Introduction
Unresectable hepatocellular carcinoma (HCC) is a formidable clinical challenge associated with poor prognosis and limited therapeutic options. For many years, sorafenib, a multikinase inhibitor, remained the standard systemic treatment, improving survival modestly but with substantial adverse effects. Recently, immune checkpoint inhibitors have transformed the therapeutic landscape of HCC. The phase III HIMALAYA trial introduced the STRIDE regimen, combining a single priming dose of tremelimumab (an anti-CTLA-4 antibody) with scheduled durvalumab (an anti-PD-L1 antibody), showing promising survival advantages over sorafenib. This article critically examines the updated 5-year overall survival (OS) data from HIMALAYA, elucidating the long-term efficacy and safety of STRIDE in unresectable HCC and discussing its clinical implications.
Study Background and Disease Burden
HCC represents the most common primary liver malignancy and is a leading cause of cancer mortality worldwide. Most patients are diagnosed at an unresectable stage when curative surgery or locoregional therapies are not feasible. The historically poor survival rates necessitate effective systemic therapies that provide durable benefit and acceptable safety. Sorafenib, approved in the late 2000s, conferred a median OS improvement of approximately three months over placebo. Immune checkpoint blockade strategies target tumor immune evasion mechanisms and have shown superior outcomes in various cancers, including HCC. The HIMALAYA trial investigated the novel STRIDE combination to enhance antitumor immune activation and improve long-term survival in unresectable HCC.
Study Design
HIMALAYA (NCT03298451) was a randomized, open-label, phase III multicenter trial enrolling patients with unresectable HCC. Participants were allocated into three arms: STRIDE (single dose of tremelimumab plus regular interval durvalumab), durvalumab monotherapy, or sorafenib monotherapy. The primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival, tumor response metrics according to RECIST v1.1 criteria, and safety profiles. This 5-year update reports exploratory analyses of OS with extended follow-up (median follow-up ~62 months for STRIDE and ~60 months for sorafenib), emphasizing survival outcomes stratified by tumor response and assessment of long-term safety.
Key Findings
The updated analysis included data until 01 March 2024, with median follow-up durations of 62.49(59.47-64.79) months for STRIDE and 59.86(58.32-61.54) months for sorafenib.
At the 5-year data cut-off, 309 participants (78.6% OS data maturity) in the STRIDE arm and 332 participants (85.3% OS data maturity) in the sorafenib arm had died. The OS HR (95% CI) for STRIDE vs. sorafenib was 0.76 (0.65-0.89; Fig. 1). The survival rates for STRIDE and sorafenib at 60 months were 19.6% and 9.4%. The OS rate ratio for STRIDE vs. sorafenib has improved further over time in favour of STRIDE, reaching 2.09 at 60 months. The OS HR (95% CI) for durvalumab vs. sorafenib was 0.85 (0.73-1.00). The restricted mean (95% CI) survival time – defined as the average survival time during a defined time period ranging from 0 to 60 months at the 5-year follow-up data cut-off – was 25.5 (23.4-27.7) months with STRIDE, above the 20.7 (18.8-22.6) months with sorafenib; at the primary analysis data cut-off, the restricted mean (95% CI) survival times were 21.6 (20.0-23.2) months and 18.4 (17.0-19.9) months, respectively, for a time period ranging from 0 to 42.8 months.
More nuanced analyses revealed that patients achieving disease control (stable disease or better per RECIST v1.1) had improved OS rates at 60 months: 28.7% under STRIDE versus 12.7% with sorafenib. Moreover, patients with >25% tumor shrinkage demonstrated particularly favorable survival—50.7% vs. 26.3% at 5 years—implying that depth of response strongly correlates with durable benefit.
Importantly, no new late-onset treatment-related serious adverse events were reported for STRIDE, affirming the regimen’s manageable safety over long-term use. Extended long-term survivors (defined as alive ≥48 months post-randomization) were twice as frequent in the STRIDE arm (21.1%) compared to sorafenib (11.6%), with survival benefits distributed across diverse clinically relevant subgroups including varied etiologies, performance status, and disease burden.
Expert Commentary
These 5-year data consolidate STRIDE as a transformative regimen in the treatment paradigm of unresectable HCC. The durable OS advantage over sorafenib, coupled with an acceptable safety profile, underscores the potential of combining CTLA-4 and PD-L1 inhibition to invigorate anti-tumor immunity effectively. Notably, the findings challenge traditional response-based paradigms; any degree of tumor shrinkage, not just complete or partial responses, correlates with improved outcomes, suggesting immunotherapy-mediated benefits extend beyond the metrics captured by RECIST assessments.
While this exploratory update is compelling, limitations include the open-label design and lack of continued tumor assessment uniformity beyond protocol-specified visits. Additionally, the evolving landscape with other immunotherapeutic combinations necessitates comparative research to optimize patient selection and sequencing of therapies. Nevertheless, STRIDE sets a new benchmark for long-term survival, prompting reconsideration of treatment goals and patient counseling in unresectable HCC.
Conclusion
The five-year update from the HIMALAYA trial reaffirms STRIDE’s role as an efficacious and tolerable frontline immunotherapeutic strategy in unresectable HCC. Nearly one in five patients treated with STRIDE achieve 5-year survival, markedly surpassing historical controls treated with sorafenib. The correlation between tumor shrinkage and OS highlights the need for nuanced clinical assessment beyond conventional response criteria. These data support integrating STRIDE into clinical practice and ongoing research focused on biomarkers, combination approaches, and personalized immunotherapy to further improve outcomes in this challenging patient population.
References
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