Immune Checkpoint Inhibitors Retain Their Role in the HCC Treatment Paradigm

Updated data from key trials with immune checkpoint inhibitor (ICI) regimens, including those from the 4-year overall survival (OS) analysis of the phase 3 HIMALAYA trial (NCT03298451), continue to show why ICI-based combinations are the frontline treatment of choice for patients with hepatocellular carcinoma (HCC), according to Gentry King, MD.

“[HIMALAYA was] another study that further cemented the arrival of ICI combinations and the passing of time with sorafenib [Nexavar] as the prior standard [of care in HCC],” King said in an interview with OncLive® following a State of the Science Summit™ on gastrointestinal cancers, which he chaired.

The HIMALAYA trial introduced the combination of the anti–PD-L1 antibody durvalumab (Imfinzi) and the anti–CTLA-4 antibodytremelimumab (Imjudo) to the HCC treatment landscape, King explained. In October 2022, the FDA approved tremelimumab/durvalumab for the treatment of patients with unresectable HCC.1 The regulatory decision was based on findings from the HIMALAYA study, which demonstrated that the combination led to a statistically significant improvement in OS vs sorafenib monotherapy. These data reflected a median OS of 16.4 months (95% CI, 14.2-19.6) vs 13.8 months (95% CI, 12.3-16.1) in the combination vs sorafenib arms, respectively (HR, 0.78; 95% CI, 0.66-0.92; 2-sided P = .0035).

Furthermore, at the 4-year OS update from the HIMALAYA trial, the 36-month OS rate was 30.7% vs 19.8% with tremelimumab/durvalumab vs sorafenib alone, respectively; the respective 48-month OS rates were 25.2% and 15.1%.2

In the interview, King highlighted the evolution of the HCC treatment paradigm, the impact of the HIMALAYA trial, and safety profile considerations from the study. King is an assistant professor in the Clinical Research Division at Fred Hutch Cancer Center and Division of Hematology and Oncology at the University of Washington School of Medicine in Seattle.

OncLive: How would you characterize the frontline treatment landscape for patients with advanced HCC?

King: Nowadays, the first-line treatment for [patients with] HCC is not just 1 drug, it's a combination of drugs, and it involves a combination of an ICI and something else. That other partner could be a monoclonal antibody against VEGF, which would be bevacizumab [Avastin] as shown in the IMbrave150 study [NCT03434379], or another ICI. When we talk about ICIs for HCC, for a while we had been dealing with anti–PD-1 or anti–PD-L1 monoclonal antibodies. More recently, there has been a demonstration of better long-term benefit with the addition of an anti–CTLA-4 antibody.

[There were also] some frontline combination trials that were negative. Some of these were the phase 3 LEAP-002 [NCT03713593] and COSMIC-312 [NCT03755791] trials, which tried to combine a TKI, either cabozantinib [Cabometyx] or lenvatinib [Lenvima], with an ICI. These did not pan out in some of the global studies that we’ve participated in, and as such, these are not first-line therapies.

There are also some relevant insights that we can get when we look at not only our experience here in the West or globally, but also specifically in the East and China. Underpinning all those studies is the question of potential differences in the etiology of HCC, whether it be hepatitis C or hepatitis B, as well as race and regionality. We tend to associate studies with the very simplistic view of race, so in some studies, there’s a larger population of patients of European descent, whereas in other studies, [more patients are of] Asian descent. What’s also not very clearly defined in some of these studies is that there are also very different ways [patients with] cancer are treated in different parts of the world. I think that may have [affected] some of the results of these studies and how we look at them.

What was the background for the phase 3 HIMALAYA trial, and the patient population enrolled on the study?

HIMALAYA was a randomized study looking at a combination ICI strategy with durvalumab and tremelimumab vs sorafenib in the first-line advanced HCC setting. Patients needed to have good liver function—Child-Pugh A. This study also excluded [patients with] main portal vein [tumor] thrombosis because the study did not [evaluate] bevacizumab or an anti-VEGF monoclonal antibody. Patients did not need an endoscopy prior. This study was unique because it used a specific priming regimen of tremelimumab, whereas in other cancer types, we use an anti–CTLA-4 antibody ipilimumab [Yervoy] which is often given either 4 times or over multiple cycles.

In this study, they only used one priming dose. This was a result of Study 22 [NCT02519348], where they looked at that single priming dose, which resulted in a distinct immune subset that translated into a subset of clinical responders with the best objective response. This was a positive study and showed that patients did develop better outcomes when they were treated with the STRIDE regimen, which is otherwise known as the single tremelimumab, regular interval durvalumab dosing strategy. This is a big deal because we now have a new combination strategy.

The other thing worth noting in the [HIMALAYA] study was that it was a global study [and] the [represented] viral etiologies [were] hepatitis B, hepatitis C, and nonviral. The demographic distribution was [also] fairly well split. Asian study sites were about 40%, the rest of the world was 60%, and the viral etiologies were somewhat equally split in thirds. [The patient population was] representative [of the real world], so the results apply to a good swathe of patients that we see in the clinic.

A long-term, 5-year follow-up [analysis] showed that the 60-month OS rate for the STRIDE regimen was practically double that [of what] we see with just sorafenib alone. The benefit with the combination of these 2 ICIs is not something that you see upfront in the first year or so, but it does clearly pan out the longer you go. This is also relevant because these are numbers that we have never seen with HCC treatments.

Were there safety profile concerns with the STRIDE regimen?

The adverse effect [AE] profile of a combination ICI strategy is still more tolerable than sorafenib. [We may see] diarrhea as an immune AE, but that can be addressed. When [considering] TKIs and sorafenib-induced diarrhea, that can also be addressed, but [we would] have to lower the dose, [but we also know responses] depend on whether [patients] can stay on treatment, whereas with the new ICIs, there seems to be potential benefit, even when [they] stop the ICI for an AE.

One of the other interesting things that was reported for HIMALAYA was the potential for patients to benefit long-term even if they had objective evidence of worsening disease in the first few months. Some patients had growth of their tumors and then eventual response and long-term benefit. That’s something we also haven’t seen with sorafenib. They did the same analysis in HIMALAYA in the sorafenib arm, and that was not the case.

Additionally, when the STRIDE regimen was compared with durvalumab monotherapy [we saw] a higher uptick of immune-related AEs, but it was still within expectations, and it was not [a dramatic difference]. This is compared with what we saw with the CheckMate 040 study [NCT01658878] of nivolumab [Opdivo] and ipilimumab in the second line, where the rate of grade 3/4 AEs was nearly 50%. In context with all our other treatments, STRIDE is a pretty well-tolerated treatment regimen.

References

1. FDA approves tremelimumab in combination with durvalumab for unresectable hepatocellular carcinoma. FDA. Updated October 24, 2022. Accessed February 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-unresectable-hepatocellular-carcinoma
2. Sangro B, Chan SL, Kelley RK, et al. Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann Oncol. 2024;35(5):448-457. doi:10.1016/j.annonc.2024.02.005