Survival benefit with STRIDE for HCC sustained at 5 years

The updated exploratory analysis of the phase III HIMALAYA trial demonstrates a significant overall survival (OS) benefit at 5 years with the STRIDE* regimen comprising tremelimumab and durvalumab for patients with unresectable hepatocellular carcinoma (HCC).

“STRIDE sustained an OS benefit vs sorafenib and demonstrated unprecedented long-term survival benefit at 5 years, with 5-year survival rates of 19.6 percent with STRIDE vs 9.4 percent with sorafenib,” said Dr Masatoshi Kudo from the Kindai University Faculty of Medicine, Osaka, Japan, who presented the findings at ESMO Asia 2024. “One in five patients was alive at 5 years.”

The median OS with STRIDE was 16.43 months as opposed to 13.77 months with sorafenib. A comparison between arms yielded a hazard ratio (HR) of 0.76 and a two-sided p-value of 0.0008. [ESMO Asia 2024, abstract 127O]

Separation of the Kaplan-Meier curves was evident by month 6 and diverged consistently. The trend favouring the STRIDE regimen over sorafenib was consistent from month 18 onwards.

The OS rate ratios for STRIDE vs sorafenib increased over time, from 1.17 at month 18 to 2.09 by month 60, noted Kudo in his presentation.

“There were more participants on the STRIDE regimen who were still alive and on study treatment at 5 years, more who achieved deep responses, and fewer who received subsequent therapy,” Kudo said. Subsequent therapy was initiated later in STRIDE recipients than those who received sorafenib.

The OS benefit was consistent even when participants were stratified according to albumin-bilirubin (ALBI) status. In the ALBI grade 1 subgroup, the 60-month OS was higher with STRIDE than sorafenib (24.3 percent vs 13.6 percent) and median OS was longer (23.43 vs 19.02 months; HR, 0.79). A similar pattern favouring STRIDE over the comparator was seen in the ALBI grade 2/3 subgroup (60-month OS 13.7 percent vs 4.7 percent; median OS 11.30 vs 9.72 months; HR, 0.79).

There were more extended long-term survivors (eLTS) with STRIDE than with sorafenib, be it in the full analysis set (21.1 percent vs 11.6 percent) or baseline ALBI subgroups (26.3 percent vs 17.7 percent [grade 1] and 14.9 percent vs 4.8 percent [grade 2/3]). The eLTS were participants who have survived ≥48 months beyond randomization.

“The rates of treatment-related serious adverse events with STRIDE did not change from the primary analysis for either ALBI subgroups and were generally consistent with all participants in the safety analysis set,” said Kudo.

Sets new benchmarks

Individuals with HCC often have underlying liver cirrhosis, leading to impaired liver function, safety issues, and poor prognosis. [J Hepatol 2020;72:307-319]

Kudo and his team set out to evaluate 5-year OS with STRIDE compared with sorafenib , as well as OS by baseline liver function. Participants were eligible for the HIMALAYA trial if they had confirmed unresectable HCC who were Child-Pugh A and BCLC** B (ineligible for locoregional therapy) or C. They should not have received prior systemic therapy for HCC or have main portal vein thrombosis.

A total of 1,171 participants (mean age 63 years, ~85 percent men) were randomized 1:1:1 to receive the STRIDE regimen comprising tremelimumab 300 mg (one dose) and durvalumab 1,500 mg Q4W, durvalumab alone, or sorafenib 400 mg BID. Over a third of participants were from Asia (excluding Japan). The most common aetiology of liver disease was nonviral (37–45 percent) and a majority of the overall cohort were BCLC C.

The current findings (data cutoff March 1, 2024) reinforce those reported in the primary analysis, wherein STRIDE demonstrated a favourable benefit-risk profile as opposed to sorafenib, regardless of baseline liver function. [Ann Oncol 2022;33(suppl 9):abs 79P]

“The present data shows that STRIDE continues to set new benchmarks in unresectable HCC,” Kudo concluded.

A new first-line standard of care

The recent advances in first-line systemic therapy for advanced HCC have significantly improved the treatment landscape, reflecting a move towards more personalized and effective therapeutic strategies, noted discussant Dr Joon Oh Park from the Samsung Medical Center, SungKyunkwan University School of Medicine, Seoul, South Korea.

“There is a strong rationale for combined anti-PD1/L1 and anti-CTLA4 therapy in HCC. The dual approach aims to leverage different immune mechanisms, potentially improving treatment outcomes for patients with advanced HCC,” said Park.

STRIDE had gained global approval for the treatment of unresectable HCC. [Target Oncol 2024;19:115-123; https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-unresectable-hepatocellular-carcinoma, accessed January 5, 2025]

“Given the sustained OS benefit with STRIDE vs sorafenib – with the benefit improving over time in the global population – STRIDE may be a potential new first-line standard-of-care treatment for patients with unresectable HCC,” Park said.

He pointed out that ALBI grade appeared to be prognostic for outcomes in another study, wherein the combination of atezolizumab and bevacizumab improved OS compared with sorafenib in a subgroup of patients with ALBI grade 1 but not among those with ALBI grade 2/3.

With the sustained OS benefit irrespective of liver function and the sustained tolerable safety profile in both ALBI subgroups, the updated HIMALAYA findings imply that STRIDE may be administered to patients who have decreased liver function without compromising safety, Park added.