Role of immune checkpoint inhibitor combinations in resectable and unresectable,embolization-eligible hepatocellular carcinoma

Abstract

Immune checkpoint inhibitor (ICI) combination regimens have recently become the new standard of care for advanced hepatocellular carcinoma (HCC). Large, phase III registrational trials of ICI-containing regimens in resectable and embolization-eligible settings are now reading out. This review summarizes and critically appraises efficacy and safety data from these studies with consideration of the optimal use of ICIs in conjunction with antiangiogenic agents including important issues in management of HCC across the continuum of care such as those related to patient selection, treatment sequencing, and liver preservation. IMbrave050 assessed atezolizumab plus bevacizumab in resected HCC and EMERALD-1 and LEAP-012 evaluated addition of durvalumab–bevacizumab and pembrolizumab–lenvatinib to transarterial chemoembolization in unresectable, embolization-eligible HCC. Both EMERALD-1 and LEAP-012 met the primary endpoint of progression-free survival. While IMbrave050 initially met its primary endpoint of recurrence-free survival, the adjuvant atezolizumab–bevacizumab benefit was not maintained in an updated analysis. Survival benefits remain unclear for all phase III trials. Safety outcomes can be generally described as predictable based on experience with the respective experimental regimens in the advanced setting. Treatment selection in embolization-eligible settings should consider risks and benefits with special consideration of liver preservation. Additional research is required to optimize ICI combination use in the perioperative and peri-embolization settings.

Plain language summary

Immunotherapy before and/or after liver cancer resection or ablation and embolization—review of key studies and important clinical considerations

Immune checkpoint inhibitors (ICIs) are a type of immunotherapy that promotes the recognition of cancer cells by our immune system. Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is a leading cause of cancer-related mortality. Systemic treatment with ICIs is the standard of care for advanced HCC that cannot be embolized or removed by surgery or ablation and is a promising strategy for earlier disease where tumors can be removed or embolized. Large clinical studies of ICIs in combination with therapies targeted against blood vessel growth (antiangiogenics) administered before and/or after HCC removal or embolization have recently read out. Our review summarizes and critically appraises their clinical efficacy and safety data as well as discusses important issues related to HCC management such as those related to patient selection, treatment sequencing, and preservation of liver function. While one study of ICI-antiangiogenic combination therapy after surgery failed to confirm efficacy in preventing tumor recurrences, two studies in patients undergoing embolization procedures met their clinical goal of delaying tumor progression. The safety profile of ICI regimens is predictable, although their use is associated with increased adverse effects. Additional data, including survival outcomes from current studies, is required to confirm their benefit and optimize their use in HCC patients eligible for embolization.

Keywords

embolization-eligible hepatocellular carcinoma immune checkpoint inhibitors locoregional therapy resectable VEGF/R inhibitors

Introduction

Liver cancer remains one of the most frequent causes of malignancy-related death and its incidence is increasing worldwide.^1–3 Hepatocellular carcinoma (HCC) accounts for 75%–85% of liver cancers.^3,4 Although patterns of HCC stage at presentation vary across the globe,⁵ a trend towards earlier stage has been recently observed both in the West and Asia-Pacific regions^6,7 due to the development of formalized screening criteria for the at-risk populations.^8,9 Treatment options for potentially curable HCC include liver transplantation (LT), resection along with intra-arterial and ablative therapies (such as radiofrequency ablation, microwave ablation, cryoablation, stereotactic radiotherapy, and radioembolization).^3,10–14 Although LT is preferred since it can treat the tumor and the underlying chronic disease, organ availability is limited and subject to stringent selection criteria.^11,15 Eradication of visible tumor with surgical resection or ablation has become the therapy of choice for asymptomatic patients with preserved liver function that meet resection criteria (“resectable” HCC). For unresectable patients with liver-confined disease and preserved liver function, transarterial chemoembolization (TACE) or radioembolization (TARE) are the most common initial locoregional therapies (LRTs) and remain the preferred treatment option for unresectable intermediate-stage tumors with limited tumor burden while systemic therapy is considered in tumors in which intraarterial therapies are not technically feasible, ineffective, or deemed futile.^12,16–19 In patients with unresectable and LRT-ineligible (“advanced”) HCC, sorafenib was the first agent to demonstrate a survival benefit in large randomized controlled trials (RCTs).^20,21 Subsequently lenvatinib demonstrated non-inferiority to sorafenib with more pronounced responses, significantly longer tumor control and lower overall toxicity.²² These multi-targeted tyrosine kinase inhibitors (TKIs) act by inhibiting pro-angiogenic targets such as vascular endothelial growth factor (VEGF) receptors (VEGFRs).²³

HCC often develops in the context of immune dysfunction due to chronic liver inflammation in a tolerogenic environment.^24,25 Immune checkpoint inhibitors (ICIs) have the potential to demonstrate anti-tumor activity by enhancing immune recognition in an immune-cell-rich environment,^26,27 offering a new biological mechanism by which to complement or even synergize with antiangiogenic agents and LRTs.^28–31 Antiangiogenic agents promote vascular normalization and reduce neoangiogenesis thereby preventing tumor growth and spread as well as enhancing immune cell infiltration and anti-tumor immunity³⁰ and VEGF(R) targeting has been shown to have direct and indirect effects on immune cells.^31,32 Combination regimens of ICIs with a monoclonal antibody (mAb) against VEGF (atezolizumab plus bevacizumab) or VEGFR-TKIs (camrelizumab plus apatinib), or dual ICI therapy (durvalumab plus tremelimumab) have demonstrated superior outcomes compared to sorafenib in registrational trials^33–36 and have emerged as new standards of care in the advanced setting.^3,37 The field is rapidly evolving with multiple ICI combination regimens currently undergoing phase III trial testing^37–41 with reports of increasingly longer survival (nivolumab plus ipilimumab)⁴² and additional approvals on the horizon.

In resectable and embolization-eligible settings, there is an unmet clinical need to improve outcomes from LRTs.^43–46 However, periprocedural use of antiangiogenic agents in these settings has produced mixed results with no regulatory approvals to date.^{12,43,45,47–51} Following approval of ICI combinations in the advanced setting, investigations into how to incorporate these agents into earlier treatment settings have been initiated. Notably, ICI-containing regimens have demonstrated frequent, extensive, and durable responses, presenting new possibilities for clinically meaningful tumor downsizing and curative conversion of HCCs that were previously unsuitable for surgery and local ablation.^52–58 In resectable and embolization-eligible settings, multiple retrospective and early-phase prospective studies have shown promising activity for ICI-containing regimens and multiple proof-of-concept phase III studies have been undertaken to assess this approach.^{47,48,59–63} There are, however, important considerations relating to the use of these regimens in earlier settings, including undesired immunomodulatory effects, impact on LT timing, and the potential for cumulative hepato-toxicity from both systemic and locoregional therapies.^56,64–67 Given the potential of combining systemic and locoregional therapies, discussion of therapeutic approaches is best suited to a multidisciplinary tumor board where the overall treatment aim, including the possibility of curative treatment can be evaluated in light of baseline tumor and patient characteristics. This consideration is especially important in intermediate-stage HCC where there are competing treatment modalities and treatment selection can be particularly challenging in borderline cases where clinical equipoise exists.

Large, phase III registrational trials of ICIs plus antiangiogenic agents in combination with or as adjuvant therapy after LRTs are now reading out with the potential to change standards of care in earlier settings. This review will comprehensively identify, summarize, and critically appraise efficacy and safety data from these studies with consideration of the optimal use of ICIs in conjunction with VEGF(R) inhibitors including important issues in management of HCC across the continuum of care such as those related to patient selection, treatment sequencing, and liver preservation.

Findings and discussion

A total of three phase III trials assessing ICI combinations in resectable^36,68 and embolization-eligible^69–72 HCC with efficacy and safety outcomes were identified using systematic search methods (Figure S1—see Supplemental Methods). One evaluated atezolizumab plus bevacizumab in resected HCC^36,68 and two assessed the addition of durvalumab with or without bevacizumab and lenvatinib plus pembrolizumab to TACE in unresectable, embolization-eligible HCC.^69–72

What is the clinical impact of adjuvant ICI-regimens in resected HCC?

The IMbrave050 trial assessed atezolizumab (a mAb against the programmed death-ligand 1 (PD-L1)) plus the anti-VEGF mAb bevacizumab as adjuvant therapy following resection or ablation. HCC patients at high risk of recurrence following surgical resection (88%) or ablation (12%) with primarily early-stage (86% Barcelona clinic liver cancer stage (BCLC) 0/A), and good liver function (Child-Pugh A 100%) were randomized to the adjuvant ICI-combination (n = 334) or active surveillance (n = 334).³⁶ High risk of recurrence was defined as ⩽3 nodules with largest >5 cm or poor tumor differentiation, ⩾4 nodules ⩽5 cm or poor tumor differentiation, ⩽3 nodules ⩽5 cm with vascular invasion, and/or poor tumor differentiation for resectable tumors while for those undergoing ablation as single tumor >2 cm and ⩽5 cm or ⩽4 tumors ⩽5 cm.

At the primary interim analysis with a median follow-up of 17.0 months in the investigational arm, IMbrave050 became the first adjuvant phase III trial to demonstrate a statistically significant improvement in the primary endpoint of recurrence-free survival (RFS) with a 28% reduction in the risk of recurrence or death (median not yet reached (NYR) vs NYR, hazard ratio (HR) 0.72, 95% confidence interval (CI) 0.53–0.98, p = 0.012).³⁶ However, this benefit was not maintained in an updated, descriptive analysis at a median follow-up of 35.1 months (median RFS 33.2 vs 36.0 months, HR 0.90, 95% CI 0.72–1.12; Table 1).⁶⁸ Approximately three quarters of the recurrences in both arms were intrahepatic and approximately 13% of these involved macrovascular invasion. Results from prespecified subgroup analyses of RFS were consistent with those for the overall population.^36,68 Overall survival (OS) data remained immature at the time of the latest analysis with a 15% event-to-patient ratio. There were 100 deaths across the study, 54 (16%) in atezolizumab plus bevacizumab arm and 46 (14%) in the active surveillance arm and median OS was NYR in both arms (HR 1.26, 95% CI 0.85–1.87). In the updated safety analysis, more than one-third of patients receiving adjuvant atezolizumab–bevacizumab experienced grade 3/4 treatment-related adverse events (TRAEs) and 18.7% discontinued any treatment due to adverse events (AEs; Table 2).⁶⁸ The rate and percentage of deaths due to any AE were also substantially larger in the experimental arm compared to controls (1.8% vs 0.3% and 11.1% vs 4.3%, respectively).^36,68 Therefore, this combination ICI regimen is not recommended in the adjuvant setting due to the lack of RFS as well as OS benefit.⁷³

Table 1.

Efficacy outcomes of phase III trials assessing periprocedural use of immune checkpoint inhibitor regimens in resectable and embolization-eligible HCC.

Trial nameNCT#	Population	Regimen(s)	n	Median follow-up,months(range)	Overall response rate,^a %(95% CI)	Median recurrence/progression-free survival,^a monthsHR (95% CI)	Median overall survival, monthsHR (95% CI)
Resected, Adjuvant
IMbrave050 NCT04102098^36,68	High-risk surgically resected (88%) or ablated (12%); BCLC stage 0 (1%) A (85%), B (8%) or C (6%); ECOG 0 (79%) or 1 (21%); Child-Pugh A (100%); ALBI grade NR; HBV/HCV-positive (73%) or nonviral (13%) etiology	Atezolizumab 1200 mg plus bevacizumab 15 mg/kg Q3W * 17 cycles	334	35.1 (NR)	NA	33.2 HR 0.90 (0.72–1.12) p = NA	NYR HR 1.26 (0.85–1.87) p = 0.25
		Active surveillance	334		NA	36.0	NYR
Unresectable, TACE-eligible
EMERALD-1NCT03778957^69,70	Unresectable, TACE eligible; BCLC stage A (26%), B (57%) or C (16%); ECOG 0 (84%) or 1 (16%); Child-Pugh A (98%) or B7 (2%); ALBI grade 1/⩾2 57%/43%; HBV/HCV-positive (59%) or nonviral (41%) etiology	Durvalumab 1500 mg Q4W^b plus TACE^c then durvalumab 1120 mg Q3W plus bevacizumab 15 mg/kg Q3W	204	27.9 (95% CI: 27.4–30.4)	43.6OR 1.87 (1.24–2.84)CR: 3.0	15.0HR 0.77 (0.61–0.98)p = 0.032	NR
		Durvalumab 1500 mg Q4W^b plus TACE^c then durvalumab 1120 mg Q3W plus placebo for bevacizumab	207		41.0OR 1.67 (1.10–2.54)CR: 1.5	10.0HR 0.94 (0.75–1.19)p = 0.64	NR
		Placebo for durvalumab^b plus TACE^c then placebo for durvalumab plus placebo for bevacizumab	205		29.6CR: 2.5	8.2	NR
LEAP-012NCT04246177^71,72	Unresectable, TACE eligible; BCLC stage 0/A (31%), B (59%) or C (10%); ECOG 0 (89%) or 1 (11%); Child-Pugh A (100%); ALBI grade 1/⩾2 72%/28%; HBV/HCV-positive (72%) and/or alcohol (46%) etiology	Pembrolizumab 400 mg Q6W plus lenvatinib^d 12 mg (body weight ⩾60 kg) or 8 mg (body weight <60 kg) QD for up to 2 years plus TACE^e	237	25.6(IQR: 19.5–32.4)	46.8^f ∆14.6% (5.9–23.1) p = 0.0005CR: 3.4^f	14.6^f HR 0.66 (0.51–0.84)p = 0.0002^g	NR2-year OS: 75%HR 0.80 (0.57–1.11)p = 0.087g
		Placebos plus TACE^e	243		33.3^f CR: 4.1^f	10.0^f	NR2-year OS: 69%

Based on independent assessment by RECIST 1.1 or otherwise footnoted.

Durvalumab/placebo started ⩾7 days after first TACE session and continued until initiation of concurrent durvalumab plus bevacizumab, at least 14 days after the last TACE.

DEB-TACE or cTACE—participants will receive up to four TACE procedures within the 16 weeks following Day 1 of their first TACE procedure.

The administration of lenvatinib or oral placebo was suspended for 2 days before and at least 7 days after TACE was performed.

DEB-TACE or cTACE—first TACE occurred 2–4 weeks after the start of systemic therapy, with a maximum of two treatments per tumor (four total), each separated by at least 9 weeks to allow for radiological assessment between procedures with exception of cases where split TACE (up to two procedures no less than 1 month apart to treat all tumors) was used.

Per RECIST 1.1 modified for the current study to allow for up to five target tumors in the liver and requiring new intrahepatic tumors to meet LI-RADS 5 criteria to be considered progressive disease.

Significance thresholds for progression-free and overall survival were p = 0.025 and p = 0.0012, respectively.

ALBI, albumin-bilirubin; BCLC, Barcelona clinic liver cancer (staging); CI, confidence interval; CR, complete response; cTACE, conventional transarterial chemoembolization; DEB, drug-eluting bead; ECOG, Eastern Cooperative Oncology Group (performance score); HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; IQR, interquartile range; LI-RADS, Liver Imaging Reporting and Data System; n, number; NA, not applicable; NCT#, ClinicalTrials.gov identifier; NR, not reported; NYR, not yet reached; OR, odds ratio; OS, overall survival; QD, once a day; QXW, every X weeks; RECIST, Response evaluation criteria in solid tumors; TACE, transarterial chemoembolization.

Table 2.

Safety outcomes of phase III trials assessing immune checkpoint inhibitors in resectable and embolization-eligible HCC.

Trial nameNCT#	Treatment	Safety population	Treatment discontinuation^a due to TRAEs, %	Overall TRAEs, %		Deaths due to TRAEs, %	Most common grade 3/4 investigational TRAEs, %
Trial nameNCT#	Treatment	Safety population	Treatment discontinuation^a due to TRAEs, %	Any grade	Grade 3/4	Deaths due to TRAEs, %	Most common grade 3/4 investigational TRAEs, %
Resected, Adjuvant
IMbrave050NCT04102098^36,68	Atezolizumab plus bevacizumab	332	NR^b	88.9	36.1	0.6	Grade 3/4 AEs: hypertension 18.4; proteinuria 8.7; platelet count decrease 4.5; AST increase 0.9; ALT increase 0.6
	Active surveillance	330	NA	NA	NA	NA	Grade 3/4 AEs: hypertension 0.9; proteinuria 0; platelet count decrease, 1.2; AST increase 0.6; ALT increase 0.9
Unresectable, TACE-eligible
EMERALD-1NCT03778957^69,70	Durvalumab plus bevacizumab plus TACE	154	12.3	80.5	26.6	0	Grade 3/4 AEs: hypertension 5.8; anemia 4.5; acute kidney injury 3.9; proteinuria 3.9; post-embolization syndrome 3.2; hepatic encephalopathy 3.2
	Durvalumab plus TACE	232	3.4	50.4	6.5	1.3	Grade 3/4 AEs: hypertension 2.2; anemia 4.3; acute kidney injury 1.7; proteinuria 0; post embolization syndrome 3.4; hepatic encephalopathy 0.4
	Placebos plus TACE	200	3.0	45.0	6.0	1.5	Grade 3/4 AEs: hypertension 0.5; anemia 1.5; acute kidney injury 0; proteinuria 0; post-embolization syndrome 4.0; hepatic encephalopathy 1.5
LEAP-012NCT04246177^71,72	Pembrolizumab plus lenvatinib plus TACE	237	27.0^c	98.7	69.6	1.7	Hypertension 24.1; platelet count decrease 11.4; AST increase 6.8; lipase increase 5.9; diarrhea 5.5; PPE 5.1
	Placebos plus TACE	241	3.7^c	84.6	31.1	0.4	Hypertension 7.5; platelet count decrease 6.2; AST increase 5.4; lipase increase 0.8; diarrhea 0; PPE 0

Studies are ordered by treatment setting then publication date and the most common TRAEs for the investigational arm and the respective values in the control arm are listed.

Discontinuation of any treatment.

Rate of discontinuation due to any AE: 18.7%.

Rate of discontinuation of both drugs in pembrolizumab plus lenvatinib plus TACE versus placebos plus TACE arms: 8.4% versus 1.2%.

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; G3/4, grade 3 or 4; HCC, hepatocellular carcinoma; NA, not applicable; NCT#, ClinicalTrials.gov identifier; NR, not reported; PPE, palmar-plantar erythrodysesthesia; TACE, transarterial chemoembolization; TRAEs, treatment-related AEs.

What is the direction of ongoing ICI combination research in resectable HCC?

Several questions remain regarding the optimal use of ICI combinations in resectable HCC including impact of the underlying liver disease in recurrence patterns, patient selection, treatment duration, components and sequencing for maximal benefit, and optimal timing of systemic therapy administration (adjuvant and/or neoadjuvant). Adjuvant systemic therapies are designed to prevent recurrence by eliminating residual disease after surgery (due to incomplete resection or microscopic tumor dissemination (“micrometastases”)).^36,74 Although there is currently an unmet clinical need for strategies to prolong RFS in HCC,^{43,44,75–77} a challenge for any adjuvant therapy is the risk not only for true recurrence but also for the ongoing development of de novo tumors due to underlying liver disease. These are reported in up to 30% of patients with an early (⩽2 years) HCC return and are thought to be predominant among late-returning patients.^76,78,79 The predominance of intrahepatic lesions in HCC patients returning after resection^75,80,81 may indicate a strong contribution of underlying liver disease, which could further limit the benefit from adjuvant strategies.⁸² At 3 years of follow-up, half of the patients enrolled in both arms of IMbrave050 had experienced an RFS event and most recurrences were intrahepatic (73.0% vs 68.1% without extrahepatic disease).⁶⁸ An inspection of the RFS curves showed an early separation at 3 months, which occurred at the first radiological assessment after treatment initiation; and the curves began to approximate after maximum separation between 6 and 11 months, which was roughly coincidental with treatment cessation (median treatment duration of ~11 months). However, it is unclear if this indicates a transient benefit in preventing early recurrences given that both atezolizumab and bevacizumab are associated with tumor and microenvironment response patterns that may impact the relationship between radiological parameters and tumor burden.^83–87

In light of the generally promising findings from smaller prospective and retrospective studies of ICI-based adjuvant regimens,^88–94 the lack of significant RFS benefit in the updated analysis of IMbrave050 highlights the need to address questions regarding optimal patient selection,^90,92,93 treatment components (combination^88,89 or single-agent ICI^90–92), and duration of therapy^91,95 required to maximize the benefit–risk ratio. As in other settings, the optimal adjuvant regimen will maintain or improve anti-tumor activity while minimizing toxicity and variceal screening. Ongoing phase III trials investigating other ICI regimens such as KEYNOTE-937 (ClinicalTrials.gov identifier: NCT03867084), CA209-9DX,⁹⁶ ClinicalTrials.gov identifier: NCT04639180, and EMERALD-2 (ClinicalTrials.gov identifier: NCT03847428) will help clarify the role of adjuvant ICIs moving forward.

An increasing number of ongoing trials are now evaluating the effect of neoadjuvant and perioperative strategies, which may be more promising compared to the pure adjuvant approach. Although immune and antiangiogenic activity may still be relevant in the adjuvant setting, immune mechanisms are expected to be less effective relative to a neoadjuvant approach due to removal of the primary source of neoantigens.^56,97 Neoadjuvant use of ICIs has been shown to promote specific immune priming and boosting against tumor antigens which may not only contribute to tumor response prior to surgery but also to clearance of postoperative microscopic tumor remnants.^56,60,97,98 Response to neoadjuvant therapy may enable tumor resection in downstaging strategies, increase the size of the liver remnant after resection in liver-sparing strategies, and provide prognostic information to guide subsequent treatment decisions such as use of adjuvant therapy.^56,97,99 A pooled, cross-trial analysis found that rates of major and complete pathological response predict for significantly longer RFS in HCC patients receiving neoadjuvant ICIs.¹⁰⁰ Phase I–II trials of neoadjuvant and perioperative single-agent and combination ICI regimens generally showed promising results with rates of pathological complete response (CR) and major pathological response ranging from 5.9% to 25% and 17.6% to 33.3% in meta-analysis, respectively.¹⁰¹ More recently, perioperative pembrolizumab and lenvatinib, camrelizumab plus apatinib, and neoadjuvant TACE plus perioperative cadonilimab (a bi-specific antibody against the programmed cell death protein 1 (PD-1) and the cytotoxic T-lymphocyte associated protein 4) also showed promising results with major pathological response rates of 37.8%, 40%, and 46.7%, respectively, in resectable HCC at intermediate-high risk of recurrence.^63,102,103 There is strong rationale to evaluate ICIs in resectable HCC and multiple proof-of-concept studies (such as NeoLEAP-HCC,¹⁰³ ADVANCE HCC (ClinicalTrials.gov identifier: NCT05137899), PRIME-HCC,⁶⁰ and NEOTOMA (ClinicalTrials.gov identifier: NCT05440864)) and phase III trials (ClinicalTrials.gov identifier: NCT05613478 and ZS-ZJ-SK-2020 (ClinicalTrials.gov identifier: NCT04521153)) are currently evaluating ICI regimens in this setting.^98,104

What are the clinical benefits of ICI-antiangiogenic combinations in unresectable, embolization-eligible HCC?

EMERALD-1 assessed the addition of an ICI with or without a VEGF mAb to TACE in embolization-eligible patients with unresectable HCC.^69,70 This phase III trial enrolled patients with therapy-naïve, early to advanced stage HCC (BCLC-A/B/C 26%/57%/16%) without tumor thrombi in the first branch of the portal vein or in the main portal trunk, and with preserved liver function (Child-Pugh A/B7 98%/2%). Participants were randomized to durvalumab plus bevacizumab (n = 204), durvalumab plus placebo (n = 207), or placebos (n = 205) following initiation of conventional (59.1%) or drug-eluting bead (40.9%) TACE. TACE procedures were completed in a maximum of four sessions during 16 weeks and most patients received up to two sessions (63%). Administration of single agent durvalumab started 1 week after the first TACE session and was followed by durvalumab plus bevacizumab starting at least 14 days after the last TACE session (a median of 14 weeks after the first) and continued until progressive disease or other treatment discontinuation criteria.

At a median follow-up of 27.8 months in the combination arm, treatment with TACE plus durvalumab and bevacizumab was associated with a statistically significant increase in the primary endpoint of median progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 relative to TACE alone (15.0 vs 8.2 months, HR 0.77, 95% CI 0.61–0.98, p = 0.032; Table 1).⁷⁰ PFS benefit with TACE-durvalumab–bevacizumab was generally consistent across subgroups and with analysis according to modified RECIST (mRECIST) criteria. No PFS improvement was observed with TACE-durvalumab compared to TACE alone (median PFS 10.0 vs 8.2 months, HR 0.94, 95% CI 0.75–1.19, p = 0.64) after 30.3 months of median follow-up in this investigational arm. Analysis of the secondary endpoint of time to progression (TTP) revealed a 12-month improvement in median TTP with TACE-durvalumab–bevacizumab (22.0 vs 10.0 months, HR 0.63, 95% CI 0.48–0.82) that was greatly diminished with TACE-durvalumab (11.5 vs 10.0 months, HR 0.89, 95% CI 0.69–1.15). Although the overall response rate (ORR) was improved relative to the control arm in both the TACE-durvalumab–bevacizumab (43.6% vs 29.6%, odds ratio (OR) 1.87) and TACE-durvalumab (41.0% vs 29.6%, OR 1.67) arms, a longer median duration of response (DoR) was only observed with TACE-durvalumab–bevacizumab (22.1 vs 16.4 months). Survival data remain immature. Rates of grade 3/4 TRAEs and of discontinuation of any treatment due to TRAEs were higher in the TACE-durvalumab–bevacizumab relative to TACE-durvalumab and TACE arms (26.6% vs 6.5% vs 6.0% and 12.3% vs 3.4% vs 3.0%, respectively; Table 2). Rates of death due to TRAEs were ⩽1.5% across arms (0%, 1.3%, and 1.5%, respectively). While rates of grade 3/4 AEs possibly associated with TACE were similar across arms (8.4% vs 9.1% vs 8.5%), rates of grade 3/4 AEs possibly related to durvalumab/bevacizumab (or respective placebos) were higher in the durvalumab–bevacizumab combination arm compared to TACE-durvalumab and TACE arms (15.5%/18.8% vs 5.2%/3.0% vs 5.0%/4.0%). The most frequent grade 3/4 AEs observed with TACE-durvalumab–bevacizumab (vs TACE-durvalumab vs TACE) were hypertension (5.8% vs 2.2% vs 0.5%), anemia (4.5% vs 4.3% vs 1.5%), acute kidney injury (3.9% vs 1.7% vs 0%), proteinuria (3.9% vs 0% vs 0%), post-embolization syndrome (3.2% vs 3.4% vs 4.0%), and hepatic encephalopathy (3.2% vs 0.4% vs 1.5%).

LEAP-012 assessed the addition of an ICI plus the TKI lenvatinib to TACE in embolization-eligible patients with unresectable HCC.^71,72 This phase III trial enrolled patients with early to advanced stage HCC (BCLC-0-A/B/C 31%/59%/10%) without portal vein thrombosis or extrahepatic disease, and with good liver function (Child-Pugh A 100%). Participants were randomized to treatment with pembrolizumab plus lenvatinib (n = 237) or respective placebos (n = 243) for up to 2 years. A maximum of two TACE treatments per tumor (four total) were allowed and vast majority of patients (94%) were treated in up to two procedures. In contrast to EMERALD, systemic treatment with both drugs was started before the first TACE.

At a median follow-up of 25.6 months, treatment with TACE plus pembrolizumab and lenvatinib was associated with a statistically significant increase in the co-primary endpoint of median PFS by BICR per RECIST 1.1 relative to TACE alone (14.6 vs 10.0 months, HR 0.66, 95% CI 0.51–0.84, p = 0.0002; Table 1). RECIST 1.1 was amended in this study to allow up to five target lesions and to meet Liver Imaging Reporting and Data System (LI-RADS) 5 for new intrahepatic lesions; results from PFS analyses according to other criteria (without LI-RADS 5 modification and by mRECIST) were consistent with those of the primary endpoint. Results from prespecified subgroup analyses of PFS were consistent with those for the overall population. Median TTP was improved with the addition of pembrolizumab and lenvatinib to TACE (16.6 vs 10.3 months, HR 0.59, 95% CI 0.46–0.77, p < 0.0001).^71,105 While ORR was significantly improved relative to the control arm (46.8% vs 33.3%, ∆14.6%, p = 0.0005), the impact on median DoR was not that apparent (12.6 vs 10.7 months). Data for the second co-primary endpoint of OS were still immature at the time of the analysis with the experimental arm associated with a favorable yet non-statistically significant risk reduction in survival (2-year OS rate: 75% vs 69%; HR 0.80, 95% CI 0.57–1.11, p = 0.087). Rates of discontinuation of any systemic therapy due to TRAEs were substantially higher with TACE-pembrolizumab–lenvatinib relative to TACE (27.0% vs 3.7%; Table 2). Frequency of grade 3/4 TRAEs and deaths due to TRAEs were also higher in the combination arm (69.6% vs 31.1% and 1.7% vs 0.4%, respectively).⁷¹ The most frequent grade 3/4 TRAEs observed with TACE-pembrolizumab–lenvatinib (vs TACE) were hypertension (24.1% vs 7.5%), platelet count decreased (11.4% vs 6.2%), increased aspartate transaminase levels (6.8% vs 5.4%), increased lipase (5.9% vs 0.8%), diarrhea (5.5% vs 0%), and palmar-plantar erythrodysesthesia (5.1% vs 0%).

EMERALD-1 and LEAP-012 trials are the first large phase III trials of TACE and systemic therapy combinations to meet the primary endpoint of PFS.^69–72 The addition of ICI-antiangiogenic combinations produced statistically and clinically significant reductions in risk of progression or death of 23% and 34% and improvement in median PFS of 6.8 and 4.6 months, respectively. There were also numerical increases in key safety measures such as rates of discontinuation of any treatment due to TRAEs (12.3% vs 3.0% and 27.0% vs 3.7%, respectively; Table 2), although the longer duration of experimental treatment in both trials (13.8 vs 8.7 months and 12.4 vs 8.4 months, respectively) may account for some of the increased toxicity as evidenced by the lower exposure-adjusted event rates in the TACE-durvalumab–bevacizumab arm of EMERALD-1 (67.6 vs 81.8 per 100 person-years). Rates of death due to TRAEs were below 2% across both trials (0% vs 1.5% and 1.7% vs 0.4%, respectively). A recent exploratory safety analysis by treatment period from EMERALD-1 suggested that a fraction of all AEs were provoked by TACE during the TACE-durvalumab (37.3%–46.6%) and durvalumab–bevacizumab (8.3%–10.5%) periods.¹⁰⁶ In the absence of mature OS data and given the weak-to-moderate correlation between progression endpoints and OS in unresectable HCC,^107–109 PFS delays should be carefully weighed against the increased risk of toxicity associated with ICI combinations.

Significant differences in patient survival would clearly prove clinical benefit, however, is important to consider that attainment of that endpoint in the palliative setting is challenged by limited statistical power and the possibility of multiple lines of subsequent treatment. While EMERALD-1 was not powered to assess OS,^69,70 LEAP-012’s study size was reduced by almost half relative to the initial design where a sample size of ~950 was calculated to achieve 90% power for OS at 5 years.^71,110 It is well established that post-progression therapies greatly influence survival,^111,112 and since there are now multiple treatment options with established benefits in the advanced setting, it is also important to consider whether sequential rather than combination locoregional-systemic strategies offer comparable outcomes with a more favorable safety profile. Data from LEAP-012 show that most of the trial-eligible patients receiving subsequent treatment (n = 114 vs n = 142) were treated with liver-directed therapies in both arms (82.5% vs 79.6%), with LRT being the most common treatment modality (73.7% vs 73.2%).^71,72,105 Close to half of these patients were treated with second-line systemic regimens (47.4% vs 53.5%), with an apparent reduction in the percentage of those receiving second-line ICI-based regimens in the experimental arm (22.8% vs 33.1%). Although the same level of detail is not available from EMERALD-1, intrahepatic lesions were the most common pattern of progression¹¹³ and is therefore possible that, similar to LEAP-012, liver-directed therapies were the most common subsequent treatment choice.

Regimens that can produce substantial and durable tumor responses can expand the scope of treatment choices including the possibility for curative-intent treatment after successful downsizing.^11,12 Conversion to curative-intent treatment (resection/ablation or LT) with ICI-containing regimens has been recently shown in multiple small, prospective, and retrospective studies.^52–58 Recently, the use of TACE-ICI-bevacizumab combinations led to a notable surgical conversion rate of 22.6% in a retrospective study.⁵⁷ Although surgical conversion rates were not formally assessed in EMERALD-1 and LEAP-012,^69–72 subsequent therapy analyses showed an increased proportion of patients that were treated with curative-intent procedures (surgery, ablation, or transplant) after TACE-ICI combinations compared to TACE alone (28.6%/30.7% vs 21.0% and 13.2% vs 8.5% of those receiving any subsequent treatment in each arm and trial, respectively).^70–72 Efficacy analyses from both trials showed significant net improvements in ORR of 14% and 14.6% with TACE-durvalumab–bevacizumab and TACE-pembrolizumab-lenvatinib, respectively; however, CR rates per RECIST 1.1 were low across arms of both trials (3.0% vs 1.5% vs 2.5% and 3.4% vs 4.1%, respectively).^69–72 Compared to RECIST 1.1, analysis per mRECIST¹¹⁴ in LEAP-012 showed higher rates of overall (71.3% vs 49.8%) and complete response (56.1% vs 33.7%) across both arms and larger improvements associated with the addition of pembrolizumab–lenvatinib to TACE (∆ORR 21.0% (p < 0.0001) and ∆CR rate 22.4%).^71,72 These differences have the potential to be clinically relevant. mRECIST was developed to improve the assessment of tumor response to molecular-targeted therapies and differs from RECIST 1.1 in that only the contrast-enhanced portion of the target lesion is measured.^114,115 The differences between RECIST 1.1 and mRECIST assessments in LEAP-012 are consistent with other studies^86,115–117 and further demonstrate the impact that necrotic areas can have on evaluation of tumor response. A recent meta-analysis found that ORR per mRECIST was a better prognostic factor for OS compared to ORR per RECIST 1.1 (HR 0.56 (p = 0.0004) vs HR 0.68 (p = 0.08)).¹¹⁵ However, additional studies are needed to clarify the optimal response assessment criteria for molecular-targeted therapy in HCC and the impact of CRs according to different criteria on subsequent treatment options.^86,118,119 Future trials of ICI regimens in unresectable HCC should consider multiple response criteria and formal assessment of curative conversion rates.

As ICI regimens are the standard of care in first-line treatment of advanced HCC, the optimal treatment following progression in patients initially treated with ICI combinations in earlier settings is currently unclear. Evidence to guide treatment sequencing is lacking even in advanced settings where most of the data on second- or higher-line systemic therapies is in the context of sorafenib pretreatment.^120,121 In the absence of strong evidence and clear guidelines, treatment selection for patients previously treated with ICI regimens should follow general treatment sequencing principles. Selection should be informed by demonstrated survival benefit following progression on initial systemic therapy, TRAE risk, therapies and types of therapy previously received (and respective tumor response), liver function status, and eligibility criteria to the pivotal trials that assessed therapies being considered for subsequent treatment.^12,37,122 Data available from phase III trials of ICI regimens in non-advanced settings^68,70–72 suggest that early initiation of systemic therapy does not preclude subsequent treatment with liver-directed therapies and these should be considered according to established eligibility criteria. Curative-intent strategies should be prioritized whenever possible with consideration for the potential of curative conversion following extensive clinical responses to ICI regimens.^123,124

What is the direction of ongoing ICI combination research in unresectable, embolization-eligible HCC?

The use of ICI combinations in unresectable, embolization-eligible HCC may be optimized with improvements in embolization techniques and systemic therapy administration, including treatment timing, components, duration, and sequencing. Current embolization studies can benefit from the experience from LAUNCH,¹²⁵ TACTICS,^50,126 and TACTICS-L¹²⁷ trials which provided a template for successful combination of TACE and systemic agents with preferential use of super-selective TACE on an on-demand schedule (which minimizes hepatotoxicity)^{28,29,128,129} and upfront administration of clinically-active systemic agents. This schedule has the potential to maximize synergies between TACE and ICI plus antiangiogenic therapy (involving immune boosting/priming and vascular changes)²⁹ and therefore improve the feasibility and efficacy of embolization strategies.^28,29 In unresectable, TACE-eligible HCC, TACTICS was the first RCT to meet the co-primary endpoint of TACE-specific PFS with the addition of a systemic agent (sorafenib) to TACE.^28,126 Systemic therapy in TACTICS, EMERALD-1, and LEAP-012 was administered continuously and for longer (median duration of treatment 8.9–13.8 months)^50,69–71 compared to other RCTs of systemic-TACE combinations (only 3.9–4.8 months).^12,45,130

In both LEAP-012 and TACTICS, systemic therapy was initiated before TACE while in EMERALD-1 patients received single-agent durvalumab following the first TACE procedure and combined ICI-antiangiogenic therapy only started after completion of all TACE sessions. Inspection of the PFS curves from both EMERALD-1 and LEAP-012 suggests that timing of combined ICI-antiangiogenic therapy initiation may impact disease progression. In EMERALD-1, PFS curves only began separating at approximately 2 months after the addition of bevacizumab to single-agent durvalumab (at 5–6 months of follow-up) while separation occurred at the first radiographic assessment in LEAP-012 (at 9 weeks or approximately 2 months) where systemic therapy was initiated with combined pembrolizumab–lenvatinib treatment.^69–72 The impact of the systemic components was also apparent on the overall trial outcomes from EMERALD-1, with only the TACE-durvalumab–bevacizumab combination showing significant differences in the primary endpoint of PFS and in the secondary endpoints of TTP and DoR.^69,70 Multiple prospective and retrospective studies have now reported promising outcomes for TACE-ICI-antiangiogenic combinations in unresectable HCC,^131–136 and the recent CARES-005 RCT showed a statistically-significant and clinically-meaningful improvement in median PFS (10.8 vs 3.2 months; HR 0.34, p < 0.0001) with addition of camrelizumab plus apatinib to conventional TACE,¹³⁷ further supporting the initial positive results from EMERALD-1 and LEAP-012.

Several of these questions are being addressed in ongoing trials comparing ICI regimens to embolization (REPLACE and ABC-HCC; Clinical Trials.gov identifiers: NCT04777851 and NCT04803994), and combining ICIs with antiangiogenic agents and TACE (EMERALD-3 (ClinicalTrials.gov identifier: NCT05301842), IMPACT, and TALENTACE).^138,139 ICIs have also the potential to synergize with other LRTs, for example, by enhancing the abscopal effect observed with radiotherapy and thermoablation, which is thought to result from systemic immune responses induced by these therapies.^140–142 This approach is under evaluation in trials combining ICIs with Yttrium-90-TARE or stereotactic body radiation therapy (IMMUWIN, ROWAN, EMERALD-Y90, STRATUM, and others; ClinicalTrials.gov identifiers: NCT05582278, NCT06040177, NCT05377034, NCT04913480, NCT04522544, and NCT06040099)¹⁴³ in unresectable, embolization-eligible patients.

Liver function and hepatotoxicity

One of the main treatment goals of HCC involves treating the tumor and underlying liver disease while preserving liver function.^144,145 Due to its prognostic and clinical importance,^146,147 liver function is an integral component of HCC staging systems^11,148 and should be assessed regularly using Child-Pugh or albumin-bilirubin score.^3,44,149 HCC development can be a risk factor for liver decompensation^144,150 and HCC treatment has the potential to positively impact liver function by reducing tumor burden, delaying recurrence or progression or, more directly, by increasing liver remnant volume after resection in neoadjuvant approaches.^56,104 However, the use of systemic and locoregional therapies is often associated with some degree of hepatotoxicity, requiring careful balancing between benefits and harms. Liver decompensation may not only occur due to the natural progression of the underlying liver disease but also as a symptom of tumor progression or as a side effect of systemic and locoregional treatment^144,151 and is a relevant limiting factor in administration of subsequent therapies in intermediate-to-advanced HCC.¹⁵² Hepatic decompensation and HCC progression were the strongest predictors for worse survival (HRs of 19.04 and 9.91, respectively) in advanced HCC patients treated with first-line atezolizumab–bevacizumab in the AB-real observational study.¹⁵³

Chemoembolization is associated with hepatic AEs such abnormal levels of hepatic markers, ascites, and encephalopathy resulting from liver inflammation and cytotoxicity that are directly or indirectly induced by treatment. Although most of these events are reversible, substantial rates of irreversible liver damage (around 15%–25%) have been reported in retrospective cohort and observational studies.^153–156 ICI-containing regimens are also associated with hepatotoxicity arising from inflammatory and autoimmune mechanisms and occurring most commonly in the form of elevated transaminases.^157,158 In EMERALD-1 and LEAP-012, addition of ICI-antiangiogenic combinations to TACE showed comparable or slightly higher rates of grade 3/4 increase in AST (0.6% vs 0.5% and 6.8% vs 5.4%), ALT (1.3% vs 1.0% and 4.6% vs 4.1%), and blood bilirubin (0% vs 0% and 3.8% vs 1.7%) levels, hepatic encephalopathy (3.2% vs 1.5% and 1.7% vs 0%) and cirrhosis (1.3% vs 0% and 0.4% vs 0%), ascites (2.6% vs 1.5% and NR vs NR), liver abscess (0.6% vs 0% and 0.8% vs 2.1%), and abnormal hepatic function (0% vs 0.5% and 0.4% vs 0.4%).^70,71 Rates of discontinuation due to any AE in IMbrave050, EMERALD-1, and LEAP-012 were relatively high (18.7%, 27.9%, and 33.3%, respectively),^36,68,70,71 indicating a need to improve tolerability of ICI-antiangiogenic regimens. Moreover, all or nearly all discontinuation events due to AEs involved discontinuation of the anti-VEGF(R) component and AEs commonly associated with antiangiogenics (e.g., hypertension and proteinuria) were among the most common any-grade and grade 3/4 AEs, a finding that is supported by results from meta-analysis of ICI-antiangiogenic studies across different solid tumors.¹⁵⁹ The use of ICI-antiangiogenic regimens should ideally be performed in collaboration with hepatologists to minimize hepatic AE risk, improve AE management, and ensure safe administration. Is also important to note that treatment selection in patients with poor liver function (Child-Pugh B/C) is particularly challenging due to the lack of validated treatment options as large, well-conducted RCTs often exclude these patients and systemic therapy is avoided due to safety concerns.^145,151

Portal hypertension is a major driver for complications from advanced chronic liver disease (ACLD) such as ascites, esophageal or gastric varices, and hepatic encephalopathy. Hepatic decompensation and clinically significant portal hypertension (CSPH) have been identified as major prognostic factors in ACLD patients.^160–164 Monitoring and management of portal hypertension need to be implemented in the care of HCC patients due to the risk of life-threatening variceal bleeding and is becoming increasingly important with longer HCC survival and use of agents that may increase bleeding risk (e.g., bevacizumab).^160–163 Currently available guidance recommends assessment of CSPH in ACLD patients with liver stiffness measurement (LSM) by transient elastography combined with platelet count on a yearly basis.^160,163,165 The recent Baveno VII consensus has established β-blocker prophylaxis as the primary strategy to manage risk of variceal bleeding in ACLD patients with CSPH (LSM >25 kPa), with a reduction of indications for endoscopic screening and monitoring of variceal status.^160,163,166 In interpreting results from CSPH assessments and applying Baveno guidance to HCC patients is important to consider that the presence of liver tumors may impact elastography and platelet level measurements.¹⁶⁰ Modifications to Baveno recommendations have been proposed for HCC patients, including that screening endoscopy is still advisable in those with favorable Baveno criteria (platelets >150,000/μl and LSM <20 kPa).^{35,160,165,167} However, recent retrospective studies suggest that the need for endoscopic assessment may be substantially reduced by using clinical and imaging variables to rule out high-risk varices,^168,169 and that a selective approach to esophagogastroduodenoscopy screening does not appear to adversely affect treatment outcomes or increase the risk of gastrointestinal bleeding in HCC patients treated with atezolizumab–bevacizumab.¹⁷⁰

Management of hepatitis B and C virus (HBV and HCV) infection and other causes of liver chronic liver diseases (e.g., alcohol abstinence and control of metabolic risk factors) and their complications can have positive effects on patient survival by improving liver function and should be considered as part of early treatment strategies.^44,171 Data from multiple RCTs and large, multicenter studies in HBV- or HCV-associated HCC show that direct-acting antiviral therapy following successful treatment of early HCC does not negatively impact the risk of recurrence and can improve survival.^172–177 Effective antiviral treatment has also been shown to potentially protect from liver decompensation in patients with viral etiology treated with systemic therapy in the advanced setting^146,178 and is recommended for patients with chronic HBV infection receiving immunosuppressive or cytotoxic cancer treatments^179–184 and following complete tumor resection or ablation in HCC patients with HBV or HCV infection.^185–187

Summary

Phase III trials assessing ICI combinations in non-metastatic HCC settings have reported event-free-survival primary endpoints. In unresectable, embolization-eligible HCC, combinations of ICI and antiangiogenic agents with TACE significantly improved PFS in EMERALD-1 and LEAP-012 trials, however, mature OS data are required to confirm benefit and recommend their use outside clinical trials. The updated analysis of the IMbrave050 trial failed to demonstrate continued RFS benefit with atezolizumab–bevacizumab in resected HCC and adjuvant treatment with this regimen cannot be recommended. As the use of ICI combinations in earlier settings continues to evolve, questions regarding timing, sequencing, and duration of therapies in relation to LRT will need to be addressed and additional research will be required to optimize ICI combination use in perioperative and peri-embolization settings.

Supplemental Material

sj-docx-1-tam-10.1177_17588359251357719 – Supplemental material for Role of immune checkpoint inhibitor combinations in resectable and unresectable, embolization-eligible hepatocellular carcinoma

Supplemental material, sj-docx-1-tam-10.1177_17588359251357719 for Role of immune checkpoint inhibitor combinations in resectable and unresectable, embolization-eligible hepatocellular carcinoma by Brandon M. Meyers, Howard J. Lim, Mayur Brahmania, Dave M. Liu, Vincent C. Tam, Deanna McLeod, Ravi Ramjeesingh, Jennifer J. Knox and Arndt Vogel in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

We would like to thank Ilidio Martins and Akhil Padmanabhan from Kaleidoscope Strategic Inc. for their research and editorial support.

Declarations

ORCID iD

Deanna McLeod

Supplemental material

Supplemental material for this article is available online.

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