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FAQs: IO in HCC
Immunotherapy in the Management of Patients With HCC: Answers to Frequently Asked Questions

Released: June 24, 2024

Expiration: June 23, 2025

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Key Takeaways
  • For patients with advanced hepatocellular carcinoma in need of a rapid disease response, atezolizumab plus bevacizumab is a good immunotherapy approach, while a dual immunotherapy regimen may be considered for small and slower progressive disease.
  • If FDA approved, trans-arterial chemoembolization (TACE) plus systemic therapy consisting of durvalumab with or without bevacizumab may be a potential option for large or bulky disease [>6 cm] that is likely to progress on conventional TACE [beyond up-to-7 criteria], and/ or who have multiple nodules [≥7]).

The role of immunotherapy in patients across hepatocellular carcinoma (HCC) is rapidly evolving, with a growing need for clinical oncologists, hepatologists, and interventional radiologists to remain up-to-date on the individualized treatment of patients with early stage, intermediate stage, and advanced/recurrent HCC, as well as exciting new options on the horizon. In this commentary, we provide answers to questions posed by a live audience of oncology healthcare professionals (HCPs) during a satellite symposium on HCC held on May 31, 2024.

What is your thought process when choosing an immunotherapy regimen in patients with advanced/metastatic HCC?

Mark Yarchoan, MD:
Making the best treatment selection for advanced/metastatic HCC can be challenging, mainly because the available regimens have not been compared head-to-head. Other than this, some consideration has to be given to the tempo of the disease, an example being impending liver failure. In a patient with impending liver failure I might go with atezolizumab plus bevacizumab because of the higher response rate in this patient population (30%; 95% CI: 25%-35%) based on data from IMbrave150. In a patient with a small/limited disease who has more time for achieving a response, I might go with durvalumab plus tremelimumab. But I do not believe there is really one single best answer.

In patients with advanced HCC who achieve an excellent response on immune checkpoint inhibitor therapy but who previously may have had beyond up-to-7 criteria (defined as the sum of the diameter of the largest tumor [in cm] and the number of tumors), vascular invasion, and/or small extrahepatic metastases, would you recommend referring to interventional radiology for consolidative treatment?

Sarah B. White, MD, MS, FSIR, FCIRSE:
If we have stable disease, we do not typically pursue consolidative therapy for HCC. By contrast, if we see progression or if we have oligoprogression, for example most of the disease is in check and then we have one site with progression, we will refer to interventional radiology. In a scenario like that, I think any of us would do consolidative therapy.

Mark Yarchoan, MD:
I think our practices are a bit varied right now and we are still trying to determine the best approach for different presentations. I have started to consolidate.

How do you manage the follow-up for your patients receiving immunotherapy for advanced HCC?

Mark Yarchoan, MD:
Most of my patients are seen at every cycle. We have participated in studies exploring the use of nivolumab and ipilimumab. I believe the rate of immune-related adverse events (AEs) is often higher with that regimen and many of the serious immune-related AEs are observed at the early time points. For that reason, I like to see those patients a little more often. Initially, I see these patients at 2- and 4-weeks in between cycles, for the first couple of cycles. These early visits can be particularly important if you practice in an area where patients tend not to call in for AEs. So, we monitor them a little more closely.

In patients receiving systemic treatment (eg, immune checkpoint inhibitor, VEGF inhibitor, tyrosine kinase inhibitor, Y-90) how do you assess response?

Sarah B. White, MD, MS, FSIR, FCIRSE:
Over the years, we have gone through changes to our systems for assessing tumor response. I will use Y-90 as an example. With this agent the tumors will often look a bit bigger, and they will have less enhancement. Enhancement is key and size is not necessarily as important in that scenario. Thus, we think of tumor enhancement first and size as secondary. When we measure size, we are measuring residual disease. When we do liver-directed therapy, the 1-month scan is a key milestone to watch. However with Y-90, it does not show us much. We have a better chance to see what the response is at approximately 3 months. However, if we observe an 80% reduction in alpha-fetoprotein levels, then we know we have done a good job and potentially would not pursue imaging at that 1-month time point. In the setting of bilobar disease, some of us get imaging at 1-month because we want to see what is happening on the other side of the liver―sites that we have not treated. But mainly, we look at enhancement of tumor(s) when assessing for a response.

How do you decide between the TACE vs TARE (trans arterial radioembolization) use?

Sarah B. White, MD, MS, FSIR, FCIRSE:
I will use watershed tumors as an example to answer this question. Watershed tumors can be challenging to manage.

Nonwatershed tumors can undergo radiation segmentectomy while sitting in the middle of a segment where one blood vessel comes in and there is an area or a margin around it. I can go into one artery that is going to segment 8 and it is only being supplied by segment 8, making it a primary target. I can take segment 8 out with a radiation segmentectomy, which would be equivalent to surgical resection. By contrast, a watershed tumor may reside in segment 5, 8—it is sitting in the middle. Thus, there is segment 8 blood flow coming in from the top and there is segment 5 blood flow coming in from the bottom or maybe there is a little something else―this is one of the main considerations with a watershed tumor. In those areas of the liver where you are not getting only segment 8 blood supply, you are getting segment 5 blood supply. In those watershed tumors I can blast away 8, but I still have 5 on the bottom that has blood supply. Another scenario is if the tumor is sitting off to the side of the liver and/or does not have a good margin around it, then we know that we are probably not going to get a great response with Y-90. For these types of tumor, I would treat segment 8 with a radiation segmentectomy and clean up the bottom with TACE. By contrast, if there is a patient that has a high hepatopulmonary shunt fraction, suggesting some of the Y-90 beads are going to move around, usually those patients have portal vein invasion and are better off pursuing TACE.

How would you implement the EMERALD-1 trial regimen if it is approved (eg, vs TACE or TARE)? Will all patients with intermediate-stage, Child-Pugh A-B7 receive TACE plus systemic therapy?

Sarah B. White, MD, MS, FSIR, FCIRSE:
I will start by saying that liver transplant surgeons at our site do not believe that immunotherapy is a contraindication to transplant. As a reminder, the multicenter, randomized, phase III EMERALD-1 study is evaluating TACE plus durvalumab with or without bevacizumab in patients with unresectable, previously untreated intermediate-stage HCC. In my presentation, I discussed TACE unsuitable disease, which includes patients with large or bulky disease (>6 cm), those who are likely to have poor response to conventional TACE (beyond up-to-7 criteria), or who have multiple nodules (≥7). I believe those patients will be considered for combined modality therapy with TACE and systemic treatment.

Mark Yarchoan, MD:
I am a bit more skeptical because we do not yet have the overall survival data from EMERALD-1. Without the survival data I do not know whether we are just trading a later benefit for an earlier benefit. For me, there are many unanswered questions in EMERALD-1. At the end of the day, it was a study of systemic therapy added to TACE. I think it also would be informative to see systemic therapy compared with TACE.

Richard S. Finn, MD:
On a related note, the phase III REPLACE study is evaluating systemic treatment with regorafenib plus pembrolizumab vs TACE or TARE in patients with intermediate HCC and Child-Pugh class A (N = 496; NCT04777851).

When we talk about sequencing, in patients receiving adjuvant atezolizumab plus bevacizumab in early disease or durvalumab plus bevacizumab with TACE who then at some point experience progression, how will that previous therapy weigh on your next treatment when they develop metastatic disease?

Mark Yarchoan, MD:
There are data that anti-VEGF therapy is beneficial post progression on anti-VEGF therapy. Cabozantinib, regorafenib, and ramucirumab all have shown benefit following sorafenib, and I think we can extrapolate that in a postbevacizumab setting. In principle, I think targeting VEGF remains a useful strategy. I also think there are patients who respond to CTLA-4 who are different from patients who respond to PD-1. I feel strongly that there is a role for CTLA-4 in the postbevacizumab/PD-L1 setting.

Richard S. Finn, MD:
Future studies might help inform how we sequence these therapies in the future. Do you automatically switch or will you look at an oligometastatic disease (single lesion) differently?  Dr White, you commented that you will ablate something and then continue. Although I believe we do not have evidence for that, I too tend to do that sometimes―for small growth, continue with the addition of a local treatment. [Link: https://clinicaloptions.com/CE-CME/oncology/io-in-high-risk-early-hcc/36244]

Your Thoughts?
What are your thoughts or questions on the rapidly evolving treatment landscape for patients with advanced, intermediate, and early liver cancer? Answer the polling question and join the conversation by leaving a comment. Also, feel free to visit the overall program page to view the on-demand webcast from the live event and access downloadable slides on this topic.

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