Tremelimumab/Durvalumab Produces Favorable OS Benefit in Unresectable HCC Irrespective of ALBI Grade

A single priming dose of tremelimumab added to regular interval durvalumab (Imfinzi; the STRIDE regimen) generated significantly improved overall survival (OS) compared with sorafenib (Nexavar) in the frontline setting for patients with unresectable hepatocellular carcinoma (HCC), irrespective of of their baseline albumin-bilirubin (ALBI) grade, according to updated data from the phase 3 HIMALAYA trial (NCT03298451) presented at the 2022 ESMO World Congress on Gastrointestinal Cancer.¹

In patients with ALBI grade 1, the STRIDE regimen elicited a median OF of 23.43 months (95% CI, 19.19-28.75), compared with 19.02 months (95% CI, 15.67-23.16) for sorafenib (HR, 0.79; 95% CI, 0.62-1.01). In patients with ALBI grade 2/3, the STRIDE regimen produced a median OS of 11.30 months (95% CI, 9.33-14.19), vs 9.72 months (95% CI, 7.23-11.76) for sorafenib (HR, 0.83; 95% CI, 0.65-1.05).

Additionally, single-agent durvalumab produced favorable OS outcomes vs sorafenib, irrespective of ALBI grade. In patients with ALBI grade 1, the median OS for durvalumab was 21.16 months (95% CI, 17.38-25.86), compared with 19.02 (95% CI, 15.67-23.16) for soreafenib (HR, 0.91; 95% CI, 0.71-1.15). In patients with ALBI grade 2/3, the median OS for durvalumab was 12.29 months (95% CI, 9.30-16.03), vs 9.72 (95% CI, 7.23-11.76) for sorafenib (HR, 0.87; 95% CI, 0.69-1.09).

“We need to acknowledge that this was a post-hoc analysis, and all analyses that we have performed so far have been in respect to liver function, and they have never been prospectively evaluated,” said Arndt Vogel, MD, PhD. “We have a very clear picture that liver function has a strong prognostic impact, which is important when we talk to our patients.”

In an interview with OncLive^®, Vogel, a managing senior consultant and professor in the Department of Gastroenterology, Hepatology and Endocrinology, and the head of the GI-Cancer Center at the Hannover Medical School, discussed the post-hoc analysis from the randomized, open-label, multicenter, global HIMALAYA trial presented at the 2022 ESMO World Congress on Gastrointestinal Cancer.

OncLive^®: Can you expand on the rationale of combining tremelimumab and durvalumab in the phase 3 HIMALAYA trial?

Vogel: We have seen in the past that immunotherapy has activity in HCC, but monotherapy with just a PD-1 or PD-L1 inhibitor has not been sufficient enough to achieve a positive phase 3 study. We have seen this in trials with pembrolizumab [Keytruda] and nivolumab [Opdivo].

We have seen in the past that CTLA-4 has activity in a subgroup of patients with HCC. This led to a clear rationale to combine CTLA-4- and PD-1­–targeted agents, as we have seen in other tumor types.

There were early data from the phase 3 CheckMate040 trial [NCT01658878] with nivolumab and ipilimumab [Yervoy] that suggested synergistic activity. There was a clear rationale to proceed with [HIMALAYA] in this setting.

What were the unmet needs that the trial aimed to address?

The majority of our patients are diagnosed in an advanced setting. In early HCC, we can perform resection or liver transplantation, but when the tumor gets bigger, a patient [can present] with vascular infiltration or extra hepatic metastases. We are in a palliative setting, and for many years, we had few options. The major breakthrough came with immunotherapy-based combinations, and this combination of PD-1 and CTLA-4 antibodies is now another important step for the armamentarium for advanced HCC.

What were the primary objectives of the HIMALAYA trial?

The HIMALAYA study was a 3-arm study looking at the combination of durvalumab and 1 single [dose] of tremelimumab, referred to as the STRIDE regimen. This was compared to sorafenib, with a primary end point of showing superiority [in efficacy]. Additionally, the third arm [evaluated] durvalumab monotherapy. Here, this was a key secondary end point to show noninferiority compared with sorafenib.

This was a global study for patients with unresectable HCC that were not suitable for local regional therapies.

What key findings have been found thus far, and what updates were presented at the 2022 ESMO World Congress on Gastrointestinal Cancer?

The HIMALAYA study has been now published as a full paper, and it was a positive study. For the STRIDE regimen, there was superior activity shown in terms of OS compared with sorafenib. Additionally, [single-agent] durvalumab was noninferior to sorafenib.

In HCC, we usually have 2 diseases, including chronic liver disease in many cases, such as liver cirrhosis, and the tumor. Based on past post-hoc analyses from phase 3 studies, liver function is a very important prognostic marker. At the 2022 ESMO World Congress on Gastrointestinal Cancer, we analyzed the affect of liver function on OS for the 2 immunotherapy-based regimens. We grouped patients according to their liver function scores, which was part of the inclusion criteria.

To distinguish 2 groups of patients with different preserved liver function, we utilized the ALBI score, where half of the patients were ALBI grade1, with a good liver function, and the other half was ALBI grade 2/3.

We were able to show in the HIMALAYA study that liver function has a very important prognostic effect. The median OS was almost twice as long in patients with a more well-preserved liver function compared with those with ALBI grade 2.

In terms of efficacy, it was very evident that the STRIDE regimen specifically has clear activity in both groups of ALBI grade 1 and ALBI grade 2/3. There was almost no significant difference in terms of the hazard ratio. We can say the prognostic impact of liver function was confirmed. Importantly, the STRIDE regimen was effective independent from the underlying liver function.

What should be known regarding the safety profile and toxicities associated with the STRIDE regimen?

In the HIMALAYA study, we saw the expected adverse effect [AE] profile, though we have slightly more AEs with the STRIDE regimen compared with the durvalumab monotherapy. There were more immune-related AEs and more steroid use, but overall, there was no negative impact on the quality of life. In our analysis here, there was no impact of liver function on the safety prolie for the patients.

Based on the findings from this trial, what could this potentially mean for the treatment paradigm for patients with unresectable HCC?

We need to acknowledge that this was a post-hoc analysis, and all analyses that we have performed so far have been in respect to liver function, and they have never been prospectively evaluated. We have a very clear picture that liver function has a strong prognostic impact, which is important when we talk to our patients.

In terms of efficacy, the data are not crystal clear. But for the HIMALAYA study, we can clearly conclude that more impaired liver function of ALBI grade 2/3 has no negative impact on the efficacy of durvalumab and tremelimumab. These data need to be confirmed in a real-world setting. But it is reassuring that we do not need to select our patients based on liver function when we consider the use of durvalumab or durvalumab/tremelimumab.

Reference

1. Vogel A, Chan SL, Furuse J, et al. Outcomes by baseline liver function in patients with unresectable hepatocellular carcinoma treated with tremelimumab and durvalumab in the Phase 3 HIMALAYA study. Presented at: 2022 ESMO World Congress on Gastrointestinal Cancer; June 29-July 2, 2022; Barcelona, Spain. Abstract O-5.