Integration of local and systemic immunotherapy: setting new standards in liver-confined hepatocellular carcinoma

The management of unresectable, non-metastatic hepatocellular carcinoma (HCC) continues to present significant clinical challenges. The majority of patients with liver confined HCC who are not eligible for resection or transplantation, the so-called “intermediate stage” group according to the Barcelona Clinic Liver Cancer staging system, still experience a life-limiting diagnosis. For more than two decades, transarterial chemoembolization (TACE) has been the standard of care for patients with intermediate-stage HCC, yet its efficacy remains modest, with median progression-free survival (PFS) typically less than 8 months (1). The recent advent of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) has transformed the therapeutic landscape for advanced HCC (2), raising important questions about how these systemic agents might be integrated with established locoregional therapies or even replace them.

The LEAP-012 trial, led by Dr. Masatoshi Kudo and colleagues and recently published in The Lancet, represents a pivotal effort to enhance the efficacy of TACE by combining it with lenvatinib and pembrolizumab (3). This approach is grounded in a compelling biological rationale: leveraging the immunomodulatory and anti-angiogenic properties of these agents to amplify the ischemic tumor necrotic effects of TACE (4,5), potentially transforming a locoregional intervention into a systemic immunologic catalyst.

LEAP-012 was a global, multicenter, double-blind, randomized phase 3 trial conducted at 137 sites worldwide in 33 countries or regions, enrolling 480 patients with unresectable, non-metastatic HCC eligible to TACE (3). Patients were randomized to receive either TACE with lenvatinib plus pembrolizumab or TACE with dual placebo. The co-primary endpoints were PFS, assessed by blinded independent central review according to response evaluation criteria in solid tumors version 1.1 (RECIST v 1.1) for up to five target tumors in the liver, and overall survival (OS) in the intention-to-treat population. At a median follow-up of 25.6 months, the study met its primary endpoint for PFS: median PFS was 14.6 months in the lenvatinib plus pembrolizumab arm vs. 10.0 months in the placebo arm [hazard ratio (HR): 0.66; P=0.0002]. The objective response rate (ORR) was also notably higher in the combination arm, both by RECIST v1.1 (47% vs. 33%) and by mRECIST (71% vs. 50%). However, the interim analysis of OS, while demonstrating a numerical trend in favor of the multimodal therapy strategy (HR: 0.80), did not cross the pre-specified boundary for statistical significance (P=0.087). Improved PFS and ORR came at the cost of a higher incidence of grade 3 or higher treatment-related adverse events compared to the control arm (71% vs. 32%), with hypertension, thrombocytopenia, and proteinuria being the most common. Immune-mediated events and infusion reactions were observed in nearly half of patients receiving pembrolizumab.

The significant improvement in PFS observed in LEAP-012 underscores the potential of intensifying locoregional therapy with concurrent systemic agents to achieve superior tumor control compared to TACE alone. This finding is clinically meaningful in a patient population for whom durable disease control has historically been elusive. A key aspect of success from this strategy will be strongly dependent upon whether combination immunotherapy with TACE results in a clinically meaningful and statistically significant OS benefit. The lack of an immediately evident OS benefit at interim OS analysis has so far precluded a universal change in clinical practice.

The lack of a correlation between intermediate endpoints such as PFS or ORR and patients’ survival highlights a persistent challenge in HCC clinical research: the difficulty of translating early radiologic improvements into definitive survival gains (6). Whilst some evidence exists as to the relationship between PFS benefit and OS gains in advanced disease, such surrogacy has not been proven in intermediate-stage HCC (7). In this segment of the HCC patient population, combination of TACE and systemic therapy is inherently complex and several factors come into play in influencing patient outcome, including heterogeneity in TACE techniques, varying immunogenic effects of embolization, differences in patients’ tumor biology and liver functional reserve. Most importantly perhaps, the wide availability of numerous, highly active subsequent systemic therapies—particularly immunotherapy may have diluted the observed OS signal.

In addition, when considering the opportunity of escalating intensity of therapeutic standards, safety, tolerability and quality of life remain a paramount concern. The notable increase in grade 3 or higher adverse events needs to be evaluated carefully on an individual patient basis before wide clinical adoption. While treatment-related toxicities were generally manageable, their frequency underscores the necessity for vigilant monitoring and experienced multidisciplinary care, especially in patients with marginal liver reserve. The risk-benefit profile of such intensive regimens must be carefully weighed, and patient selection will be critical to optimizing outcomes.

LEAP-012 distinguishes itself from previous negative trials that combined TACE with TKIs alone, such as SPACE (8) and TACE-2 (9), by introducing a novel immunologic rationale. The disappointing results of those earlier studies may reflect the limitations of combining TACE solely with anti-angiogenic agents, without the added immunologic synergy provided by ICIs. In contrast, the combination of immunotherapy and anti-vascular endothelial growth factor (VEGF)/VEGFR agents (10,11)—already established as effective in advanced HCC—appears to offer a more rational and potentially effective pairing with TACE. Nevertheless, LEAP-012, just like the recent LEAP-002 trial (12), demonstrates that promising biological hypotheses do not always translate into overall survival gains in phase 3 trials, at least within conventional statistical thresholds.

A useful comparison with the results of LEAP-012 can be made by the joint appraisal of the EMERALD-1 trial (13), which also evaluated the addition of immunotherapy and anti-angiogenic treatment to TACE in unresectable HCC. EMERALD-1 demonstrated that durvalumab plus bevacizumab with TACE significantly improved PFS compared to TACE alone (median PFS 15.0 vs. 8.2 months; HR: 0.77), with a manageable safety profile and no significant OS benefit at interim analysis. These results, closely paralleling those of LEAP-012, reinforce the potential of combining TACE with immune-based and anti-angiogenic therapies to enhance tumor control. However, just like LEAP-012, EMERALD-1 does not provide evidence for a significant OS benefit at interim analysis, underscoring the complex interplay between locoregional and systemic therapies and the confounding effects of post-progression treatments. Whilst direct cross-trial comparisons cannot be made across studies, the numerically lower rates of high-grade toxicity observed in EMERALD-1 compared to LEAP-012 may reflect differences in patient selection, drug regimens, or trial design, and highlights the importance of balancing efficacy with safety when considering these intensive combination strategies.

Looking forward, the positive PFS readouts for LEAP-012 and EMERALD-1 open several important avenues for future investigation. Optimizing the timing and sequencing of TACE and systemic agents is a critical question that remains unresolved. The interplay between TACE-induced hypoxia and inflammation and the priming of anti-tumor immunity is complex and incompletely understood (14); whether TACE should precede, follow, or be intercalated with immunotherapy deserves further study. Additionally, the identification of predictive biomarkers—such as immune profiles, tumor mutational burden, molecular signatures, and circulating biomarkers—could help to stratify patients and identify those most likely to benefit from combination regimens. The interpretation of OS in this and similar trials is complicated by the high frequency of post-progression therapies, suggesting that alternative endpoints such as PFS, durable response, time to TACE refractoriness, maintenance of liver function, and quality-adjusted survival may be more sensitive and clinically relevant in future studies (1). Finally, future trials should consider adaptive designs, novel therapeutic combinations, and real-world effectiveness, including cost-effectiveness analyses in more diverse patient populations.

In summary, LEAP-012 marks a significant step forward in the evolution of therapy for intermediate-stage HCC and represents a landmark effort to bridge locoregional and systemic treatment modalities. The significant PFS benefit and the trend toward improved OS, despite increased toxicity, affirm the potential of combining TACE with immunotherapy and TKIs. The parallel findings from EMERALD-1 further reinforce the concept that dual or triple combination strategies can improve tumor control, but also highlight the urgent need for better patient selection, toxicity management, and more sensitive clinical endpoints. While neither trial yet warrants a change in the standard of care, together they lay the groundwork for a more nuanced, multimodal, and ultimately personalized approach to HCC management. The ongoing maturation of survival data, integration of translational research, and refinement of patient selection strategies will be essential as we move closer to the goal of precision oncology in liver cancer.

Acknowledgments

D.J.P. acknowledges infrastructural support from the NIHR Imperial Experimental Cancer Medicine Centre and the Imperial College Biomedical Research Centre. P.C.L. is supported by the Yin Shu-Tien Medical Education Memorial Foundation and the Taipei Veterans General Hospital-National Yang Ming Chiao Tung University Excellent Physician Scientists Cultivation Program (No. 113-V-A-007) during his academic visit at Imperial College London.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article did not undergo external peer review.

Funding: This work was supported by the Wellcome Trust Strategic Fund(No. PS3416, to D.J.P.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-90/coif). P.C.L. received grants from Yin Shu-Tien Foundation and the Taipei Veterans General Hospital-National Yang Ming Chiao Tung University Excellent Physician Scientists Cultivation Program (No. 113-V-A-007). Y.H.H. received research grants from Gilead Sciences and AstraZeneca, honoraria from AstraZeneca, Gilead Sciences, Eisai, and Roche, and had advisory role for AstraZeneca, Eisai, and Roche. D.J.P. is supported by grant funding from the Wellcome Trust Strategic Fund (No. PS3416) and from the Associazione Italiana per la Ricerca sul Cancro (AIRC MFAG Grant ID 25697); and acknowledges infrastructural and grant support from the NIHR Imperial Experimental Cancer Medicine Centre and the Imperial College BRC. He received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, Eisai, and Falk Foundation; travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra, Mursla, Exact Sciences and Astra Zeneca; and research funding (to institution) from MSD and BMS. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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