Durvalumab and bevacizumab plus transarterial chemoembolization in unresectable hepatocellular carcinoma: a new paradigm?

Introduction

It has quietly approached 18 years since the Food and Drug Administration (FDA) approved the utilization of sorafenib in the treatment of unresectable hepatocellular carcinoma (HCC) (1-3). Since then, new drugs and treatments using advanced therapies, combined with vascular endothelial growth factor (VEGF) inhibitors and local treatments, have greatly improved the results for patients with unresectable HCC (1,4). The progress in programmed death-(ligand) 1 [PD-(L)1] and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapies, particularly in combined utilization, has made tolerable and flexible treatment plans for HCC patients that are not eligible for traditional curative options, such as resection or transplantation (2,3,5-8). Unresectable HCC remains a formidable clinical challenge despite advances in locoregional and systemic therapies. Transarterial chemoembolization (TACE) has long been the cornerstone for patients with intermediate-stage disease, yet recurrence and disease progression are common, partly due to the biologic sequelae of embolization (9). In this context, the recently reported phase 3 EMERALD-1 trial, evaluating the addition of durvalumab with or without bevacizumab to TACE, represents a potentially practice-changing approach. The trial’s findings, by Sangro et al. (10), provide compelling evidence that integrating systemic therapy with an established locoregional treatment can significantly prolong progression-free survival (PFS).

The unmet need in HCC treatment

HCC is a leading cause of cancer-related mortality worldwide (11). A large proportion of patients are diagnosed at an advanced stage, rendering curative therapies such as resection, ablation, or transplantation infeasible (1,5-8,12). For those with intermediate-stage HCC, TACE has been the standard of care for decades. Despite its widespread use, the median PFS with TACE alone hovers around 7–8 months, reflecting the limited durability of response. One of the principal mechanisms underlying treatment failure is the TACE-induced hypoxic microenvironment, which drives upregulation of VEGF and subsequent neoangiogenesis. This biological rebound phenomenon has provided the rationale for combining TACE with agents that modulate the tumor microenvironment.

Recent years have witnessed significant progress in systemic treatments for advanced HCC, especially with the advent of immune checkpoint inhibitors (ICIs) and antiangiogenic therapies. Durvalumab, a PD-L1 inhibitor, has shown promise in various malignancies and, when coupled with an anti-VEGF agent such as bevacizumab, may counteract the proangiogenic surge following embolization. The EMERALD-1 trial was conceived to test whether this combinatorial approach could improve outcomes in patients with unresectable HCC amenable to embolization.

Study design and rationale review

The EMERALD-1 study was designed as a multiregional, randomized, double‑blind, placebo-controlled phase 3 trial. A total of 616 adult patients with unresectable HCC across 157 medical sites in 18 countries, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and at least one measurable intrahepatic lesion was enrolled. The median age was 65 years, with 78% male and 22% female participants. The majority were Asian (61%), followed by White (29%), with smaller proportions of other racial groups. Patients were deemed eligible for TACE based on established criteria and were stratified by TACE modality, geographic region, and the presence of portal vein invasion. They were then randomized into three arms: arm A: TACE combined with durvalumab plus bevacizumab; arm B: TACE combined with durvalumab plus placebo; and arm C: TACE combined with double placebo (i.e., TACE alone).

The primary endpoint is PFS, as assessed by a blinded, independent central review using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR), time-to-progression (TTP), and patient-reported outcomes. Importantly, the trial design was predicated on the hypothesis that adding both an ICI and an anti-angiogenic agent to TACE would exert a synergistic effect by both enhancing immune-mediated tumor cell death and mitigating TACE-induced angiogenesis.

Key findings and their interpretation

At a median follow-up of approximately 28 months, the results demonstrated a statistically significant improvement in PFS in the durvalumab plus bevacizumab arm (median PFS of 15.0 months) compared with the TACE-alone group (median PFS of 8.2 months). The hazard ratio (HR) of 0.77 [95% confidence interval (CI): 0.61–0.98; P=0.032] underscores a meaningful delay in disease progression when the dual systemic therapy is added (10).

In contrast, the arm that combined durvalumab with TACE (without bevacizumab) reported a median PFS of 10.0 months, which did not reach statistical significance vs. TACE alone (HR of 0.94, P=0.638). These findings suggest that the addition of an anti-VEGF agent is critical for realizing the full potential of the combination strategy. The improvement in PFS with the triplet regimen (durvalumab plus bevacizumab plus TACE) represents an approximately 6.8-month delay in progression relative to TACE alone, a substantial clinical benefit in a patient population with historically limited options. Bevacizumab plays a key role by inhibiting tumor angiogenesis and normalizing tumor vasculature. This anti-angiogenic effect can enhance the efficacy of ICIs such as durvalumab and may have a synergistic effect with TACE.

Notably, the ORR was also superior in the triplet arm, and median TTP was significantly prolonged (22.0 months in the combination arm vs. 10.0 months in the TACE alone arm). Although OS data remain immature, these PFS and TTP improvements are important, especially given the historical challenges of extending survival in HCC through locoregional therapies alone (Table 1, Figure 1).

Figure 1 Multimodal approach in EMERALD-1: integrating TACE with durvalumab and bevacizumab in unresectable HCC. Schematic illustration of the EMERALD-1 trial design and its mechanistic rationale. (A) The patient enrollment and randomization into three treatment arms. (B) The synergistic mechanism of combining TACE with durvalumab and bevacizumab, where TACE induces a proinflammatory and hypoxic tumor microenvironment that promotes VEGF release, while durvalumab reactivates immune responses and bevacizumab blocks angiogenesis. ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; PD-L1, programmed death ligand 1; TACE, transarterial chemoembolization; VEGF, vascular endothelial growth factor.

The biological rationale behind the EMERALD-1 approach is rooted in the interplay between tumor hypoxia, angiogenesis, and immune modulation (10). TACE, by design, induces ischemia in tumor tissue, leading to tumor cell death but also resulting in a hypoxic environment that triggers the release of VEGF (10). This surge in VEGF not only promotes neovascularization but can also create an immunosuppressive microenvironment. In this context, bevacizumab may normalize the tumor vasculature, enhance immune cell infiltration, and mitigate the rebound angiogenesis following TACE (10).

Simultaneously, durvalumab acts by blocking PD-L1, thereby reinvigorating exhausted T cells and promoting a robust anti-tumor immune response. The combination of these mechanisms creates a multifaceted assault on the tumor. The TACE procedure debulks the tumor and releases neoantigens; the anti-VEGF component curtails the deleterious effects of post-embolization hypoxia, and the ICI amplifies the immune-mediated cytotoxic response. Together, these effects may convert a locoregional therapy with limited systemic impact into a treatment modality with the potential to control micrometastatic disease and prolong survival (13).

Safety and tolerability: balancing efficacy and adverse effects

As with any combination therapy, safety remains a paramount concern. In the EMERALD-1 study, the most frequently observed grade 3–4 adverse events varied by treatment arm (10). In the triplet arm (durvalumab plus bevacizumab plus TACE), hypertension was the most common severe adverse event, whereas the durvalumab plus TACE arm saw a higher incidence of anemia, and the TACE alone group experienced post-embolization syndrome (10). Importantly, treatment-related adverse events (TRAEs) that led to death were rare across all arms.

While the combination of durvalumab and bevacizumab was associated with a higher incidence of TRAEs compared to TACE alone, these events were generally manageable and consistent with the known safety profiles of the individual agents (10). The results indicate that the significant improvement in PFS and, potentially, OS justifies the added toxicity. Nevertheless, careful patient selection and vigilant monitoring remain critical, particularly in patients with compromised liver function or other comorbidities.

Placing EMERALD-1 in the landscape of HCC therapies

The treatment landscape for HCC has evolved considerably over the past decade. Landmark trials such as TACTICS (14), which combined TACE with sorafenib, and more recent studies evaluating lenvatinib-based regimens have sought to overcome the limitations of TACE alone by integrating systemic therapy. The EMERALD-1 trial builds on this evolving paradigm by demonstrating that a combination strategy involving both immunotherapy and anti-VEGF therapy can yield superior results (Table 2).

Compared with previous efforts, the EMERALD-1 study is notable for its multiregional, double-blind, placebo-controlled design, a feature that enhances the generalizability of its findings across diverse patient populations. Moreover, the inclusion of a durvalumab plus TACE arm provides an important internal control, highlighting that the addition of bevacizumab appears to be the differentiating factor in achieving statistically significant improvements in PFS.

The results also invite comparisons with ongoing studies such as LEAP-012 (15), which examines the combination of lenvatinib and pembrolizumab with TACE, and other trials evaluating triplet therapy strategies. Although each of these studies employs different agents and trial designs, they share a common goal: to exploit the synergy between locoregional therapies and systemic agents in order to convert an initially palliative approach into one that offers durable disease control (Table 2).

In addition to the ongoing trials investigating ICIs plus anti-VEGF therapy combined with TACE, there is also the CARES-310 study, a randomized, phase 3 international trial, which evaluated camrelizumab plus the VEGFR2-targeted tyrosine kinase inhibitor rivoceranib in patients with unresectable HCC as compared to sorafenib in first-line setting. The study demonstrated significant improvements in both PFS (5.6 vs. 3.7 months; HR =0.52) and OS (22.1 vs. 15.2 months; HR =0.62) compared with sorafenib. The trial population included patients with macrovascular invasion and varying tumor burden, which may differ from the populations included in TACE-combination studies, where patients often had more localized disease suitable for embolization. These differences should be considered when interpreting efficacy outcomes across trials.

Potential implications for clinical practice

Should the mature OS data from EMERALD-1 confirm the early signals observed in PFS and TTP, the implications for clinical practice could be profound (10). In many parts of the world, TACE remains the mainstay of treatment for patients with intermediate-stage HCC (10). For these patients, the integration of durvalumab and bevacizumab into the treatment algorithm could represent a new standard of care.

From a practical standpoint, the use of a triplet regimen would necessitate adjustments in treatment protocols. Multidisciplinary teams, including interventional radiologists, hepatologists, and medical oncologists, will need to coordinate more closely to manage both the locoregional and systemic aspects of therapy. Furthermore, the economic implications of adding two expensive systemic agents to a standard procedure must be weighed against the potential for prolonged disease control and improved quality of life.

Another important consideration is patient selection. Not all patients with unresectable HCC may be ideal candidates for combination therapy. The EMERALD-1 study enrolled patients with relatively preserved liver function (Child-Pugh A or B7) and a good performance status. As such, the benefits observed may not be generalizable to patients with more advanced liver dysfunction (10). Future research will need to explore biomarkers that can predict which patients are most likely to benefit from this combination approach.

Limitations and future directions

Despite its promising results, the EMERALD-1 study (13) has several limitations that warrant discussion. Initially, although the enhancement in PFS is statistically significant, the conclusive OS data remain forthcoming. In the immunotherapy era, it is usual for PFS advantages to occur before significant OS enhancements due to delayed therapeutic effects or the impact of subsequent medicines (13). Prolonged monitoring will be essential to ascertain if the initial advantages result in a significant survival benefit.

The study’s design, featuring both a durvalumab plus bevacizumab arm and a durvalumab monotherapy arm, prompts significant inquiries about the respective contributions of each agent (13). While the data indicates that bevacizumab is essential for attaining the observed PFS benefit, more biomarker-driven studies could clarify which individuals may benefit from monotherapy vs. the complete triplet treatment.

The elevated incidence of TRAEs in the combination group, albeit tolerable, highlights the necessity for refined dosage and timing methods. The equilibrium between optimizing efficacy and reducing toxicity will be a primary emphasis on current and forthcoming research (13). Explorations of alternate sequences or timings of TACE in relation to systemic therapy administration may provide insights that enhance this methodology.

Several potential routes for future investigation are evident. Mature OS data and patient-reported outcomes from EMERALD-1 will be anticipated to confirm the clinical significance of the triplet regimen (10). Secondly, direct comparisons of various triplet regimens (e.g., durvalumab combined with bevacizumab vs. lenvatinib combined with pembrolizumab) may elucidate the most effective agent combinations for distinct patient populations. Ultimately, research into the incorporation of these systemic therapies in the preliminary phases of HCC, or in combination with other locoregional interventions like radioembolization, could enhance the treatment options available for this lethal malignancy.

Conclusions

The EMERALD-1 trial (10) represents a significant step forward in the treatment of unresectable HCC. By combining the immunomodulatory effects of durvalumab with the antiangiogenic properties of bevacizumab and the locoregional efficacy of TACE, this study offers a compelling example of how multidisciplinary, combinatorial strategies can overcome the limitations of monotherapy. The statistically significant prolongation of PFS observed in the triplet arm is not only an important clinical milestone but also a testament to the power of rationally designed combination therapies in oncology.

Although the ultimate OS data are pending, the preliminary results offer compelling justification for the incorporation of dual systemic therapy with TACE in specific patients. The EMERALD-1 trial substantiates the notion that a multifaceted approach to tumor treatment-simultaneously addressing the immune system, angiogenic pathways, and tumor vasculature, can produce synergistic advantages that exceed the efficacy of any singular modality.

In the overarching framework of HCC management, our findings could transform therapy paradigms and enhance outcomes for a patient demographic that has historically been neglected by conventional therapeutic methods (16). As clinicians and researchers eagerly await longer-term follow-up data, the EMERALD-1 trial stands as a beacon of hope, illuminating a future in which combination therapy may finally overcome the hurdles of tumor recurrence and progression in unresectable HCC.

For now, the oncology community must balance cautious optimism with the need for further evidence, while also considering practical issues such as patient selection, toxicity management, and cost-effectiveness. Ultimately, the promise of improved survival and quality of life for patients with HCC makes the challenges of implementing such a strategy well worth the effort.

As we look to the future, continued innovation and rigorous clinical investigation will be essential to refine these approaches and to identify which patients stand to benefit the most. The journey from a locoregional procedure with modest outcomes to a sophisticated, multimodal treatment strategy represents a major evolution in the management of HCC. In this light, the EMERALD-1 study not only sets the stage for new clinical standards but also inspires further research that may one day lead to even more effective and personalized therapies for liver cancer.

The integration of durvalumab and bevacizumab with TACE is poised to redefine the treatment landscape for unresectable HCC. The combination leverages the strengths of each modality to address the complex biology of HCC, offering a promising pathway toward prolonged disease control (17,18). As additional data emerge and as our understanding of the interplay between locoregional and systemic therapies deepens, we can anticipate a future where such combination strategies become the cornerstone of HCC management, ushering in an era of improved survival outcomes and enhanced quality of life for patients afflicted with this challenging malignancy.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-34/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-34/coif). The authors have no conflicts of interest to declare.

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