (minimum follow-up 33.6 months) survival outcomes with nivolumab versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma. Ann Oncol. 2020;31(3): S241-S242. doi: 10.1016/j.annonc.2020.04.078}