Ongoing Research Could Help Define the Role of Immunotherapy in Earlier-Stage HCC

Immunotherapy-based combinations are a standard of care for patients with unresectable hepatocellular carcinoma (HCC); however, emerging data from the phase 3 ImBRAVE050 (NCT04102098) and EMERALD-1 (NCT03778957) studies could help define the role of these types of treatments in earlier stages of the disease, according to James J. Harding, MD.

Harding highlighted findings from these 2 studies in a presentation on moving systemic therapy to earlier stages of HCC at the 42nd Annual Chemotherapy Foundation Symposium (CFS).

In an interview with OncLive^®, Harding discussed the efficacy data from the ImBRAVE050 and EMERALD-1 studies, the limitations to using progression-free survival (PFS) as a study end point, and unmet needs future research will help address in HCC.

Harding is a gastrointestinal medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: What was the goal of your presentation at the 42nd Annual CFS on multimodal approaches for early-stage HCC?

Harding: We talked about the utilization of combination immunotherapy at earlier stages of HCC, focusing on the application of immunotherapy as an adjuvant [treatment] in patients who have resected or ablated HCC, as well as combination immunotherapy in patients with liver-limited disease. We've seen a lot of data in the last year regarding this potential approach.

Although the ImBRAVE050 trial results were not practice-changing, were they practice-informing?

[The phase 3] IMbrave150 trial [NCT03434379] was a critical study in the metastatic and advanced setting. ImBRAVE150 showed that [treatment with] atezolizumab [Tecentriq] plus bevacizumab [Avastin] led to superior overall survival [OS] when compared with sorafenib [Nexavar].

It was a logical next step to move that combination to earlier stages of disease, and ImBRAVE050 essentially assessed that question in patients with liver-limited HCC who were candidates for resection or ablation and were at high risk for recurrence. They were either treated with [adjuvant] atezolizumab and bevacizumab or [underwent] observation after surgery. The study, as noted, ultimately did not [demonstrate] an improvement in OS [with atezolizumab plus bevacizumab], nor was a recurrence-free survival advantage observed at a long-term study follow-up.

However, this study is still informative. At least in an early look, combination immunotherapy did have some role in preventing very early recurrence. The question will become: is there a specific subset of very high-risk patients who we can identify and intervene early for a better impact [with combination therapy]? However, adjuvant therapy for HCC remains elusive.

What were the implications of the EMERALD-1 findings?

EMERALD-1 was another critical study for HCC. This [trial] was restricted to patients with liver-limited HCC who were not candidates for a transplant or surgical resection, where the standard of care has been transarterial chemoembolization [TACE]. In this study, patients were [randomly assigned] to receive TACE plus durvalumab [Imfinzi], TACE plus durvalumab and bevacizumab [Avastin], or TACE alone [to test] the principle of a combined PD-L1 and antiangiogenic [strategy] at the earliest stage of disease. The primary end point of the trial was PFS comparing the doublet to TACE alone, and this was positive; [the study] met its end point, which was statistically significant.

We saw in subset analysis that there was a higher objective response rate [with the addition of durvalumab], although [there were] more frequent toxicities. The first indication [from these data] is that the combination of immunotherapy at the earliest stage of disease may impact PFS.

What were some of the limitations of using PFS as an end point?

Typically, the things that oncologists—and probably patients—care about most is how long [patients] will live with a particular treatment and what [their] quality of life will be. [OS and safety/quality of life] are the 2 critical end points in oncology that help us make our decisions, and these are also regulatory end points. The FDA usually requires [beneficial data with these end points] for approval of new drugs.

PFS is a surrogate [end point], where we're looking at both the composite of radiographic progression and death from any cause. [A PFS benefit] does not necessarily translate to an OS [benefit], and there are a number of factors that play into that.

When you have a new drug at an earlier stage of disease [that] improves PFS but [does] not improve in OS, it begs the question: Do you need to give that therapy at that stage, or can you wait for disease recurrence or progression to give it? It's an important question for the field, and we'll have to wait for additional follow-up on [EMERALD-1], as well as others, to read out.

What other challenges persist in HCC? What research is planned or ongoing to meet these needs?

Although there's been a great deal of progress in HCC over the last decade, we still need to raise the bar for patients in general. The majority of patients do not have curative-intent surgeries. The majority of patients are not cured by our treatment, so the unmet need certainly is raising the tail of the [OS] curve in the advanced setting, curing more people of cancer.

Continued drug development in this space is critical, and we're seeing a move now toward bispecific antibodies, novel triplet combinations, and cellular therapeutics. Hopefully, with these, we'll see those needs met in the years to come.

Reference

Harding JJ. Systemic therapy for hepatocellular carcinoma: moving to earlier stages of disease. Presented at: 42nd Annual CFS; November 13-15, 2024; New York, NY.