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Immunotherapy for HCC: FAQs
Redefining Hepatocellular Carcinoma Treatment in the Immunotherapy Era: Experts Answer Your Questions

Released: July 11, 2025

Expiration: July 10, 2026

Joseph W. Franses
Joseph W. Franses, MD, PhD
Neehar Parikh
Neehar Parikh, MD, MS
Mark Yarchoan
Mark Yarchoan, MD
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Key Takeaways
  • Multiple first-line immunotherapy-based combinations are approved for metastatic hepatocellular carcinoma (HCC) (eg, atezolizumab plus bevacizumab, durvalumab plus tremelimumab [STRIDE], or nivolumab plus ipilimumab) with choice based on safety profile, patient comorbidities, and goals of therapy.
  • Adding systemic therapy with immune checkpoint inhibitors (ICIs) (durvalumab/bevacizumab or lenvatinib/pembrolizumab) to transarterial chemoembolization improves PFS, response rates, and duration of response in patients with unresectable Barcelona Clinic Liver Cancer stage B or intermediate HCC.
  • Guidelines no longer recommend adjuvant ICI-based therapy (atezolizumab plus bevacizumab) for patients with resected high-risk HCC based on the absence of recurrence-free survival benefit reported with longer follow-up from IMbrave050.

In this commentary, hepatocellular carcinoma (HCC) experts Joseph W. Franses, MD, PhD; Neehar Parikh, MD; and Mark Yarchoan, MD, answer frequently asked questions posed by an audience of healthcare professionals at a live webinar on applying the latest data for immunotherapy across the disease spectrum of HCC, which took place during the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

Immune-checkpoint Inhibitors in Advanced Metastatic HCC

What do you think about when making a recommendation of first-line immune Checkpoint–inhibitor (ICI)-based therapy in the advanced/metastatic setting

Joseph W. Franses, MD, PhD:
We have several options to choose from in the first-line setting. One such option is the combination of atezolizumab plus bevacizumab, which is supported by the results from the global randomized phase III IMbrave150 trial. In that study, atezolizumab plus bevacizumab compared with sorafenib improved median progression-free survival (PFS) (6.9 vs 4.3 months; HR: 0.59;  P <.001), median overall survival (OS) (19.2 vs 13.4 months; HR: 0.66; P <.001), response rate (30% vs 11%), and duration of response (DoR) (18.1 vs 14.9 months). Those results led to FDA approval of atezolizumab plus bevacizumab for the treatment of adult patients with unresectable or metastatic HCC who had not received systemic therapy.

Another viable option we have as first-line therapy is durvalumab plus tremelimumab based on data from the phase III HIMALAYA study, which showed that a priming dose of tremelimumab with durvalumab therapy, also-called the STRIDE regimen, when compared with sorafenib also improved median OS (16.4 vs 13.8 months; HR: 0.78; P =.0037), response rates (51.5% vs 15.6%), and DoR (22.3 vs 18.4 months). However, the median PFS was not different between the STRIDE regimen and sorafenib arm (HR: 0.90; 95% CI: 0.77-1.05). These data led to FDA approval of durvalumab in combination with tremelimumab for the treatment of adult patients with unresectable HCC.

And more recently, we have the option of nivolumab plus ipilimumab based on the results from the phase III CheckMate 9DW study of nivolumab plus ipilimumab vs investigator's choice of lenvatinib or sorafenib for patients with unresectable HCC. In CheckMate 9DW there was no difference in the median PFS (9.1 vs 9.2 months), but there was numerical improvement in median OS (23.7 vs 20.6 months; HR: 0.79; P = .018), response rate (36% vs 13%; P <.0001), and median DoR (30.4 vs 12.9 months). Nivolumab plus ipilimumab is now FDA approved as a first-line treatment option for adult patients with unresectable or metastatic HCC.

Mark Yarchoan, MD:
We certainly have good options to choose from that show improved outcomes vs sorafenib, which used to be our standard first-line therapy for quite some time. In the absence of head-to-head clinical trial data for trials using ICI as first-line therapy, I can only say that the DoR observed with the cytotoxic T-lymphocyte associated protein 4–based regimens in HIMALAYA and CheckMate 9DW is quite impressive. The IMbrave150 regimen was the first approved and it has remained a standard first-line option for patients with advanced HCC in most clinical practices. And in patients with a complete response to atezolizumab plus bevacizumab in first line, which we have started to see more frequently, I might even consider stopping therapy and just watch how they do over time.

Joseph W. Franses, MD, PhD:
However, there are significant differences for these 3 regimens regarding immune-related adverse events (AEs) necessitating steroid management. Dr Parikh, would you mind commenting about how AEs with the various options informs your decision of which ICI-based combination you might recommend to your patients with unresectable/metastatic HCC?

Neehar Parikh, MD:
When selecting first-line therapy, I also consider bevacizumab-related toxicities. I consider the potential need for performing an upper endoscopy because of the established risk of gastrointestinal bleeding with this agent. By contrast, the immune-related AEs can be higher when you add a cytotoxic T-lymphocyte associated protein-4 together with a PD-1 inhibitor. Overall, I think we need to think of a good balance of risk and benefit when choosing any particular ICI-based combination as first-line therapy. In a patient with minimal portal hypertension, atezolizumab plus bevacizumab might be a good first-line therapy. For those with more “intermediate” hypertension, I think the STRIDE regimen might be given safely.

The emerging data for the combination of nivolumab and ipilimumab is relatively new to us and we are still trying to assess how to integrate this combination into everyday practice. One caveat is that the toxicity with that regimen has been consistent in both the second-line and the first-line setting. In CheckMate 9DW, the most common any grade AEs were pruritus (28%), aspartate aminotransferase elevation (20%), alanine aminotransferase elevation (19%), and rash (19%). The most common ≥3 AEs included aspartate aminotransferase elevation (6%), alanine aminotransferase elevation (5%), and lipase increase (5%). These AE findings are similar to what was reported in the CheckMate 040 for this combination as second-line therapy following progression on sorafenib. Of importance, 29% of patients receiving nivolumab plus ipilimumab in the first-line setting required high-dose steroid treatment for the management of AEs.

Mark Yarchoan, MD:
Both of my colleagues make very good points. Also, because patients are living longer with incorporation of ICIs for HCC, we have to think about sequencing treatments and I wish that we had data not just of these agents in isolation but about how patients did with various types of subsequent therapy. In my practice, I have previously followed atezolizumab plus bevacizumab with ipilimumab plus nivolumab in the second line and I saw some patients respond very well, even in second-line and third-line therapy.

In patients receiving atezolizumab plus bevacizumab as first-line therapy, does the response to this regimen inform what you would consider in the second-line setting?

Mark Yarchoan, MD:
After atezolizumab plus bevacizumab in the first-line setting, a tyrosine kinase inhibitor (eg, sorafenib or lenvatinib) remains a good choice. I also think there is a role for dual ICI in that setting. Previously, I would have anticipated that patients whose disease responded to atezolizumab with bevacizumab would be the ones to subsequently respond to ipilimumab plus nivolumab. However, based on small analysis (n = 32) from our center, we noted that it was the exact opposite. Patients who had primary progression on atezolizumab plus bevacizumab respond to nivolumab plus ipilimumab. The objective response of the overall study was 22% in our small study, and objective response correlated with improved PFS and OS. However the small sample size limits the strength of the conclusions.

Immunotherapy in Intermediate HCC 

What are your thoughts on the role of systemic immunotherapy for patients with intermediate HCC?

Neehar Parikh, MD:
It is important to note that the Barcelona Clinic Liver Cancer stage B (BCLC B) Intermediate HCC is a very heterogeneous disease and this might also be a patient that you consider eligible for locoregional therapy. Under the different categories of BCLC B, we may have a unifocal lesion that is greater than 5 centimeters with an elevated alpha-fetoprotein biomarker. You may also see a patient with intrahepatic lesions only, with well-defined nodules, preserved portal flow, and selective access. And another scenario is a patient with diffuse, infiltrative, extensive bilobar liver involvement without clear vascular invasion. These are all variations for BCLC B or intermediate HCC and are important considerations when selecting systemic treatment in this stage.

The most recent data for systemic ICI-based treatment options for intermediate HCC come from the placebo-controlled phase III EMERALD-1 trial of transarterial chemoembolization (TACE) plus durvalumab or placebo followed by treatment with durvalumab with or without bevacizumab or placebo in previously untreated unresectable HCC (N = 616) and the placebo-controlled phase III LEAP-012 trial of TACE plus lenvatinib and pembrolizumab vs TACE in patients with confirmed localized HCC with no portal vein thrombosis or extrahepatic disease and not eligible for curative therapy (N = 847).

Data from EMERALD-1 showed that TACE and durvalumab with bevacizumab vs TACE alone for unresectable HCC yielded superior median PFS (15.0 vs 8.2 months; HR: 0.77; P = .032) and 12-month PFS rates (55% vs 39%), which was maintained through 18 months. Addition of durvalumab only to TACE did not show a statistically significant PFS benefit (10.0 vs 8.2 months; HR: 0.94; P = 638).

Looking at recent data from the LEAP-012 study, we see that adding lenvatinib plus pembrolizumab to TACE compared with TACE with placebos also improved median PFS (14.6 vs 10.0 months; HR: 0.66; P = .0002), and although OS data was not yet mature, there was a trend suggestive of 24-month OS rate improvement as well (75% vs 69%; HR: 0.80; P = .087). We also note that objective response with addition of lenvatinib and pembrolizumab to TACE was higher than TACE with placebo (47% vs 33%; difference: 14.6%; nominal P = .0005) and the DoR was 4 months longer.

Mark Yarchoan, MD:
What we can surmise from these data is that adding ICI-based systemic therapy to TACE for intermediate stage HCC  improves PFS and response rates, particularly with durvalumab appearing to drive a better response rate and bevacizumab contributing to PFS. My question for my colleagues is do you think that adding ICI-based systemic therapy earlier is going to translate to fewer rounds of TACE in the clinic? Potentially also translating into preserved liver function with fewer locoregional procedures.

Joseph W. Franses, MD, PhD:
I think this can indeed make a difference for patients. I also think that for large centers, at least in the United States, the practice of using TACE is less common these days. Other more commonly used locoregional therapies include transarterial radioembolization (TARE) or Y90 radioembolization. And that raises another aspect of this discussion that we did not get to cover and that these 2 trials cannot answer at this time.

Mark Yarchoan, MD:
One of the key differences between EMERALD-1 and the LEAP-012 is that lenvatinib has a much shorter half-life than bevacizumab, so lenvatinib was integrated right upfront in combination with TACE whereas in EMERALD-1 durvalumab was started upfront and then bevacizumab was added after up to 4 rounds of TACE. But overall, I think the takeaways for both of these studies are similar––improved response, PFS, and DoR with addition of systemic therapy to TACE.

If we require a response to downsizing multimodal intermediate HCC initially unresectable, what would you recommend for ICI combination either TARE or TACE?

Joseph W. Franses, MD, PhD:
Looking at locoregional therapy alone, local control rate is probably better with TARE. Our center preference is to use TARE, but because we do not have head-to-head data for TACE vs TARE plus systemic therapy that remains a challenging question to answer conclusively.

Mark Yarchoan, MD:
I think we need to consider that there are very heterogeneous situations. Pathologic responses appear to be higher with TARE, including for smaller tumors. I also consider whether the patient has vascular invasion, the standard of care in that setting is systemic therapy and tell them that the possibility of recurrence after surgery is very high. There is also the potential for using systemic therapy and after the tumor responds to systemic treatment the patient may become eligible for curative surgery, but the current guidelines may not support this approach.

High-risk Early HCC

Is there a role for Immunotherapy in patients with high-risk resected/ablated HCC?

Mark Yarchoan, MD:
When we look at the current guidelines, there is no standard neoadjuvant or adjuvant systemic therapy—which is unfortunate because we know that the majority of these patients recur after curative intent resection. Moreover, outside of a clinical trial, current guidelines discourage use of standard neoadjuvant, or adjuvant therapy.

With regard to systemic ICI use in high-risk HCC following resection or ablation, we had great hopes for atezolizumab plus bevacizumab compared with active surveillance. Preliminary results from the phase III IMbrave050 study had shown initial recurrence-free survival benefit which was not sustained at more mature follow up (HR: 0.90 [95% CI: 0.72-1.12]). Because of this, in 2025 several guidelines no longer recommended the use of adjuvant ICI-based systemic therapy (atezolizumab plus bevacizumab) in patients with early HCC at high risk of recurrence after liver resection or local ablation.

There is some provocative data from a phase II trial of sintilimab, a PD-1 inhibitor, vs active surveillance in patients with resected high-risk HCC showing a benefit in recurrence-free survival HR: 0.534; (95% CI: 0.360-0.792; P = .002). But in view of the recent results from IMbrave050, that data just raises more questions.

Your Thoughts
What are your thoughts on the current treatment landscape of advanced metastatic, intermediate, and high-risk early HCC? Answer the polling question and leave us a comment. Visit the program page to access the slides associated with this discussion, watch an on-demand webcast, and listen to a summary podcast from the live event.

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Which of the following topics for the management of patients with advanced metastatic, intermediate, and high-risk early HCC would you like to learn more about?

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