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Experts Answer Frequently Asked Questions on the Contemporary Management of Hepatocellular Carcinoma

Richard S. Finn, MD

Professor of Clinical Medicine
Division of Hematology-Oncology
Director, Signal Transduction and Therapeutics Program
Jonsson Comprehensive Cancer Center
David Geffen School of Medicine at UCLA
Los Angeles, California

Richard S. Finn, MD, has disclosed that he has received consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb, CStone, Eisai, Exelixis, Hengrui, Lilly, Merck, Novartis, Pfizer, and Roche/Genentech.

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Amit G. Singal, MD, MS

Chief of Hepatology
Medical Director
, Liver Tumor Program
Professor, Department of Internal Medicine
UT Southwestern Medical Center
Dallas, Texas

Amit G. Singal, MD, MS, has disclosed that he has received consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Exact Sciences, Exelixis, Glycotest, GRAIL, Merck, Roche/Genentech, and Wako Diagnostics/FujiFilm Medical Sciences.

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Mark Yarchoan, MD

Assistant Professor
The Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins
Baltimore, Maryland

Mark Yarchoan, MD, has disclosed that he has received consulting fees from AstraZeneca, Eisai, and Exelixis and funds for research support (paid to his institution) from Bristol-Myers Squibb, Exelixis, Genentech/Roche, and Incyte.

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Released: January 3, 2022

Hepatocellular carcinoma (HCC) treatment paradigms continue to evolve. In this commentary based on a webinar, Richard S. Finn, MD; Amit G. Singal, MD, MS; and Mark Yarchoan, MD, discuss best practices in treating advanced HCC and answer questions from healthcare professionals on this topic.

What is the current paradigm for first-line systemic therapy in patients with advanced HCC?

Richard S. Finn, MD:
In May 2020, the FDA approved the PD-L1 inhibitor/VEGF inhibitor combination of atezolizumab plus bevacizumab as first-line systemic treatment for patients with unresectable or metastatic HCC. This approval was based on findings from the phase III IMbrave150 trial, in which patients with advanced HCC (Child-Pugh A liver function) and no previous systemic therapy were randomized to receive either atezolizumab plus bevacizumab or sorafenib. Atezolizumab plus bevacizumab was associated with improved overall survival, progression-free survival, overall response rate, and quality of life compared with sorafenib. Certainly, clinical trials are always appropriate, and I strongly encourage patients to consider participation in research studies, but in clinical practice, atezolizumab plus bevacizumab should be considered our frontline regimen.

What is the optimal treatment for patients with advanced HCC who experience disease progression with atezolizumab plus bevacizumab?

Mark Yarchoan, MD:
This is a question we don’t have great answers for right now, because no prospective, randomized studies have assessed the optimal treatment following atezolizumab plus bevacizumab. I think we have good evidence that anti-VEGF therapy provides benefit after prior anti-VEGF therapy in HCC; for example, cabozantinib, ramucirumab, and regorafenib all have demonstrated overall survival benefits in the postsorafenib setting. We can extrapolate that principle for patients who have received prior atezolizumab plus bevacizumab. I think many would recommend an anti-VEGF tyrosine kinase inhibitor (TKI) following atezolizumab plus bevacizumab. Which anti-VEGF TKI to use, I think, is a matter of some controversy. Many would be most likely to consider options that were previously used in the first-line setting, including sorafenib or lenvatinib, because these agents have been so widely used. Others might consider agents that have demonstrated clinical benefit in the postsorafenib setting, including cabozantinib. At present, I don’t think there is a right answer among these options.

I believe that combination treatment with an anti-CTLA4 antibody plus an anti‒PD-1 antibody likely provides additional benefit over anti‒PD-1 monotherapy. In the CheckMate-040 study, nivolumab plus ipilimumab treatment appeared to be associated with approximately double the response rate observed with nivolumab monotherapy, so there may be a role for anti‒CTLA4-based combinations following atezolizumab plus bevacizumab. In addition, there is at least a small series that was published demonstrating responses with nivolumab plus ipilimumab in patients who received prior atezolizumab plus bevacizumab.

Overall, I think most of us would recommend an anti-VEGF TKI in this setting; however, if a patient was a less-favorable candidate for this therapy (eg, experienced bleeding while receiving atezolizumab plus bevacizumab), nivolumab plus ipilimumab would be a reasonable option.

Richard S. Finn, MD:
I agree. I tend to start the anti-VEGF TKI sorafenib or lenvatinib and then go from there to agents such as regorafenib or cabozantinib. As Dr Yarchoan noted, we don’t have prospective data at this time to guide this decision.

When would sorafenib or lenvatinib be preferred over atezolizumab plus bevacizumab as first-line systemic therapy for advanced HCC?

Mark Yarchoan, MD:
I think you really need a reason not to recommend atezolizumab plus bevacizumab as frontline therapy right now, based on data from the IMbrave150 study. That said, there are several scenarios in which I would not recommend this regimen. The first would be the patient for whom there is a bleeding concern, such as a history of recent bleeding or varices that look particularly at risk for bleeding. 

In addition, I might be hesitant to recommend atezolizumab for a patient with severe autoimmune disease. I’ll highlight severe—I think a lot of patients right now are not being given atezolizumab plus bevacizumab because of minor autoimmune issues, such as very minor psoriasis. Patients with well-controlled autoimmune disease who are not receiving high doses of systemic immunosuppressive therapy still should be considered for atezolizumab plus bevacizumab. 

Finally, I would be less likely to recommend atezolizumab for a patient who has received a transplant because of the risk of liver rejection.

Should varices be treated before initiating atezolizumab plus bevacizumab for patients with advanced HCC? How should varices be treated? Is portal vein invasion a contraindication to the use of atezolizumab plus bevacizumab?

Amit G. Singal, MD, MS:
The risk of bleeding should be assessed in all patients prior to starting atezolizumab plus bevacizumab. Small varices have a lower risk of bleeding; patients with these varices can likely go on a β-blocker and then start therapy. 

Patients with larger varices have a higher risk of bleeding and this should be managed before starting atezolizumab and bevacizumab. We currently don’t have good data to indicate if banding or β-blockers are better in this scenario. Bleeding related to bevacizumab isn’t portal hypertension-related, so my personal preference would be to band varices, although this carries a risk of post-banding ulcers and bleeding. Notably, there were patients included in the IMbrave150 trial with a history of treated varices.

For the second part of the question, portal vein invasion is not a contraindication to treatment with atezolizumab plus bevacizumab. There were patients in the IMbrave150 study who had main portal vein invasion. Notably, patients with main portal vein invasion have a higher risk of variceal bleeding, so it is particularly important to perform an upper endoscopy and manage any varices prior to initiation of atezolizumab plus bevacizumab. 

What is the best timing to move from repeated transarterial chemoembolization (TACE) to systemic therapy for a patient with HCC?

Amit G. Singal, MD, MS:
Objective response to TACE and liver dysfunction (eg, change in Albumin-Bilirubin score) should be evaluated. Patients with disease progression, even if they continue to have liver-localized disease or worsening liver dysfunction, should be considered for systemic therapy. The idea is to transition to systemic therapy when liver function remains preserved (eg, Child-Pugh A disease), such that the patient is eligible for potent first-line systemic therapy, with the potential to sequence later-lines of systemic therapy. I think the days of repeating TACE even after progression should be over, as we now have effective therapies in the systemic therapy space.

Would you have any concerns offering atezolizumab plus bevacizumab for a patient with decompensated liver disease? 

Amit G. Singal, MD, MS:
Even though we have seen remarkable efficacy data with atezolizumab plus bevacizumab in patients with advanced HCC, it is important to remember that this regimen was evaluated in a patient population with Child-Pugh A liver function and without high-risk varices. As patients develop more advanced liver dysfunction, whether in the form of higher Child-Pugh score or more significant portal hypertension, they have a higher competing risk of liver-related mortality, so the benefits of any HCC therapy are likely mitigated. Further, the risk of variceal bleeding increases, so the safety profile of atezolizumab plus bevacizumab may be less favorable. With this in mind, I am hesitant to start atezolizumab plus bevacizumab in decompensated patients at this time.  

There are systemic therapies that have been evaluated in a Child-Pugh B patient population. Sorafenib has the largest base of real-world data in this population via the GIDEON real-world patient registry. Nivolumab was evaluated in the CheckMate 040 study, which included an arm with a limited number of patients with Child-Pugh B7 or B8 disease. I would be more likely to consider either of these 2 agents for patients with Child-Pugh B liver function.

Richard S. Finn, MD:
I generally agree. The one caveat I would suggest is that for patients who have a very large tumor burden in their liver, we can have Child-Pugh B physiology because they have a massive tumor burden. In that case, if they have a response to therapy, there’s a good chance their liver function would improve—but obviously it’s an evolving area.

Your Thoughts?
What challenges do you experience in managing patients with advanced HCC? Please answer the polling question and join the conversation in the discussion box.

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