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BackTable / Tumor Board / Article
First-line Immunotherapy for HCC: Insights from Three Landmark Clinical Trials
Sophie Frankenthal • Updated Jun 5, 2025 • 35 hits
Hepatocellular Carcinoma (HCC) is the most common primary liver cancer and a leading cause of cancer-related death worldwide, typically arising in the setting of chronic liver disease or cirrhosis. For over a decade treatment for advanced HCC centered on sorafenib, a multikinase inhibitor, despite its limited survival benefit. The advent of immunotherapy has transformed this landscape, offering a more dynamic approach by reactivating the immune system to recognize and attack tumor cells. Immune checkpoint inhibitors – targeting PD-1, PD-L1, and CTLA-4 – have demonstrated meaningful survival benefits in recent trials, particularly when used in combination.
Oncologists and liver disease experts Dr. Jon Mizrahi, Dr. Adam Burgoyne, Dr. Zach Berman, and Dr. Lingling Du review the pivotal trials that redefined first-line treatment for advanced HCC, including IMbrave150 [1], Himalaya [2], and CheckMate-9DW [4]. This article features excerpts from the BackTable Tumor Board Podcast. We’ve provided the highlight reel here, but you can listen to the full episode below.
The BackTable Tumor Board Brief
• The IMbrave150 and Himalaya trials redefined first-line HCC therapy by demonstrating improved survival with combination immunotherapies over sorafenib, and establishing new standards using atezo/bev and STRIDE regimens.
• CheckMate-9DW confirmed the potential of Ipi/Nivo, showing strong long-term survival but with delayed benefit and higher immune toxicity, emphasizing the trade-off between durability and tolerability.
• Single-agent checkpoint inhibitors proved insufficient, reinforcing the need for dual or multi-agent immunotherapy strategies to meaningfully improve outcomes in advanced HCC.
• Studies show consistent benefit across HCC subtypes, regardless of viral etiology, supporting immunotherapy as the universal front-line approach for eligible patients.
Table of Contents
(1) Imbrave150 & Himalaya: Pioneering Combination Immunotherapy in HCC
(2) CheckMate Trials: Advancing Combination Checkpoint Blockade in HCC
(3) The Role of Etiology in Immunotherapy Outcomes
Imbrave150 & Himalaya: Pioneering Combination Immunotherapy in HCC
The IMbrave150 (2020) and Himalaya (2022) trials have significantly reshaped first-line therapy for advanced hepatocellular carcinoma (HCc) by introducing combination immunotherapies that outperformed sorafenib in overall patient survival. IMbrave150 demonstrated a significant survival advantage with atezolizumab and bevacizumab – a PD-L1 and VEFG inhibitor combination – as compared to sorafenib. This finding marked the transition to immunotherapy-based regimens in the front-line setting. [1]
In contrast, the Himalaya trial evaluated dual checkpoint blockade using the STRIDE regimen, which pairs a single priming dose of tremelimumab (anti-CTLA-4) with ongoing durvalumab (PD-L1 inhibitor) therapy. STRIDE achieved durable long-term outcomes, with five-year overall survival rates approaching 20%, while minimizing toxicity through limited CTLA-4 exposure. This strategy differentiates it from more immunogenic but less tolerable regimens used in other cancers, highlighting the importance of balancing efficacy and toxicity in HCC treatment design. [2]
[Dr. Tyler Sandow]
Treme makes a lot of sense, but I was trying to be fancy, and then I did it wrong, and so I'm done. There have been some impactful immunotherapy trials in HCC, and Lingling, I've heard you talk about this a million times over. Can you describe some of them for me? I guess the first one we really know about was IMbrave, right?
[Dr. Lingling Du]
Right. I think IMbrave 150 is the first one that came out in May 2020, and that was really the landmark trial that put front-line immunotherapy on the stage that everybody has been using immunotherapy in the front-line setting ever since then. That is the randomized untreated advanced HCC patients who receive either atezolizumab and bevacizumab. That's actually a combination of immunotherapy and TRE therapy. Atezolizumab is a PD-L1 inhibitor, and bevacizumab is a VEGFR antibody.
The randomized patients who receive either atezo/bev versus at that time standard of care sorafenib, and atezo/bev significantly improved over-survival. I think the medium over-survival was improved to 19 months with atezo/bev versus, I think, 13 months with sorafenib.
[Dr. Tyler Sandow]
I think it's important-- we on the interventional radiology side are familiar with Bev, because it's Avastin, and we see that a lot in colorectal cancer patients. That's a drug we're familiar with from being careful about not dissecting blood vessels because as it being a VEGF inhibitor, it definitely makes the blood vessels a little bit more difficult to manage. Can you all tell me about the other trials, like Himalaya? What is Himalaya?
[Dr. Jon Mizrahi]
Himalaya was the durvalumab and tremelimumab. This was a little bit different than the IMbrave, which was PD-1 and VEGF. Himalaya was looking at PD-L1 and CTLA-4. Durvalumab and tremelimumab, and it was versus sorafenib. They also had an arm that was durvalumab alone. Basically what we found was that there was a medium over-survival advantage of doing durvalumab/tremelimumab versus sorafenib. Recently they actually published their five-year overall survival data.
At five years, about 19% to 20% of patients were still alive in the durva/treme arm, which is pretty significant if you think back to-- before we started, we were talking about patients on sorafenib.
[Dr. Lingling Du]
Everybody lives for a year.
[Dr. Jon Mizrahi]
That we have a five-year survival that's in the not just double digits, but 20% is actually pretty remarkable. What's interesting about the dosing of that is that you're using-- in previous usage of PD-1 and anti-CTLA-4, like Ipi/Nivo primarily and other malignancies, you keep giving the CTLA-4, but this is a little bit different. It's the STRIDE regimen. You're giving durva and treme, and the treme you're only giving one time. That CTLA-4 you're giving one time is like a priming dose in that first infusion.
Then each subsequent infusion, which is every four weeks, it's just the durvalumab. It's a little bit easier from not only a logistical standpoint but also toxicity, you're not getting that repeat CTLA-4. Now in the study, as part of the regimen, you can reprime them and give them treme again. Let's say you had someone with a nice response, so you could go back. They lose that response after six, nine months, give them treme again. The way it's designed is that you only give it that first time. It is an interesting approach to treating them.
[Dr. Lingling Du]
I think the special part with the Himalaya trial, now that you're talking about that, they originally had the fourth arm. That is several dose of tremelimumabtremelumab with durvalumab, but treme at the lower dose. Then it turned out to be the outcome did not really change that much compared to just the one priming dose, but side effect way much worse.
[Dr. Jon Mizrahi]
You see a slight increase-- If you actually parse the data a little bit and look at the durva alone arm, and then the durva with the one dose of treme, there is a little bit of an increase in the mediated adverse events, but it's not that much. Not as much as I would say that we're typically used to seeing with the addition of anti-CTLA-4 and other malignancies like renal cell carcinoma, melanoma, that kind of thing.
[Dr. Lingling Du]
The STRIDE is a relatively easy regimen to tolerate.
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CheckMate Trials: Advancing Combination Checkpoint Blockade in HCC
Following the initial adoption of immunotherapy for HCC, subsequent trials clarified the limitations of single-agent checkpoint inhibitors such as nivolumab and pembrolizumab, which failed to improve survival in phase III studies such as CheckMate-459 (2022). Combination regimens gained momentum, culminating in CheckMate-9DW (2024), which compared ipilimumab plus nivolumab (Ipi/Nivo) to a lenvatinib-dominated TKI control arm. The combination achieved a median overall survival approaching two years, though benefits emerged only after an initial period of higher progression and mortality, as reflected in delayed crossover of survival curves. [3][4]
Earlier studies – including CheckMate-040 (2017) – showed that only the higher-dose IPI3/NIVO1 regimen was effective, raising early concerns about toxicity. CheckMate-9DW later confirmed that this combination carries relatively higher rates of immune-related adverse events compared to the STRIDE regimen tested in the Himalaya trial, but also demonstrated superior long-term survival outcomes. Taken together with IMbrave150 and Himalaya, these trials underscore the time-dependent nature of immunotherapy response in advanced HCC as well as the ongoing need to balance efficacy with tolerability in regimen selection. [4][5]
[Dr. Adam Burgoyne]
I think the other important point for both of these studies is it's really a combinatorial approach of targets. We were chatting a little bit before we started about, we think of immunotherapy usually from the PD-1/PD-L1 axis. In the earliest stages of immunotherapy or HCC, we were using single-agent PD-1 inhibitors like nivolumab or pembrolizumab, but it was really these combination strategies of either anti-PD-1, anti-VEGF or anti-PD-L1 plus CTLA-4 that really moved the needle forward in terms of improving outcomes.
[Dr. Tyler Sandow]
It's almost like you always needed something else with it.
[Dr. Adam Burgoyne]
Exactly.
[Dr. Lingling Du]
Absolutely. That's a great point. That's exactly how I remember. It was back in 2015 when single-agent nivolumab data was first presented from the CheckMate-040 study at ASCO annual meeting, we started using single-agent nivolumab. When we had a good response, we had a good, durable response, but everything after that, the front-line nivolumab trial was negative. Then pembro was not that great. We very soon realized that we definitely need more than one single agent PD-1/PD-L1 blockade.
[Dr. Tyler Sandow]
I was going to quote that trial to sound smart, CheckMate-040, just so that I could not be considered the dumb one in the table. CheckMate-459 was the phase III trial for that, and that wound up being negative. It was single-agent. There's been a CheckMate trial that was a combination that was successful. That was Ipi/Nivo.
[Dr. Lingling Du]
Right. That's a 9DW?
[Dr. Tyler Sandow]
Yes. Can you elaborate on that one, Adam?
[Dr. Adam Burgoyne]
This is the most hot-off-the-press data. Those CheckMate-9DW was presented at both ASCO and ESMO this year, which is looking at front-line ipilimumab plus nivolumab, which is, again, a combination of CTLA-4 and PD-1 inhibition. The difference here was it was dealer's choice TKI for the comparator arm. In the evolving years since IMbrave 150 and Himalaya, lenvatinib became the preferred TKI over sorafenib.
One difference of CheckMate-9DW was actually the majority of patients in the comparator arm did receive lenvatinib, not sorafenib, which is probably why we saw that comparator arm overall survival actually be quite long. The top line data itself was very impressive with a median overall survival of now approaching almost two years, which, again, we're talking about advanced HCC patients that we used to tell really had less than six months to live.
The trade-off here, as we're thinking about all of these regimens now that we have access to, is we do know that ipilimumab does have a higher rate of immune-related adverse events in these combination strategies with nivo and a bit higher than the other dual-immune CheckMate blockade strategy with STRIDE that we already have access to. This is still awaiting approval in the front-line setting. We're still waiting on the final publication of the data. It's certainly encouraging and exciting, but how it's going to fit into our treatment landscape, I think, remains to be unseen.
[Dr. Lingling Du]
I think the dosing part is very interesting. It's like when our GI oncologists look at a GI trial, a lot of GI trials, when they're using Ipi/Nivo for GI cancer, they actually use a more tolerable regimen, which is ipilimumab at one milligram per kg plus nivolumab three milligrams per kg. That's actually a relatively easy way to tolerate it, but then there's a CheckMate-040 before the 9DW study that show that the easy way, IPI1/NIVO3, actually did not work that well.
The only winner from that trial was the IPI3/NIVO1. That's the hard, difficult, toxic regimen. That was tested in 9DW. Very amazing result. Even if you look at the over-survival curves from these three trials, it's very interesting. On the IMbrave 150, the survival curve for atezo/bev and the sorafenib arm started separating from each other very early in the treatment course. Almost like once they start, they separate from each other.
On the Himalaya trial, the two curves sit on top of each other for a little while and then start separating. The medium over-survival in the durva/treme arm was 16 months or so, but it's really the tail that is impressive that a lot of people-- not a lot. There's 20% of people.
[Dr. Jon Mizrahi]
20% of five years.
[Dr. Lingling Du]
Exactly. Five-year survivors. When you look at the CheckMate-9DW trial, in the beginning, both the progression-free survival and the over-survival curves, there's a crossover. In the beginning, the Ipi/Nivo arm actually did worse. More people die and more people progress. Then there's this crossover. Then eventually, people who survive become the winner in the long term.
The Role of Etiology in Immunotherapy Outcomes
While early hypotheses suggested that viral HCC might be more immunologically active and therefore more responsive to checkpoint blockade, subsequent analyses have not supported using etiology to guide treatment decisions. Trials such as IMbrave150 and Himalaya enrolled sizable proportions of non-viral HCC (~30% and ~40%, respectively) and meta-analyses have shown no consistent difference in immunotherapy benefit based on underlying liver disease. Although preclinical studies suggest greater T cell exhaustion in non-viral HCC, this has not translated into inferior clinical outcomes. Current practice, therefore, supports first-line immunotherapy-based regimens for all eligible patients, regardless of etiology. [1][2]
[Dr. Tyler Sandow]
That's very interesting. To sum up, we have IMbrave, which is atezo/bev, we have Himalaya, which is durva/treme, and then we have CheckMate-9DW, which is Ipi/Nivo. All of those showed improvement in overall survival. The tail changes, do you think that could be related to the etiology of the cirrhosis? Now, as I understand, the IMbrave I think, was more hep B-positive patients. I might be wrong on that one. I probably shouldn't even speak to that.
[Dr. Lingling Du]
There are less non-viral compared to Himalaya. Himalaya has about 40% non-viral. IMbrave has about 30% non-viral.
[Dr. Adam Burgoyne]
That's actually a great question. We debate this all of the time. We always discuss it. What's the data on immunotherapy with viral etiologies versus non-viral etiologies?
[Dr. Lingling Du]
That's a great question.
[Dr. Jon Mizrahi]
Lingling and I were having this conversation this morning because we're really cool. I think we probably all have maybe different perspectives on this, but I think initially there was definitely a thought in the field that viral etiology does better with immunotherapy-based regimens and maybe perhaps a TKI is more appropriate for non-viral. Then I think now, study upon study and meta-analysis have shown that's actually probably not the case, that really there's not a patient where their etiology should factor into whether they're getting immunotherapy first-line or not.
Everyone should be getting immunotherapy first-line as long as they're eligible for it. That's how I interpret the most recent data. I don't know if anyone feels differently.
[Dr. Adam Burgoyne]
Yes, I totally agree. In terms of what we know about HCC and etiology now, we're not really using it clinically to choose regimens. Then I think we all do have different schools of thoughts on this. My personal bias is that if you look at the preclinical data that initially looked at this non-responsive, potentially non-viral-driven HCC, there was this exhausted T cell population. At risk of sounding like a hospital administrator, I think of this more as an opportunity to overcome that resistance.
We know that these combination strategies are important, and because these regimens are tolerated, we can bring in third agents. We can have triplet regimens that perhaps would overcome that T cell exhaustion and make that cold tumor hot, if you will, and allow patients to respond to immunotherapy regardless of etiology. I think as we learn more about that biology, perhaps viral versus non-viral etiology will become more important.
Additional resources:
[1] Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma, IMbrave150 Trial (Finn et al, 2020):
https://pubmed.ncbi.nlm.nih.gov/32402160
[2] Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma, HIMALAYA Trial (Abou-Alfa et al, 2022):
https://evidence.nejm.org/doi/full/10.1056/EVIDoa2100070
[3] Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial (Yau, 2022):
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00604-5/abstract
[4] Nivolumab (NIVO) plus ipilimumab (IPI) vs. lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW (Galle, 2024):
https://ascopubs.org/doi/10.1200/JCO.2024.42.17_suppl.LBA4008
[5] Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients with Advanced Hepatocellular Carcinoma Previously Treated with Sorafenib: The CheckMate 040 Randomized Clinical Trial (Yau, 2020):
https://pubmed.ncbi.nlm.nih.gov/33001135/
Podcast Contributors
Dr. Lingling Du
Dr. Lingling Du is an oncologist with Ochsner Health in New Orleans, Louisiana.
Dr. Jonathan Mizrahi
Dr. Jonathan Mizrahi is a medical oncologist with Ochsner Health in New Orleans, Louisiana.
Dr. Adam Burgoyne
Dr. Adam Burgoyne is a gastrointestinal / hepatobiliary oncologist and associate clinical professor with Ochsner Health in New Orleans, Louisiana.
Dr. Zach Berman
Dr. Zachary Berman is an interventional radiologist at the University of California San Diego in San Diego, California.
Dr. Tyler Sandow
Dr. Tyler Sandow is an interventional radiologist with Ochsner Health in New Orleans, Louisiana.
Cite This Podcast
BackTable, LLC (Producer). (2025, January 17). Ep. 3 – Combination Therapy and Clinical Trials for Advanced HCC: What They Really Mean [Audio podcast]. Retrieved from https://www.backtable.com
Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
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