Choosing a Frontline Therapy

Richard S. Finn, MD: Katie, you’re a busy clinician and researcher in a high-volume center [at the University of California, San Francisco]. When you’re seeing patients, how would you assess the frontline treatment for your patient given these 3 options? What would you tell a clinician in our audience who hasn’t seen as many liver cancers? What are some things to pay attention to? Is there a role for TKIs [tyrosine kinase inhibitors] given the hazard ratio for IMbrave150, for which the OS [overall survival] is 0.58? How do you approach it?

Katie Kelley, MD: That’s agreat question, and thanks again for having me today. I’ll start by saying that I definitely agree with Tony [Bekaii-Saab]: Our de facto standard and the global standard for patients with Child-Pugh A, fit advanced liver cancer patient, is the combination of atezolizumab plus bevacizumab. Based on the strong results across the board from IMbrave150 from the efficacy, the safety, and the quality of life that Peter just highlighted. The bigger question that you’re asking is this: What about patients who are not good candidates for the atezolizumab plus bevacizumab regimen? Who are those patients?

If I were asked to summarize the patients for whom we wouldn’t use atezolizumab plus bevacizumab, I would generally categorize them and maybe 3 or 4 different types of patients. First, the clear-cut exclusion criteria on IMbrave150 would be patients with active varices or those who are at higher risk for bleeding varices or other types of bleeding based on their screening, endoscopy, or other clinical factors suggesting a risk for bleeding. That’s 1 type of patient for whom we must be very cautious and should probably not use the IMbrave150 regimen: patients with high risk for bleeding. We also have to underscore the fact that we don’t have Child-Pugh B safety or efficacy data from the atezolizumab plus bevacizumab regimen. Patients staged at Child-Pugh B are not established as good candidates for IMbrave150 right now.

You touched on the fact that patients with active autoimmune disease or patients post-transplant are also patients who we don’t think are necessarily safe for checkpoint inhibition as a treatment. Those are some general categories of patients for whom, right now, we have to give pause and not use the atezolizumab-plus-bevacizumab regimen. Turning to the other options, this is a fantastic place to be in liver cancer compared with years past, when there were just 1 or 2 drugs starting after regorafenib in 2017. We have choices to choose from, depending on patients’ comorbidities and other medical features, just like in breast cancer and colon cancer. When making that choice for these groups of patients who aren’t good candidates for atezolizumab plus bevacizumab, we can look to lenvatinib and sorafenib.

How do I choose between those 2 agents? Reassuringly, for the TKIs, while they do increase the risk for bleeding, we can say that they have not shown a dramatic increase in variceal bleeding compared with placebo. If we look back to the SHARP trial of sorafenib vs placebo or the Asian Pacific Association for the Study of the Liver trial of sorafenib vs placebo, those trials did not show that TKIs increased risk for serious bleeding events dramatically when compared with placebo in a patient population that was at risk for bleeding. They were patients at stage Child-Pugh A, admittedly. I’m more likely to use lenvatinib or sorafenib with patients who are not eligible for atezolizumab-bevacizumab perhaps because of recent bleeding from varices that have now been treated.

In terms of choosing between the 2 agents in that group of patients, if it’s a patient with Child-Pugh B liver function, then it’s important to note that we don’t have prospective data for lenvatinib in patients with Child-Pugh B. Although there are some favorable points to its toxicity profile in Child-Pugh A patients overall, encephalopathy, proteinuria, and some of the other complications do not yet have prospective safety data in that liver dysfunction population. But we do have more prospective data and history, whether it’s retrospective registry data such as GIDEON, as well as some prospective studies in the phase II context for Child-Pugh B. In a patient who is staged with Child-Pugh B liver function, I’m more likely to choose sorafenib with an empiric starting dose reduction based on some of the VA [US Department of Veterans Affairs] data that have been published.

Turning to the other contraindication to atezolizumab plus bevacizumab, there is concern for patients with autoimmune disease or transplant patients. When comes to autoimmune disease, there is a huge spectrum of risk. In some patients, it may be reasonable to try a checkpoint inhibitor–based regimen with close monitoring, but in patients with active disease requiring immunosuppression and certainly in patients after liver transplant, the risk of rejection supersedes the likelihood of benefit in the advanced cancer setting with graft loss in liver transplant patients, upward of 30% in some small studies.

That’s an unacceptable toxicity from checkpoint inhibition from the limited data that we have so far. In those patients, both sorafenib and lenvatinib are reasonable choices. It’s important to note that lenvatinib does have more QTC [corrected QT interval] prolongation risk than sorafenib. In patients with complex concomitant medications, such as immunosuppressive medicines, it’s important to do drug interaction checks for both drugs, sometimes choosing sorafenib if there is a QTC liability from the combination. Those would be my answers. I’ll also comment on another question that commonly comes up in how we choose between sorafenib and lenvatinib: the question of viral status and hepatitis B vs hepatitis C.

We always have to look at the subgroup analyses for signals of interest in important populations, like patients with hepatitis B vs hepatitis C. The cautionary note is that these are not adequately powered analyses to make high-level pronouncements about which type of patient to treat in which way. It’s important to look at the REFLECT trial of sorafenib vs lenvatinib and the forest plots. The survival is similar, and there was no significant difference in the subset analyses for hepatitis B vs hepatitis C. There was a trend toward benefit for lenvatinib for time to progression and progression-free survival for both viral subgroups, perhaps it was more pronounced for hepatitis B.

Conversely for sorafenib, we’ve seen some analyses that suggest that there is perhaps more activity in the hepatitis C population than hepatitis B, again with the caveats of not overinterpreting subset analyses. Overall I would say that we don’t have enough data to make a strong decision based on viral status. Perhaps lenvatinib should be favored in patients with hepatitis B, but we can’t choose the drug based on hepatitis C status 1 way or the other. It should be based on comorbidity more than viral status.

Richard S. Finn, MD: You bring up a lot of important, practical points. IMbrave150, like other phase 3 studies, excluded patients who had a bleeding risk. The study required people to have an endoscopy within 6 months. But if we look at overall grade 3/4 bleeding events, it was fairly similar between arms. There were a few deaths related to upper-GI [gastrointestinal] bleeding: In the atezolizumab-bevacizumab arm, it was 1%. In this carefully selected population, bevacizumab appeared to be very safe.

Transcript edited for clarity.