Sequential ICI plus Anti-VEGF/TKI with On-Demand TACE beyond RECIST Progression Improves Pathological Response, Resectability, and Survival in Unresectable HCC

Introduction

The treatment landscape for unresectable hepatocellular carcinoma (uHCC) has markedly advanced with the advent of immune checkpoint inhibitor (ICI)–based combination therapies, particularly atezolizumab plus bevacizumab (Atezo/Bev). Nevertheless, disease progression still occurs in a substantial proportion of patients, underscoring the need for more effective therapeutic strategies. Currently, increasing attention has been focused on triplet therapy consisting of an ICI, an anti-vascular endothelial growth factor (VEGF) agent or tyrosine kinase inhibitor (TKI), and transarterial chemoembolization (TACE).

This combination is supported by a robust scientific rationale. TACE induces immunogenic cell death, resulting in the release of damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs), and tumor antigens, which promote dendritic cell (DC) maturation and activation of CD8-positive T cells. Concurrently, anti-VEGF/TKI therapy normalizes tumor vasculature and mitigates the immunosuppressive tumor microenvironment, thereby enhancing the antitumor activity of ICIs [1, 2].

Indeed, phase III trials such as EMERALD-1, LEAP-012, and TALENTACE have demonstrated that triplet therapy significantly prolongs progression-free survival (PFS) and achieves high objective response rates (ORR of approximately 45–50%) compared with TACE alone [3–5]. Notably, the TALENTACE trial adopted a design allowing treatment continuation beyond RECIST-defined progression, combining immunotherapy with on-demand TACE until unTACEable progression, thereby reflecting real-world clinical practice and offering the potential for overall survival (OS) benefit [5].

Furthermore, a multicenter proof-of-concept study evaluating curative conversion therapy after Atezo/Bev reported that 35% of patients achieved clinical complete response (cCR), with 23% achieving drug-free status [6]. The TALENTOP trial also demonstrated a significant improvement in time to treatment failure in patients undergoing surgical resection following induction Atezo/Bev therapy (20.4 vs. 11.8 months), with a trend toward prolonged survival [7].

Collectively, these findings substantiate the association between deep response and long-term survival [6, 7] and highlight the curative conversion potential of triplet therapy beyond conventional doublet regimens of ICI plus anti-VEGF/TKI. A critical future strategy is to abandon the automatic discontinuation at the first RECIST-defined progression and instead adopt a sequential approach, continuing immunotherapy in combination with appropriately timed, on-demand TACE until true TACE failure (unTACEable progression) [8–12].

Theoretical Rationale and Evidence Supporting Triplet Therapy

The theoretical basis for triplet therapy is biologically sound and scientifically compelling. Locoregional therapies such as TACE induce immunogenic cell death, leading to tumor antigen release. Specifically, TACE-induced tumor necrosis results in the release of danger signals such as DAMPs and PAMPs, which activate innate immune sensors such as Toll-like receptors (TLRs) on DCs. These signals promote antigen uptake, phagocytosis, and maturation of DCs, with upregulation of MHC class I and II molecules as well as costimulatory molecules CD80/86. Consequently, tumor antigens are effectively presented to CD8-positive T cells, which become activated CD8-positive T cells and mediate antitumor immune responses. Through this mechanism, TACE enhances ICI-mediated antitumor immunity [1] (Fig. 1, 2).

Fig. 1.

TACE during ICI+Anti-VEGF/TKI plays a crucial role in the achievement of pathological complete response. TACE physically destroys and induces necrosis of tumor cells, thereby driving them into immunogenic cell death (ICD). As a result, danger signals such as DAMPs and PAMPs are released, which are sensed by innate immune receptors including TLRs expressed on immature dendritic cells (DCs), leading to phagocytosis of the target tumor cells. Anti-VEGF therapy contributes to DC maturation by decreasing inhibitory signals, resulting in strong upregulation of MHC class I/II molecules as well as the costimulatory molecules CD80 and CD86. Mature DCs subsequently present tumor antigens to CD8-positive T cells and provide adequate costimulatory signals, leading to activation of cytotoxic T lymphocytes (CTLs). Furthermore, anti-VEGF therapy promotes tumor vascular normalization, facilitating CTL infiltration into the tumor microenvironment, while simultaneously inhibiting immunosuppressive cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). Consequently, the activated CTLs are expected to eradicate residual viable tumor cells remaining after TACE through the action of anti-PD-1/PD-L1 therapy, ultimately leading to a pathological complete response (pCR).

Fig. 2.

Rationale of Sequential Therapy of ICI + Anti-VEGF/TKI + TACE Upfront anti-VEGF therapy enhances the efficacy of transarterial chemoembolization (TACE) by promoting vascular normalization, reducing microvessel density, and decreasing vascular permeability, thereby improving intratumoral drug delivery. Concurrently, anti-PD-1/PD-L1 therapy enhances antitumor immune responses while suppressing pro-tumor immunity. On-demand TACE induces tumor volume reduction and necrosis while increasing the release of tumor antigens. However, TACE-induced hypoxia leads to upregulation of HIF-1α and VEGF. This VEGF surge is subsequently inhibited by continued anti-VEGF therapy. As a result, TACE further augments antitumor immunity and suppresses pro-tumor immune mechanisms, ultimately leading to tumor cell death in combination with PD-1/PD-L1 blockade. ICI, immune checkpoint inhibitor; VEGF, vascular endothelial growth factor; TKI, tyrosine kinase inhibitor; TACE, transarterial chemoembolization.

Simultaneously, anti-VEGF/TKI therapy exerts anti-angiogenic effects that normalize tumor vasculature, improving the drug delivery and efficacy of intra-arterially administered chemotherapeutic agents and embolic materials [2]. Anti-VEGF/TKI agents also promote activation and tumor infiltration of CD8-positive T cells and natural killer cells, while downregulating immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, thereby converting the tumor microenvironment into an immune-permissive state [1, 2]. Therefore, sequential therapy combining ICI, anti-VEGF/TKI, and TACE is a rational strategy with the potential to induce pathological complete response (pCR) in uHCC (Fig. 1, 2).

Three recent phase III trials provide clinical evidence supporting this synergistic potential. The EMERALD-1 trial demonstrated that durvalumab plus Bev combined with TACE significantly prolonged PFS compared with TACE plus placebo (median PFS 15.0 vs. 8.2M; HR 0.77) [3]. Similarly, the LEAP-012 trial showed that lenvatinib plus pembrolizumab combined with TACE resulted in a significant PFS benefit (median PFS 14.6 vs. 10.0 months; HR 0.66) [4]. Furthermore, the TALENTACE trial demonstrated that Atezo plus Bev combined with on-demand TACE significantly improved TACE-PFS, reflecting time to unTACEable progression (Median TACE-PFS 11.3 vs. 7.0 months; HR 0.71) [5, 13] (Fig. 3).

Fig. 3.

Difference of Combination Treatment Pattern between EMERALD-1 and LEAP-012 vs. TACTICS, TACTICS-L, ABC-TACE Sequential Therapy, ABC Conversion and TALENTACE Trial. Continuous sequential therapy with immune checkpoint inhibitors (ICI) combined with anti-VEGF agents or tyrosine kinase inhibitors (TKI) and transarterial chemoembolization (TACE), administered beyond RECIST-defined progressive disease (PD) until the development of unTACEable progression, provides a high likelihood of achieving a pathological complete response and/or improving overall survival. ICI, immune checkpoint inhibitor; VEGF, vascular endothelial growth factor; TKI, tyrosine kinase inhibitor; TACE, transarterial chemoembolization.

However, trial designs differed substantially. In EMERALD-1 and LEAP-012, protocol treatment was discontinued at RECIST-defined progression in both experimental and control arms [3, 4], potentially diluting OS benefit due to crossover effects (Fig. 3). In contrast, TALENTACE allowed continuation of Atezo/Bev and on-demand TACE beyond RECIST progression until unTACEable progression [5], a design conceptually consistent with the TACTICS and TACTICS-L trials [8–10] and identical to real-world ABC-TACE sequential therapy in Japan (Fig. 4).

Fig. 4.

Atezo + Bev Combined with TACE (ABC-TACE) Sequential Therapy. For patients with TACE-unsuitable intermediate-stage hepatocellular carcinoma (HCC), immune-boosting TACE should be considered not only in those achieving partial response (PR) but also in patients with stable disease (SD), slow progressive disease (PD), or PET-positive tumors. In this setting, immune checkpoint inhibitor (ICI) therapy combined with anti-VEGF treatment should be continued. To preserve liver function and enable sustained systemic therapy, super-selective partial embolization targeting one to three lesions should be performed, rather than total embolization of all intrahepatic tumors. This approach allows repeated on-demand TACE while maintaining ICI plus anti-VEGF therapy, potentially leading to cancer-free and treatment-free status.

Strategies for Achieving Deeper Responses and Curative Conversion

Exploratory analyses of the IMbrave150 trial revealed a strong association between depth of response (DpR) to Atezo/Bev and overall survival [14], an observation confirmed by extended follow-up data from the HIMALAYA trial [15]. Importantly, DpR in patients receiving immunotherapy plus TACE was also correlated with OS, which was confirmed in the exploratory analysis of the TALENTACE trial [13] (Fig. 5).

Fig. 5.

OS by DpR per RECIST v1.1 by INV (6-month Landmark Analysis) in TALENTACE Trial. In an ad hoc analysis of the TALENTACE trial – a prospective, phase III, open-label, multicenter, randomized study (NCT04712643) – depth of response (DpR) was associated with overall survival (OS) not only in systemic therapy with Atezo plus Bev, but also in the combination of TACE with Atezo and Bev. This analysis included patients with measurable disease at baseline and at least one post-baseline tumor assessment. DpR was defined as the maximum tumor shrinkage from baseline in the sum of the longest diameters of target lesions prior to the initiation of subsequent anticancer therapy. Six-month landmark analyses were performed for OS comparisons across DpR subgroups to minimize immortal time bias. Hazard ratios were estimated using an unstratified Cox proportional hazards model, with Group A serving as the reference. Consistent with findings from Atezo plus Bev monotherapy [ref. 14], the TALENTACE study demonstrated a clear association between DpR and OS in the Atezo plus Bev plus TACE arm. Notably, few patients exhibited stable disease without tumor shrinkage (n = 27), and no patients experienced progressive disease due to the tumor-reductive effect by TACE.

The most expected therapeutic benefit of triplet therapy is its capacity to induce deep responses that enable curative conversion therapy (Fig. 3). The clinical significance of curative conversion was first demonstrated in a multicenter proof-of-concept study in Japan, in which 35% of patients achieved a cancer-free status, and 23% achieved a drug-free status [6].

This concept was further validated in the TALENTOP phase III trial, which demonstrated a statistically significant improvement in time to treatment failure (time from randomization to the first recorded treatment failure such as local recurrence or progression, extrahepatic spread [EHS], or all cause of death) following surgical resection after Atezo/Bev induction therapy (20.4 vs. 11.8 months, HR 0.60, p = 0.015) [7]. TALENTOP trial thus provides the first phase III evidence that conversion surgery after immunotherapy is feasible and beneficial in advanced HCC.

Although conversion surgery rates were not explicitly reported in EMERALD-1, LEAP-012, and TALENTACE, all three trials demonstrated significantly higher ORRs (EMERALD-1: ORR 44% vs. 30%, LEAP-012: ORR 47% vs. 33%, TALENTACE: ORR 49% vs. 34%) [3–5], suggesting that triplet therapy increases the likelihood of curative conversion relative to TACE alone.

Recent retrospective and phase II studies have reported conversion rates ranging from 26% to over 54% with triplet therapy [16–20], even among 49% to 78%patients with BCLC-C stage with macrovascular invasion (MVI) and/or EHS. For example, in a multicenter study conducted by Wu et al. [16] investigating the combination of TACE with lenvatinib plus an anti-PD-1 antibody, it was reported that 38.7% of patients who were initially diagnosed with uHCC successfully underwent conversion surgery. In a subsequent, larger study by the same group that included 241 patients, the conversion surgery rate reached an excellent level of 44.4% [20]. Of critical importance, this study further demonstrated that achievement of cCR, defined by radiological complete response (CR) and normalization of tumor markers, was significantly correlated with pCR and could be used as a strong predictor of favorable long-term survival. These findings suggest that cCR may serve as an important surrogate endpoint for favorable clinical outcomes.

Importance of Continuous Sequential Triplet Therapy beyond RECIST Progression

The key to achieving pCR is not a single session of TACE followed by ICI plus anti-VEGF/TKI, but continuous sequential therapy consisting of ICI plus anti-VEGF/TKI with on-demand TACE beyond RECIST PD until unTACEable progression (Fig. 3). Despite consistent PFS benefit [3–5], OS benefit has not yet been definitively demonstrated, likely due to premature discontinuation of protocol treatment at first RECIST-defined progression [3, 4] and a possible dilution of the OS benefit due to effective post-progression therapies (Fig. 3), such as Atezo plus Bev combination therapy, both in testing and control arms.

As we have previously pointed out [6], it is frequently observed in intermediate-stage HCC that lesions considered to be “resistant” to systemic therapy may still retain response to TACE [2]. In real-world clinical practice, therefore, newly developed lesions arising during triplet therapy, as well as previously TACE-treated target lesions that show regrowth, can once again achieve CR through the administration of additional TACE. In other words, in patients for whom TACE remains an applicable treatment option, the emergence of new lesions or regrowth of previously TACE-treated tumors does not indicate treatment failure, nor does it necessarily suggest the need to transition to subsequent systemic therapy. Rather, repeat TACE can achieve CR again. This represents a fundamentally important distinction from cases of advanced HCC treated with systemic therapy alone (Fig. 3).

Furthermore, TACE has the potential to reprogram the intratumoral microenvironment, thereby restoring conditions under which the same immunotherapy may once again exert its therapeutic effects. Specifically, DAMPs and PAMPs generated by TACE activate innate immune mechanisms via TLRs. In concert with the effects of anti-VEGF agents, these processes promote the maturation of immature DCs, which subsequently present tumor antigens released by TACE to CD8-positive T cells. Through this sequence of events, the cancer immunity cycle is activated, ultimately leading to the elimination of residual cancer cells (Fig. 1).

Under this approach, the first PD as defined by RECIST version 1.1 (PFS1) does not mandate treatment discontinuation but instead prompts consideration of repeat superselective partial TACE for newly developed lesions or regrowth of previously treated tumors. If these progressive lesions can be adequately controlled by TACE, continued systemic therapy can further enhance the tumor necrotic effect, thereby leading to prolongation of the interval until subsequent progression (PFS2).

The objective of this strategy is to extend the total duration of disease control, defined as PFS1 + PFS2 + PFS3, and so on, until the tumor becomes uncontrollable by either TACE or systemic therapy. This approach is considered to be the key to maximizing deep and durable responses, maximizing the likelihood of transition to curative conversion therapy (i.e., achievement of cancer-free and drug-free status), and ultimately contributing to prolongation of OS (Fig. 3).

In a multicenter cohort study from China, Zhao et al. [21]. retrospectively compared the treatment outcomes of triplet therapy consisting of TACE combined with lenvatinib plus tislelizumab (TLT) with those of TACE combined with lenvatinib alone (TL). In this study, disease progression was defined as the occurrence of any of the following conditions:

• 1.a ≥25% increase in tumor size from baseline,
• 2.transient deterioration of liver function to Child-Pugh class C,
• 3.worsening of MVI, or
• 4.development of EHS.

In other words, treatment was continued until progression reached what we originally proposed as “unTACEable progression.” This definition directly follows the endpoints we employed in the TACTICS, TACTICS-L, and TALENTACE trials [5, 8–10]. As a result, OS (26.0 vs. 20.0 months), PFS (14.0 vs. 9.0 months), and ORR based on mRECIST (66.1% vs. 46.9%) were all reported to be significantly improved in the TLT triplet group compared with the TL group.

Notably, 83% of patients in the TLT-treated population were classified as BCLC stage C, with 48% presenting with MVI and 71% with EHS, making these favorable outcomes particularly remarkable given the advanced disease characteristics. In Japan, following our initial report [6], multiple real-world studies have been conducted, and the clinical usefulness of triplet therapy combining TACE with Atezo plus Bev has been widely reported across diverse clinical settings, including patients with stable disease (SD) as well as those who experienced progression after first-line systemic therapy [22–26].

The TALENTACE trial was designed using a more real-world oriented approach, with the intention of continuing immune-based systemic therapy accompanied by multiple sessions of on-demand TACE until progression reached “unTACEable progression” [5]. Although the OS data from this trial are currently immature, if an OS benefit is demonstrated with longer follow-up, this would support the treatment strategy we propose, namely, not discontinuing triplet therapy at RECIST-defined PD, but instead continuing systemic therapy together with on-demand TACE until the disease becomes refractory to both systemic therapy and TACE, a condition referred to as “true resistance to triplet therapy.” Such findings would indicate that this treatment strategy represents a key approach for achieving pathological CR and prolonging OS. It should be noted, however, that TACE may occasionally exert unfavorable biological effects on tumors, including tumor progression, dedifferentiation, or sarcomatous transformation of HCC, highlighting the need for careful patient selection and appropriate TACE procedure.

Conclusion

Triplet therapy combining ICI, anti-VEGF/TKI, and TACE is driving a paradigm shift in uHCC treatment. Its ability to induce deep responses, facilitate curative conversion, and potentially extend survival is supported by growing evidence [3–6, 16–26]. To fully realize its potential, treatment should not be discontinued solely on the basis of the first RECIST-defined progression. but continued sequentially until true triplet-therapy resistance emerges [16–26] (Fig. 3).

This approach not only maximizes patient benefit in real-world practice but also provides critical insights for future clinical trial design. Endpoints such as TACE-PFS and time to unTACEable progression may be adopted to capture clinically meaningful survival benefit [5, 16–26] (Fig. 2, 3). Through this strategy, improved outcomes, long-term survival, and true cure via curative conversion may become achievable for more patients with uHCC.

Statement of Ethics

No statement is needed because this study was based exclusively on published data.

Conflict of Interest Statement

Lectures: Chugai, Eisai, AstraZeneca. Grants: Otsuka, Taiho, Chugai, GE Healthcare, and Eisai. Advisory consulting: Chugai, Roche, Eisai, and AstraZeneca. Masatoshi Kudo is the Editor-in-Chief of Liver Cancer.

Funding Sources

There was no funding for this editorial.

Author Contributions

Masatoshi Kudo conceived, wrote, and approved the final manuscript.

Funding Statement

There was no funding for this editorial.

Data Availability Statement

Data availability is not applicable because this is not a research article.