Advanced HCC: Updates in First-line Systemic Therapy

Moderator Josep Llovet, MD, centers discussion on advanced hepatocellular carcinoma and provides a broad overview of treatment options in the frontline setting.


Josep Llovet, MD: Let’s move to advanced stage. First, let’s talk about what updates we have. I’ve prepared a few slides on the upper view. You’re familiar with sorafenib; we published a trial in 2008. This was a breakthrough in the management of the disease, and it’s been in the field for 12 years as a single frontline therapy, [with a median overall survival of] 10.7 vs 7.9 months [with placebo]. As a result, it was adopted in guidelines as a single treatment. Afterward, there were several trials. In the slides, you can’t see all the trials; there are around 30. I’ve highlighted in green the trials in frontline positive, excluding those of ESMO [European Society for Medical Oncology] because these just happened. We have atezolizumab positive and durvalumab positive. Then we have lenvatinib, which keeps the end point of noninferiority compared with sorafenib. These are the drugs in the front line. In second line, all the trials have been designed to progress to sorafenib. We have 3 trials that hit the primary end point of superiority for OS [overall survival]. These are ramucirumab in patients with AFP [alpha-fetoprotein] of more than 400 ng/mL, regorafenib, and cabozantinib.

We have some slides showing the data of the trials in principle. Lenvatinib is a multikinase inhibitor that is unique in terms of hitting the target because it’s blocking FGL receptor 1,2,3, and 4. As you know, FGL4 is where the lagging FGF19 hits and has been considered a very important oncogene in 20% of the patients. In this trial, lenvatinib showed similar survival: over 13 months compared with over 12 months with sorafenib, which was a similar survival with a manageable adverse events profile. In the group analysis, interestingly enough, lenvatinib worked slightly better in patients with aggressive tumors, patients with high AFP, extrahepatic spread, vascular invasion, and also in patients with hepatitis B–related HCC [hepatocellular carcinoma].

The other combination that has been a breakthrough in the management of the disease has been atezolizumab plus bevacizumab. You’re familiar with the data presented a year ago or so. The median survival is moving from 11 to 13 months that we reported with sorafenib and lenvatinib, respectively, to 19 months’ median survival. With sorafenib, median survival was 13.2 months. This was a breakthrough. As a result, it has been adopted in guidelines as front line.

More recently, we have durvalumab plus tremelimumab, another combination that also hit the primary end point of superiority to sorafenib in the front line. In this trial, the STRIDE combination had a median survival of 16.5 months compared with 13.7 months of sorafenib. This represents a novel combination because it’s the first I/O–I/O [immuno-oncology] combination that we have in front line. To summarize the profile of adverse events: in principle, we tend to check the treatment-related adverse events, particularly those that made use, that drove the treatment or decrease of the dose. These are grade 3/4. The falling rate is 35% to 40% …, so sorafenib was probably around 45% and lenvatinib was around 55%. The adverse events are manageable, but sometimes they lead to discontinuation of the drug. This happens with atezolizumab-bevacizumab, with the 2 drugs at 7% of the cases and 1 drug at 16%. With sorafenib, it’s 10% to 15%. With lenvatinib, it’s around 10%.

Finally, I’d like to show you a slide that summarizes the treatment strategy for advanced HCC. First, we need to ask ourselves if the patient has any contraindication for immunotherapy: autoimmune disease or liver transplantation. If the answer is yes, then lenvatinib and sorafenib are considered frontline options for these patients. If the answer is no, we can think about combination therapies, including checkpoint inhibitors. The question that we’ll address today is whether a high risk of bleeding, particularly esophageal or gastric bleeding, is a result of the adverse event related to bevacizumab. In the atezolizumab trial, an endoscopy was required. Because this has become the standard of care, an upper–GI [gastrointestinal] endoscopy is required prior to treatment. Therefore, if we have varices at high risk—large or intermediate-size varices with red spots—then the consensus is that if these varices are there, you should move to durvalumab-tremelimumab or treat the varices with banding and carvedilol. This is more or less the flow chart. If the physician and the patient are OK waiting—the wound healing and so on—then atezolizumab is indicated. If not, they can start durvalumab-tremelimumab. If there’s no risk of bleeding, they can start atezolizumab. For the second line, we’ll talk afterward.

Transcript edited for clarity.

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