Systemic treatment paradigms for unresectable and advanced hepatocellular carcinoma in Europe

Summary

The management of unresectable and advanced hepatocellular carcinoma (HCC) has been transformed by the introduction of immune checkpoint inhibitor-based combinations, which have improved response and survival and expanded first-line treatment options. The availability of multiple effective regimens has introduced new challenges in therapeutic decision making. In the absence of validated predictive biomarkers or head-to-head comparisons, first-line treatment selection remains largely guided by clinical characteristics, contraindications and anticipated toxicity, while the optimal sequencing of therapy following first-line immunotherapy remains uncertain. Locoregional therapies continue to play an important role in selected patients with liver-confined disease, further broadening the range of therapeutic strategies available in clinical practice. In Europe, these evolving treatment paradigms are implemented within a heterogeneous landscape of regulatory approval, reimbursement and access, resulting in important differences in care across countries. In this Series paper, we discuss contemporary systemic treatment strategies for HCC from a European perspective, focusing on treatment selection and sequencing, the role of predictive biomarkers and locoregional therapies, and disparities in access to effective treatments. Generating prospective evidence to inform treatment selection and sequencing, while ensuring more timely and equitable access to effective therapies will be essential to optimise HCC care across Europe.

Introduction

Systemic anti-cancer therapy has traditionally played a modest role in the management of patients with hepatocellular carcinoma (HCC).

In stark contrast to the majority of malignancies, patients with HCC remained deprived of effective systemic therapy options until publication of the SHARP and Asia-Pacific trials in 2007,¹ which afforded sorafenib the role of global and unchallenged systemic option for over a decade.

The use of tyrosine kinase inhibitors (TKIs) progressively expanded over the years to include lenvatinib,² a non-inferior option to sorafenib in first-line. A number of effective second-line options, including regorafenib,³ cabozantinib⁴ and the anti-Vascular Endothelial Growth Factor receptor-2 (VEGFR-2) antibody ramucirumab in patients with alpha-fetoprotein (AFP) levels ≥400 ng/mL⁵ were established post sorafenib use.

Whilst judicious, sequential use of first- and second-line TKIs enabled a significant improvement in patients’ overall survival (OS) previously not seen in HCC, the predicted life-expectancy of patients treated with first-line systemic therapy during the TKI era rarely exceeded 12–13 months.⁶ Progressive liver dysfunction and emerging clinical decompensation, alongside challenges in long-term tolerance to TKIs, became evident limitations to the achievement of long-term survivorship from molecularly targeted therapies, exposing the need for novel mechanisms of actions to enter the clinical arena.

The development of immune checkpoint inhibitors (ICI), as monotherapy in first-line and in second-line, failed to demonstrate superiority to sorafenib in prospective randomised phase III studies.^7,8 Immunotherapy combinations through inhibition of programmed cell death-1 (PD-1) pathway and VEGF or cytotoxic T-lymphocyte antigen 4 (CTLA-4) quickly revolutionized the treatment landscape by improving the OS of patients with unresectable-advanced HCC from a median of 6 months in the absence of treatment to estimates ranging between 16 and 23 months in contemporary phase III clinical trials.⁹ This was also associated with improvements in response and safety profile, translating in improvement in Quality of Life (QoL).

Whilst positive improvements from phase III clinical trials have been largely reproduced in routine practice,10, 11, 12 fundamental areas of uncertainty persist in planning care of patients with unresectable-advanced HCC. All novel therapeutic combinations have been tested against historical standards of care, mostly sorafenib. In absence of reliable biomarkers of therapeutic benefit, choice of each individual treatment remains to this day a largely empirical exercise, often guided by predicted risk of toxicity (i.e., bleeding risk or immunotoxicity) as well as patient’s preference.¹³ In addition, therapeutic sequencing beyond first-line remains unsupported by strong level I evidence, leaving significant uncertainty as to how to best manage patients who achieve a sustained response to immunotherapy, oligoprogression, as well as those who progress following initial exposure to systemic therapy.¹⁴

In Europe, significant heterogeneity exists in the approval and reimbursement process of anti-cancer medicines. The European Medicines Agency (EMA) works closely with all 27 European Union member states and three European Economic Area states including Iceland, Liechtenstein and Norway. Prospective marketing authorization holders for cancer medicines are mandated by EMA to follow a central approval process leading to a single EU-wide authorization in accordance with European Council Regulation No 2309/93, applicable since 1995. However, national human medicines regulatory agencies (National Competent Authorities, NCAs) retain authority to ultimately permit marketing in the different EU countries. Switzerland and, since 2021 the United Kingdom, retain independent standalone regulatory agencies for medicines regulation: Swissmedic and the Medicines and Healthcare products Regulatory Agency (MHRA) respectively.

In many European countries, a separate process of value-based health technology assessment (HTA), needs to be conducted before novel therapies are adopted into national formularies and reimbursed for routine patient use. HTA assessment of novel therapies is led at a country-level by independent executive public bodies or agencies such as, for instance, the Institute for Quality and Efficiency in Health Care (IQWiG, Germany), the Haute Autorite’ de Sante’ (HAS, France), the National Institute for Health and Care Excellence (NICE, UK) or the Swiss Federal Office of Public Health (FOPH). Whilst there are methodological commonalities to HTA assessment procedures across European countries, with each independent body being tasked to evaluate clinical efficacy, safety, cost-effectiveness, social consequences and ethical considerations from the introduction of new therapies in the respective healthcare ecosystem, significant heterogeneity exists with regard to the thresholds set to define adequate value for money for each new intervention. Furthermore, some countries can offer early-access programs with evaluation from their health authorities, other should rely on early-access trials supported by the pharmaceutical companies. Reference standards to define comparison against current best practice may also vary and timelines required for evaluation and approval may also be heterogeneous across countries, leading to a lag between drug approval and reimbursement.

In this series article, we describe systemic treatment paradigms in Europe and portray main sources of heterogeneity in therapeutic decision-making and delivery of routine clinical care for patients with unresectable/advanced HCC. In addition, we aim to highlight disparities in approval and reimbursement timelines for novel therapeutic options for patients with unresectable-advanced HCC and discuss how to overcome challenges in the access to novel therapies, address inequalities and gaps in knowledge that may improve the current landscape.

Key messages.

• •Systemic therapy for unresectable-advanced HCC has improved since the initial approval of sorafenib two decades ago.
• •Reimbursement pathways and adoption of novel systemic anti-cancer therapies vary across European countries and alternative treatment paradigms including loco-regional therapy in selected cases of primarily unresectable HCC are commonplace in routine practice, despite lack of solid randomised evidence against novel immunotherapy combinations.
• •Whilst heterogeneity in practice is accepted and often reflects local epidemiology and reimbursement challenges, the various stakeholders and government bodies involved in planning and delivering care plans for patients with HCC should continue to overcome disparities in access to care.

Search strategy and selection criteria.

We searched PubMed (MEDLINE), conference proceedings, EMA official website and FDA official website to identify evidence on systemic treatments available in Europe for hepatocellular carcinoma and reimbursement data and disparities in access across different countries, with a focus on European Union countries and the United Kingdom. When not publicly available, information on local reimbursement was requested by email to pharmaceutical companies holding marketing authorisation for each drug. Searches covered materials published from 2006 until 2026 using as search terms “hepatocellular carcinoma”, “treatment”, “systemic therapy”, “locoregional therapy”, “biomarkers” and “reimbursement”. Only materials available in English were reviewed. All extracted information underwent verification by authors practicing medicine in countries of interest. The final reference list was generated by author-driven selection based on originality and relevance to the broad scope of this Series paper.

Systemic treatment options in unresectable-advanced HCC in first-line: a European perspective

Immune-checkpoint inhibitor combinations are now the preferred systemic treatment in suitable patients with advanced HCC. Four landmark phase III clinical trials have proven the superiority of combination immunotherapy to TKIs for unresectable-advanced HCC. Although these phase III trials established potential new standards of care, differences in patient population including aetiology of liver disease, macrovascular invasion inclusion and stage together with differences in the TKI control arm should be noted, highlighting the need for a personalised approach (Table 1 and Supplementary Table 1).^2,15,16,23, 24, 25, 26, 27, 28, 29 The IMbrave150 trial randomized patients 2:1 to receive atezolizumab plus bevacizumab (A + B) or sorafenib, and established superiority of A + B, challenging standards of care for systemic therapy for the first time in 2019.²⁴ Asian patients (excluding Japan) represented 40% of those enrolled and over 80% of patients had documented BCLC C HCC. All patients were required to have a baseline endoscopy to assess varices and 26% of those treated had evidence of varices at baseline. The median PFS was 6.8 months compared to 4.3 months (HR 0.59; 95% CI, 0.47 to 0.76; P < 0.001) and 12-month OS was 67.2% versus 54.6%. Objective response rate (ORR) was also superior for A + B (30%) compared to sorafenib (11%), leading A + B to become the first immunotherapy regimen to be adopted for the treatment of patients with unresectable/advanced HCC and Child-Pugh A liver function.²⁵ In an updated survival analysis median OS achieved with A + B was 19.2 months compared to 13.4 months for sorafenib (HR 0.66).

Table 1.

Key phase III trials of first-line systemic therapy for unresectable-advanced HCC.

	SHARP (sorafenib)15	REFLECT (lenvatinib)2	IMbrave150 (A + B)16,17	HIMALAYA (D + T)18, 19, 20	CheckMate 9DW (I + N)21	CARES-310 (camrelizumab + rivoceranib)22
Number of patients (experimental/control)	299/303	478/476	336/165	393/389	335/333	272/271
Control arm	Placebo	Sorafenib	Sorafenib	Sorafenib	Sorafenib (15%)/lenvatinib (85%)	Sorafenib
Asian population, % (experimental/control)	0/0	321/319f	40/41	39.7/40.1	42/46	83/83
Primary endpoint	OS, time to symptomatic PDb	OS (non-inferiority)	OS, PFS (BICR)	OS for D + T versus sorafenib	OS	PFS (BICR), OS
Median OS (months)	10.7	13.6	19.2	16.43	23.7	23.8
OS: HR (95%CI)	0.69 (0.55–0.87)	0.92 (0.79–1.06)	0.66 (0.52–0.85)	0.76 (0.65–0.89)	0.79 (0.65–0.96)	0.64 (0.52–0.79)
1-year OS rate, %	44	NR	67	NR	NR	77
18-month OS rate, %	NR	NR	52	48.7	NR	NR
2-year OS rate, %	NR	NR	NR	40.5	49	49
5-year OS rate, %	NR	NR	NR	19.6	NR	NR
Median PFS (months)	5.5c	7.3	6.9	5.4	9.1	5.6
PFS: HR (95%CI)	0.58c (0.45–0.74)	0.64 (0.55–0.75)	0.65 (0.53–0.81)	0.90 (0.77–1.05)	0.87 (0.72–1.06)	0.54 (0.44–0.67)
ORR, %	2a	18.8	30	20.1	36	27
CR, %	0	<1%	8	3.1	7	1.8
PR, %	2	18	22	17	29	25
SD, %	71	54	44	39.9	32	51.1
DCR, %	43	72.8	74	60.1	68a	77.9
PD, %	27a	18	19	39.9a	20	16.5
Median DOR, months (range)	NR	NR	18.1 (2.5–25.6)	22.34 (8.54–not reached)	30.4	17.5
Safety	N = 297	N = 476	N = 329	N = 388	N = 332	N = 272
G3-4 TRAEs, %	NRd	57	43	25.8	41	81
G3-4 irAEs, %	N/A	N/A	NR	12.6	28	17
Led to discontinuation of ≥1 study medication, %	11	9	22	8.2	18	37.5
Led to death, %	NRe	2	2	2.3	4	<1
High dose steroids, %	N/A	N/A	NR	20.1	29	16
Median time to deterioration of QoL versus control, months	NR	NR	11.2 versus 3.6	7.5 versus 5.7	2.6 versus 2.1	11.2 versus not reached

A + B, atezolizumab + bevacizumab; AEs, adverse events; BICR, blinded independent central review; CI, confidence interval; CR, complete response; D + T, durvalumab + tremelimumab; DCR, disease control rate; DOR, duration of response; G, grade; HR, hazard ratio; I + N, ipilimumab + nivolumab; irAEs, immune-related adverse events; N/A, not applicable; NR, not reported; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; QoL, quality of life; SD, stable disease.

^aNot reported but calculated from available data.

^bTime to symptomatic PD did not differ between sorafenib and placebo (4.1 versus 4.9 months; HR 1.08; 95% CI, 0.88–1.31; P = 0.77).

^cCalculated as time to radiologic progression.

^dNo cumulative rate of G3 TRAEs is reported; the most common ones were hypophosphatemia (11%), diarrhea and hand-foot skin reaction (both at 8%). No G4 TRAEs were reported.

^e13 deaths were not related to PD.

^fAsia-Pacific.

Furthermore A + B improved pre-specified QoL scores.²⁴ The number of adverse events are summarised in Table 1; of note in this study there were six grade 5 bleeding events in the A + B arm (one attributed to study treatment) compared to 1 in the sorafenib arm. The increased bleeding risk associated with bevacizumab and the need for endoscopy should be a consideration in the choice of first line therapy.

In 2022, the HIMALAYA study reported the superiority of the durvalumab plus tremelimumab (D + T or STRIDE) combination against sorafenib, evaluating in parallel durvalumab monotherapy to assess contribution of components. The study was not designed to compare the STRIDE versus durvalumab arm. Similarly, 40% of patients included in the HIMALAYA trial were Asian and 80% of patients had BCLC C HCC. Notably this trial excluded patients with main portal vein thrombus. A single dose of tremelimumab plus durvalumab monthly was associated with improved median OS against sorafenib (16.4 versus 13.8 months; HR 0.78),²⁶ leading to the first approval of a dual ICI combination in patients with unresectable/advanced HCC in Europe. Despite the improvement in median OS there was no difference in median PFS between D + T and sorafenib (HR 0.90). The number of treatment related AEs were similar in the STRIDE and sorafenib arms and improvements in QoL measures were also observed.²⁷ Importantly exploratory analyses of the HIMALAYA dataset confirmed a durable survival benefit in a subset of patients, with 5-year OS rates of 19.6%, compared to 9.4% for sorafenib, corresponding to an absolute difference of 10.2 percentage points.²⁸ The reporting of landmark analyses and the separation of the survival curves is clinically important in ICI trials; the identification of biomarkers to predict these patients will be important in future studies but as yet remains unclear.

A third landmark trial, the CheckMate-9DW phase III study, provided further evidence of benefit of dual ICI therapy with ipilimumab plus nivolumab (I + N) induction (up to 4 cycles) followed by nivolumab maintenance in patients with unresectable HCC. The comparator arm included lenvatinib (in 85% of participants) or sorafenib. Lenvatinib has documented higher ORR and longer PFS compared to sorafenib but was non-inferior for OS in the REFLECT trial,² but should be considered given the performance of the control arm in CheckMate-9DW. Moreover 26.6% of patients included had BCLC A/B disease reflecting a higher number of patients with earlier stage HCC. OS was improved with I + N versus investigator-choice TKIs (median OS 23.7 versus 20.6 months; HR 0.79) and ORR was significantly superior with I + N (36% versus 13%).²⁹ Similar to HIMALAYA despite an improvement in median OS, a difference in median PFS was not observed (HR 0.87 95% CI 0.72–1.06), again highlighting the disease control established with lenvatinib. What is notable is that after a follow-up of 52.5 months the 48-month OS rate was 31% versus 18% again, highlighting the long-term benefits in OS seen with dual ICI inhibition. Using the FACT-Hep score, measures of QoL were also improved.¹⁵ Critically in this trial, a number of early deaths attributed to hepatic events were observed, resulting in a crossover of the survival curves within in the first 6 months, highlighting the need for close monitoring for toxicity and liver decompensation in this patient cohort.^15,29

In addition to IMbrave150, HIMALAYA and CheckMate-9DW, CARES-310 is the fourth positive clinical trial to demonstrate a survival benefit for ICI combinations, however it included a predominantly Asian population with hepatitis B, making this difficult to extrapolate to Western HCC populations. To this day, CARES-310 remains the only study demonstrating the superiority of a PD-1 antibody (camrelizumab) plus a VEGFR-2 targeted TKI combination in unresectable HCC. Median OS was significantly improved with camrelizumab plus rivoceranib against sorafenib (23.8 versus 15.2 months; HR 0.64), with similar positive trend for ORR (27% versus 6%). This combination was associated with grade 3–4 TRAEs in 81%.¹⁶

The underlying liver disease aetiology may influence tumour biology and the applicability of trial findings across regions. Although reduced immunotherapy efficacy has been suggested in metabolic dysfunction-associated steatohepatitis (MASH)-related compared with viral HCC,¹⁷ subsequent analyses have been inconsistent, and current evidence does not support using aetiology to guide treatment selection. Nevertheless, the predominance of hepatitis B virus-related HCC in several Asian trials, including CARES-310, should be considered when extrapolating results to European populations, where alcohol-related liver disease, hepatitis C virus, and MASH account for a greater proportion of cases.¹⁸ Current ESMO guidelines recommend all of the above regimens, as well as single-agent durvalumab or tislelizumab, for patients with unresectable-advanced HCC fit for ICIs regardless of disease aetiology.¹⁹ With the exception of camrelizumab and rivoceranib, the EMA has granted marketing authorisation to A + B (November 2020), D + T (February 2023) and I + N (March 2025), paving the way to the anti-cancer immunotherapy era in unresectable HCC with variations in reimbursement based on the opinion of different NCAs (Fig. 1). Indeed, disparities in time to reimbursement represent an additional layer of complexity in access to these treatments. According to the European Union Market Access directive, the Council of European Communities recommended a 180-day reimbursement deadline for novel anticancer medicines.²⁰ During the 2016–2021 period, compliance with this threshold varied markedly across countries, with Germany achieving full adherence (100%), followed by France (51%), the UK and the Netherlands (29% each), Switzerland (14%), Norway (6%), and Belgium (3%). Shorter time to reimbursement has been associated with higher gross domestic product (GDP), along with the absence of pre-assessment procedures, and drug submission by large pharmaceutical companies.²⁰ Although these figures do not specifically reflect HCC drug approvals and should be extrapolated with caution, they still highlight substantial inequity in access among seven high-income European nations — an inequity that likely underestimates the true disparity when lower-GDP European countries are considered. Notably, not all EMA-approved treatment regimens are available to patients in all European countries (Fig. 1). Despite EMA authorisation, the absence of timely national reimbursement across many European countries remains a striking illustration of persistent inequities in access to anticancer therapies throughout Europe.

Fig. 1.

Geographical distribution of reimbursement timelines for systemic therapy agents for unresectable-advanced HCC in Europe (Panels A–H). The source of the reimbursement data is based on the official EMA website and on private correspondence with pharmaceutical companies holding marketing authorisations for each drug.

As of July 2026, two anti-cancer immunotherapy combinations, A + B and D + T have been licensed and reimbursed in most of European countries. Clinical data emerging from registries collecting oncological outcomes from routine clinical practice suggest both A + B and D + T to be delivered with comparable safety and tolerability when considering corresponding landmark clinical trials in unresectable HCC.10, 11, 12, 13 With regards to eligibility to treatment, although level I evidence supports utilisation of anti-cancer immunotherapy in patients with Child-Pugh A liver dysfunction and an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–1, the so called “real-world” practice in Europe has often included patients with more adverse features including ECOG PS 2 or Child-Pugh B.²¹

To date, patients with Child-Pugh B liver function have largely been excluded from phase III clinical trials testing systemic therapy regimens in advanced HCC. Consequently, evidence for the efficacy and safety of ICI in this population is derived primarily from meta-analyses and observational, predominantly retrospective, real-world studies. In cohort 5 of the Checkmate040, which included 49 Child-Pugh B7–B8 patients, nivolumab monotherapy achieved ORR of 12% and median OS of 7.6 months, with a safety profile comparable to that observed in Child-Pugh A patients.³⁰ Similarly, the largest meta-analysis published to date included 22 studies (699 Child-Pugh B patients and 2114 Child-Pugh A patients), found no increase in ICI-related toxicity, though survival outcomes were significantly worse than in those with preserved liver function.²² A smaller retrospective study also suggested improved survival with ICI compared with best supportive care in selected Child-Pugh B patients.²¹

Overall, current evidence underlines that Child-Pugh B liver function is a strong negative prognostic factor, but not necessarily an absolute contra-indication for ICI. Importantly, the underlying cause of liver function decline – extensive tumour burden versus chronic liver disease and hepatic decompensation – should be considered when selection patients, and alternative measures of hepatic reserve, such as the ALBI grade, may provide more refined risk stratification. Given the limited evidence base and poor prognosis of this population, treatment decisions should be individualised in the context of a Multidisciplinary Team (MDT) consensus and based on a case-by-case risk-benefit assessment.

Beyond appropriate patient selection, the recognition and management of immune-related adverse events (irAEs) have become integral to the optimal delivery of immunotherapy for HCC. Hepatic irAEs are of particular relevance in HCC in view of co-existing chronic liver disease of different aetiology, often amounting to cirrhosis and impaired hepatic reserve. Immune-related liver injury (irLI) occurs earlier and more frequently than in other solid tumours, while remaining difficult to diagnose because no specific diagnostic criteria exist and baseline liver test abnormalities are common.³¹ Careful exclusion of tumour progression, hepatic decompensation and other causes of liver injury is therefore essential. Although most cases resolve without permanent treatment discontinuation and many mild events are managed conservatively, fatal hepatic toxicities have been reported in clinical trials, highlighting the need for liver function monitoring and early multidisciplinary involvement. Balancing the survival benefits of immunotherapy against the risk of irLI has therefore become a key aspect of contemporary HCC care.

Whilst utilisation of immunotherapy in HCC was adopted approximately 4 years earlier in the United States compared to Europe (Table 2), several early marketing authorisations of anti-cancer immunotherapy agents, granted under the Food and Drug Administration (FDA) accelerated approval programme, were later on challenged by lack of demonstration of OS benefit in follow-up phase III programmes. Nivolumab, the first immunotherapy agent approved in HCC in June 2016 on the basis of an ORR of 20% in the CheckMate 040 phase I/II study,³² was withdrawn in 2021 following the lack of demonstration of OS superiority over sorafenib in the CheckMate 459 study.⁸ In Europe, no marketing authorisation of PD-(L)1 monotherapy has been granted, limiting access to therapeutic decision-making in first-line a particularly important nodal point in the management of patients with unresectable HCC. Demonstration of a statistically significant OS benefit against control in an adequately powered phase III study remains a key pre-requisite for granting marketing authorisation of novel anti-cancer therapies for EMA. Similarly, demonstration of OS benefit in patients with unresectable-advanced HCC is an essential element in the HTA process that accompanies reimbursement in many European countries.

Table 2.

Timelines of EMA and FDA approvals of systemic therapies for unresectable-advanced HCC.

Drug	First study presentation as abstract	EMA approval	FDA approval	Abstract presentation to approval interval EMA/FDA (days)
First-line systemic therapy
Sorafenib	1 Jun 2007	1 Nov 2007	19 Nov 2007	153/171
Lenvatinib	4 Jun 2017	23 Aug 2018	16 Aug 2018	445/438
Atezolizumab plus bevacizumab	22 Nov 2019	2 Nov 2020	29 May 2020	346/189
Durvalumab plus tremelimumaba	31 Jan 2022	20 Feb 2023	21 Oct 2022	385/263
Ipilimumab plus nivolumab	31 May 2024	20 Mar 2025	11 Apr 2025	244/315
Second-line systemic therapy
Nivolumab	3 Jun 2016	Not approved	22 Sep 2017	NA/476
Regorafenib	30 Jun 2016	7 Aug 2017	27 Apr 2017	403/301
Pembrolizumab	18 Jan 2018	Not approved	9 Nov 2018	NA/295
Cabozantinib	18 Jan 2018	15 Nov 2018	14 Jan 2019	301/361
Ramucirumab	1 Jun 2018	23 Jan 2020	10 May 2019	601/343
Ipilimumab plus nivolumab	31 May 2019	Not approved	10 Mar 2020	NA/284

EMA, European Medicines Agency; FDA, Food and Drug Administration; NA, not applicable.

^aDurvalumab monotherapy is approved by EMA but not FDA or by MHRA/NICE in the UK.

Therapeutic sequencing following first-line systemic therapy for unresectable HCC

Therapeutic options for patients with unresectable-advanced HCC following failure of first-line therapy strongly depend on choice of prior therapy, liver functional status, toxicity to first-line therapy, and patients’ preference. Alongside clinical considerations, availability of systemic agents in routine clinical practice in Europe is influenced by drug approval and reimbursement, which is not uniformly regulated across countries.

The majority of established second-line options in unresectable-advanced HCC have been globally approved following sorafenib discontinuation (Supplementary Table 1). Utilisation of regorafenib and cabozantinib in patients with Child-Pugh A liver dysfunction and ECOG PS 0–1 is supported by level I evidence from the RESORCE and CELESTIAL trials,^3,4 which demonstrated median OS post-sorafenib discontinuation of 10.6 and 10.2 months respectively, with a gain of 2.8 (HR 0.63) and 2.2 months (HR 0.76) over placebo. Ramucirumab, a monoclonal antibody against VEGFR-2, is the only non-TKI option in this setting following demonstration of a 1.2-month OS benefit against placebo in the REACH-2 trial (8.5 versus 7.3 months for placebo, HR 0.71), which exclusively enrolled patients with AFP ≥ 400 ng/mL.⁵

Failure to demonstrate a significant OS benefit against placebo in KEYNOTE-240⁷ hindered efforts to achieve marketing authorisation in Europe. However, a meta-analysis of KEYNOTE-240 and KEYNOTE-394, the only two phase III studies that investigated the efficacy of pembrolizumab as second-line therapy for HCC following sorafenib and/or oxaliplatin-based chemotherapy (KEYNOTE-394 only), confirmed a significant benefit in OS (HR 0.79) and PFS (HR 0.76) for the 578 patients who received pembrolizumab against the 288 who received placebo.³³

Similarly, CheckMate 040, a phase I/II multi-cohort study, aimed to evaluate different dosing schedules of I + N in sorafenib-experienced patients and generate preliminary efficacy data to inform subsequent development.³² Whilst its early efficacy data supported an FDA accelerated approval, the absence of a control arm precluded both to demonstrate an OS benefit required for EMA marketing authorisation and to generate cost-effectiveness estimates for reimbursement. Nevertheless, 5-year follow-up data confirmed durable benefit, with highest efficacy seen for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg for 4 doses followed by nivolumab maintenance, where OS reached a competitive median of 22.2 months and a 5-year OS rate of 29%.³⁴

Nonetheless, ESMO guidelines exclusively recommend TKIs (sorafenib, lenvatinib, regorafenib or cabozantinib) or ramucirumab in second-line, regardless of prior treatment with ICIs.¹⁹ Lack of second-line immunotherapy options in Europe impacted clinical care in the early immunotherapy era for unresectable HCC, where exclusive availability of A + B in first-line would have precluded safe use of immunotherapy in patients with contraindications for bevacizumab, particularly in patients at high risk of bleeding, who would be offered a TKI.¹² This constraint has declined with the approval of bevacizumab-free regimens in first-line.

Irrespective of first-line choice, the optimal therapeutic sequence following progression or intolerance to anti-cancer immunotherapy is not established and constitutes a large unmet need. Limited, non-randomised evidence supports the use of TKIs in this setting. In the LEVIATHAN registry study, which included a large number of European centres, second-line therapy with lenvatinib was superior to sorafenib both in terms of PFS (5.5 versus 2.6 months, HR 0.41) and OS (11.9 versus 7.4 months, HR 0.67).³⁵ Whilst LEVIATHAN and other series support the use of TKI post immunotherapy,¹⁴ the quality of this evidence is limited by the observational nature.

Prospective, single arm phase II studies in Asia have tested TKI monotherapy after failure of immunotherapy in patients with ECOG PS 0–1 and Child-Pugh A. Lenvatinib showed a PFS of 5.4 months and an OS of 9.8 months in 50 patients previously treated with A + B.³⁶ Regorafenib was associated with a PFS of 3.5 months and an OS of 10.5 months in 40 patients.³⁷ Another phase II study of 47 patients has provided evidence of efficacy and tolerability of cabozantinib in checkpoint inhibitor-experienced patients exposed to up to three lines of therapy.³⁸ When used as a second-line treatment (n = 27), cabozantinib led to a PFS and OS of 4.3 and 14.3 months in selected patients with Child-Pugh A and preserved ECOG PS. These results should be interpreted with caution, as they derive from small, non-randomized studies conducted exclusively in Asian populations with a predominance of hepatitis B-driven HCC.

Randomised evidence in the second line following ICI has been lacking until the recent presentation of IMbrave251.³⁹ This global phase III trial randomised patients progressing after A + B to A + lenvatinib or sorafenib, or to control with lenvatinib or sorafenib alone (TKI per physician’s choice). The study did not meet its primary endpoint, indicating that the continuation of A is not beneficial in this setting. Despite being negative, IMbrave251 provided the first randomised phase III evidence for TKI monotherapy after first-line ICI (TKI only arm: OS 12.5 months, PFS 4.8 months, ORR 5.8%). These figures align with the observational and phase II data, providing clinicians and patients with important benchmarks for TKI in this setting.

On this basis, TKI monotherapy with lenvatinib or sorafenib represents an evidence-based option for European patients with preserved liver function and performance status progressing on first-line ICI. The choice of agent should be guided by the respective side effect profiles, residual toxicity from first-line and patient preference, and is in many countries constrained by reimbursement status. Enrolment into clinical trials should be prioritised. Approaches under investigation include novel ICI-based combinations, such as anti-PD-1 with the anti-vasculogenic mimicry agent CVM-1118⁴⁰ or with livmoniplimab (targeting the GARP–TGF-β1 complex) (NCT05822752), bispecific antibodies (NCT05760599), CAR-T cell therapy,⁴¹ and strategies targeting the Wnt signalling⁴² or the gut microbiome.⁴³

Beyond TKI, no European approval is in place for any anti-cancer immunotherapy agent in the second-line setting, instigating careful evaluation of candidacy to ICI combinations in the first-line. Use of ICIs beyond first-line therefore remains off-label and may depend on institutional policies, including approval by local pharmacy and therapeutics committees. This is a significant difference compared to FDA jurisdiction, where PD-1 monotherapy with pembrolizumab⁷ or alternatively I + N⁴⁴ are approved following progression or intolerance to TKIs. The lack of solid level I evidence in support of the use of systemic therapy in second-line is particularly challenging for European patients. Whilst evidence for efficacy of TKIs now exists, off label prescribing outside specific marketing authorisations is not universally reimbursed across healthcare systems. This is of greater consequence given that most systemic therapy options for HCC are high-cost therapies. Unless country-wide provisions are in place, reimbursement of off label prescribing depends on individual hospital budgets, regional authorities, patient’s health insurer or direct out of pocket contributions from patients, fuelling inequality in access to therapy. As of May 2026, sorafenib is the only drug that has faced loss of exclusivity in Europe, driving generic entry into the market with consequent price reduction. Although loss of exclusivity for other molecules might change uptake of TKI therapy in the upcoming years, the lack of high-quality data centred on OS benefit after immunotherapy discontinuation limits a unified therapeutic approach in European countries through a rigorous cost-effectiveness assessment. As a result, whilst universal TKI (lenvatinib, sorafenib, cabozantinib, regorafenib) access is reimbursed in certain countries such as the UK, Belgium, Germany, Austria, Portugal, other countries such as Italy only reimburse sorafenib, whereas in Spain reimbursement decisions are often delegated to autonomous regions, exposing patients to intra-national access inequality.

Whilst treatments after first-line ICI remain heterogeneously funded across Europe, concerted efforts including healthcare professionals, regulatory and healthcare authorities, pharmaceutical industry, patients and their advocates should be prioritised to ensure harmonisation of treatment sequences and reduction of access disparities. A consensus statement developed by European scientific societies, informed by evidence from clinical trials and registries, could represent an important step towards a unified approach across European countries.

Molecular profiling and predictive biomarkers in HCC

Molecular profiling of tumour tissue or plasma to identify genomic alterations in DNA or RNA has become part of routine diagnosis in solid tumour oncology. Despite broadening adoption of next generation sequencing (NGS) in other hepatobiliary malignancies such as biliary tract cancers, where a wide variety of genomic alterations such as Fibroblast Growth Factor Receptor 2 gene fusions or rearrangements, Isocitrate Dehydrogenase-1 or BRAF V600E activating mutations, Human Epidermal Growth Factor Receptor 2 overexpression amongst others, have paved the way to personalised molecular therapy,⁴⁵ HCC has not benefitted from adoption of NGS in contrast with other tumours.

In Europe, definition of value and clinical significance of molecular biomarkers follows the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) systematic framework to rank molecular targets based on evidence available supporting their value as clinical targets.⁴⁶ Currently, there are no genomic alterations in HCC to have reached the top 2 tiers of the ESCAT classification, meaning there are no immediately available targeted therapies driven by specific genetic mutations in routine clinical practice nor promising targets likely to change the landscape in the immediate future based on latest clinical evidence. Most clinical biomarkers investigated so far fall into the lower tiers of the ESCAT classification (Investigational/Preclinical), due to evidence being based on small studies, pre-clinical models or inferred from other cancer types.

The majority of oncogenic drivers in HCC in fact revolve around distinctive pathogenic processes such as telomere maintenance (TERT promoter mutation), cell cycle regulation (TP53), and chromatin remodelling,⁴⁷ which historically lacked therapeutically actionable targets for systemic therapy. Presence of CTNNB1 activating mutations is a hallmark of up to 30% of patients with HCC and signifies activation of the Wnt/Beta-catenin pathway. This association remains hypothesis-generating rather than clinically actionable, and prospective testing is not currently recommended by either ESMO or EASL guidelines,^19,48 reflecting assay heterogeneity, the lack of validated cut-offs, and confounding from co-occurring TP53/TERT mutations that independently shape tumour immune contexture.⁴⁹

A paradigmatic example of the observed challenges in performing routine molecular testing in HCC stems from the published experience of the French Genomic Programme, an initiative designed to allow cancers that are refractory to systemic treatments access to off-label therapies adapted to their individual genomic profile.⁵⁰ In this study, only 14 out of 135 analysed patients with HCC harboured a molecular alteration described as a potential target in other tumour types and only 3 patients were successfully matched with a therapy which resulted in clinical benefit, making up only 2% of the tested patients. Whilst retrospective evidence has correlated Wnt/Beta-catenin pathway alterations with reduced responsiveness to immunotherapy in small scale studies, prospective testing is not recommended in routine practice either by ESMO or EASL guidelines.^19,48

Beyond individual genomic alterations, novel immunotherapy combinations also lack solid and scalable predictors of response: PD-L1 expression does not identify patients who are more likely to benefit from any of the immunotherapy combinations tested so far and individual assays have been shown to be analytically heterogeneous in HCC tissue.⁵¹

Most of available studies have evaluated compositional features of the tumour microenvironment as a predictor of response to treatment and improved survival following A + B, with comparatively inferior evidence for other approved combinations. Higher representation of effector CD8+ T cells over immunosuppressive CD4+ Treg cells in pre-treatment biopsies,⁵² and lower representation of TREM2 macrophages⁵³ are amongst traits identified to associate with improved outcome from A + B. Similarly, a 10-gene expression signature associated with response to A + B (ABRS) has been suggested as potential predictor of benefit based on post-hoc analysis. However, these traits are not scalable to routine use and have not been prospectively validated.

Beyond tissue-based molecular biomarkers, alternative approaches are emerging as complementary tools to refine patient selection. Integrated radiomic-clinical machine learning models derived from pre-treatment CT imaging have been shown to outperform conventional clinical biomarkers in predicting survival and response to A + B, offering a non-invasive route to risk stratification.⁵⁴ Composite clinical scores integrating routinely available laboratory and inflammatory parameters, such as the CRAFITY score (combining AFP and C-reactive protein), have similarly shown value in stratifying likely benefit from A + B.⁵⁵ The gut microbiota–metabolite axis, including short-chain fatty acids, has also been implicated as a modulator of the peripheral immune response in HCC, with distinctive microbiome and metabolomic profiles associated with a T-cell immunosuppressive phenotype.⁵⁶ None of these approaches have yet reached the validation threshold required for routine adoption, but together they represent scalable strategies likely to progressively refine patient stratification alongside, rather than in place of, genomic profiling.

Whilst therapeutically meaningful molecular dissection of HCC has not been achieved due to a fundamental gap in knowledge, rigorous assessment of candidate biomarkers associated with therapeutic benefit should continue to be applied across discovery, validation and qualification steps. The European Union has delegated oversight of biomarker evaluation to the EMA’s Committee for Medicinal Products for Human Use (CHMP) and since application of EU Regulation 2017/746, has defined set criteria and a EU-wide legal framework for biomarker qualification, validation and adoption in routine practice. Based on available evidence and recommendations by the Scientific Advice Working Party, a given biomarker may be given either qualification advice (QA) or a qualification opinion (QO) (i.e., a final decision on approval) by CHMP, following case-by-case definition of minimum acceptable performance.

Locoregional therapies as primary therapy for unresectable HCC

Whilst systemic standards of care have led to unquestionable improvements in survival in unresectable-advanced disease, most patients within this segment of HCC staging present with liver-confined disease. LRT and particularly trans-arterial chemoembolization (TACE), has represented for over 20 years the standard of care for patients with liver-confined HCC, good performance status and preserved liver function who cannot receive upfront curative therapy. The intermediate-stage HCC is clinically and biologically heterogeneous and the original framework defining TACE as the stage-defining therapy for this group of patients has been progressively challenged over time. Whilst TACE can be repeated, median PFS estimates from initial TACE lie typically in the region of 9 months, following which patients who are not treated in the context of downstaging protocols and therefore unsuitable for liver transplantation, are switched to other non-curative therapies, mostly with systemic agents.

In recent years, combination of ICI with TACE has moved from early-phase⁵⁷ to phase II/III clinical trials, with EMERALD-1,⁵⁸ LEAP-012,⁵⁹ EMERALD-3,⁶⁰ TALENTACE,⁶¹ and CARES-005⁶² showing evidence of significant PFS improvement from integration of various PD-1/PD-L1 based combinations together with TACE. Whilst these studies have instigated use of LRT plus ICI combinations to downstage embolisation eligible patients to curative therapies in Taiwan,⁶³ no marketing authorisation exists in Europe for the combined utilisation of TACE plus immunotherapy. Widespread adoption of this emerging strategy will be contingent on whether LRT plus ICI combinations improve OS, an objective that has not been met by any of the published studies so far.

Access to LRT varies across Europe and strongly depends on local expertise, multi-disciplinary team practice and reimbursement considerations.

Alongside TACE, selective internal radioembolization (SIRT) using Yttrium-90 (Y90) microspheres is an alternative form of trans-arterial therapy that allows targeted irradiation of the tumour parenchyma with minimal embolic effect. This technique is identified in the Barcelona Clinic Liver Cancer (BCLC) algorithm and ESMO guideline as a potential therapeutic option in selected patients with liver-confined HCC particularly those with single tumour ≤8 cm based on the results of LEGACY⁶⁴ and RASER,⁶⁵ showing high rates of objective response within these criteria.

SIRT is not considered a standard first-line treatment in patients with higher tumour burden, suboptimal liver reserve or in selected cases with main portal vein thrombosis, but rather a possible loco-regional option for selected patients when the disease is confined to the liver and the therapeutic objective is local tumour control.^19,66

Evidence for utility of SIRT outside small unifocal tumours (i.e., radiation segmentectomy) has been a debated issue, especially following the failure of the SARAH and SIRveNIB trials, whose results confirmed lack of superiority of SIRT versus sorafenib in patients with unresectable HCC, including patients with portal vein thrombosis.^67,68

Suboptimal dosimetry represents to this day a key aspect of criticism to both studies, which has contributed to the substandard performance of SIRT and may have influenced OS outcomes. The subsequent DOSISPHERE-01 trial has demonstrated, on the other hand, that delivering a tumour-absorbed dose of at least 205 Gy with a personalized dosimetry approach, may significantly improve patients’ OS, including those with portal vein thrombosis. Recent long-term data (2024) have further confirmed these findings, showing clinically meaningful improvements in OS, which were especially pronounced in patients successfully downstaged to surgical resection, including the majority of those with portal vein thrombosis.⁶⁹ Whilst encouraging and illustrative of a more mature practice of SIRT, clinical outcome data from DOSISPHERE-01 remain limited by small sample size and may be challenged by heterogeneity in dosimetry protocols across countries and institutions in Europe. Whilst SIRT is not considered a global standard of care in patients with intermediate-stage HCC, real-life retrospective studies show that SIRT has progressively become more utilised in routine clinical practice as an alternative to currently approved systemic therapeutic strategies in patients without extrahepatic disease.

The experience of 34 French centers documented in the results of the recently published PROACTIF prospective registry study underscores the choice of Y90 glass microspheres as initial treatment for patients with intermediate-advanced HCC.⁷⁰

From a total of 989 patients treated in PROACTIF, 76.8% had BCLC B or C stage and 35.3% had portal vein tumour thrombosis of any grade. OS estimates following successful SIRT were 21.8 months in the whole population, ranging from 27 months in BCLC B to 21.1 months for BCLC C disease. Data from PROACTIF are observational and non-randomized and enrolment included patients belonging to a wide range of BCLC stages, with a heterogeneous treatment intent (curative downstaging versus palliative). Whilst results are of interest, no direct comparison with anti-cancer immunotherapy regimens exists to this day, making it challenging to draw direct conclusions of equivalence or superiority of locoregional versus upfront systemic approaches. This is particularly important given that the patient populations accrued to PROACTIF is not directly comparable to any of the contemporary phase III trials of systemic therapy. These data, however, provocatively highlight an example of how European routine clinical practice may diverge from globally accepted standards of care proposed by guidelines. The use of SIRT as a potential alternative option to systemic therapy in selected patients who are candidates to this form of LRT remains unsupported by randomised evidence, leading to a gap in evidence that should be explored by prospective studies. Therefore, it is not mentioned in the ESMO guidelines and EASL guidelines do not recommend it in this specific setting.^19,48 Stereotactic body radiation therapy (SBRT) has emerged as a potential loco-regional treatment option for selected patients with unresectable HCC, particularly in the setting of limited tumour burden and preserved liver function. Current evidence supports its use in tumours unsuitable for other loco-regional therapies because of size, anatomical location, or proximity to major vascular or biliary structures. In selected clinical scenarios, SBRT can additionally be considered in the presence of portal vein tumour thrombosis, as bridging or downstaging therapy before liver transplantation, or in combination with systemic treatment. Careful multidisciplinary evaluation remains essential to optimize patient selection, balance local tumour control against the risk of radiation-induced liver toxicity and define the role of SBRT within the broader therapeutic strategy for unresectable HCC.^19,48,66 Other forms of locoregional therapy such as Hepatic arterial infusion chemotherapy (HAIC) are not routinely used in Europe. Although recent metanalyses suggest that HAIC can be suitably integrated with systemic therapy,⁷¹ the lack of high-quality prospective clinical trials with global accrual and the limited expertise in the technique outside expert centers in Asia limits the role of this form of LRT in the European landscape.

Discussion

Whilst Asia continues to remain affected by the highest incidence rates of HCC to this day,⁷² HCC ranks 13th by incidence and 6th by mortality in Europe, underscoring how this malignancy continues to represent an area of high unmet medical need across many regions of the world.⁷³

Europe harbours a fertile clinical research ecosystem for HCC (Fig. 2), where many countries have consistently played a fundamental part in the generation of evidence behind systemic standards of care in HCC through participation to major clinical trial programs from early to late phase development. It might be interesting to note that increasingly Chinese pharmaceutical companies pursue a China-only development strategy. While this was recently focusing on “me-too” drugs, increasingly innovative drugs such as bispecifics, or antibody-drug conjugates are currently under development by Chinese companies, which might have impact to the possibility for European patients to have access to innovative drugs, as clinical trials conducted on all-Chinese populations have limited generalisability to Western patients, as highlighted above. For this reason, the most recent EASL-AASLD-ILCA consensus statement promotes homogeneous worldwide distribution in the enrolment of phase III trials,⁷⁴ despite the challenges related to incorporating different local guidelines into international study designs.

Fig. 2.

Geographical distribution of participation to number of pivotal phase III clinical trials leading to marketing authorisation of systemic agents for the treatment of unresectable-advanced HCC in Europe.

Nevertheless, unlike other regions, approval of systemic therapies in Europe is intrinsically characterized by a multi-layer approval process that sees individual country adoption happen within widely heterogeneous timelines from first EMA approval. In the past 20 years, only 2 of the 10 systemic therapies approved for HCC received a positive outcome by EMA earlier than FDA (Table 2). The need for scrupulous HTA assessment of novel therapies may prevent adoption of accelerated access pathways that are more commonly seen within FDA jurisdiction. However, accelerated approvals and breakthrough designations granted by FDA have often not translated into sustainable patient benefit in HCC (i.e., nivolumab, pembrolizumab plus lenvatinib), highlighting how integration of novel standards of care in routine clinical practice should follow a stringent cost-benefit analysis in an ecosystem where healthcare costs are largely publicly funded. Despite a unifying EU-level approval granted by EMA, country-level divergence in criteria for approval and reimbursement represents to this day a source of delay and disparity in access, more so in the context of second-line therapy where solid reference standards do not exist. Despite the evident benefit of empowering each country or even smaller communities (i.e., regional bodies) to independently decide the most appropriate drug reimbursement policy based on local funding priorities and regional disease epidemiology, the consequent health inequalities that may arise based on geographical origin remains a key challenge when the European landscape is appraised as a whole.

Indeed, heterogeneity in the uptake of approved regimens across European countries is particularly noteworthy. A + B and D + T, which received initial FDA approval in May 2020 and October 2022, followed by EMA authorization in November 2020 and February 2023, respectively, are now reimbursed and available in 23 and 18 European countries, respectively. In contrast, I + N — granted EMA approval in January 2025 and FDA approval as a first-line indication in April 2025 — is, more than one year after EMA approval, reimbursed in only one European country, Germany. Even within the same country, approval timelines may vary depending on the drug: for instance, A + B was approved in France in September 2021, less than 1 year after EMA authorisation, while the request for lenvatinib approval was rejected.⁷⁵ These discrepancies likely reflect a confluence of factors, including the heterogeneous regulatory strategies adopted by different pharmaceutical companies, the varying governance frameworks of national reimbursement authorities and the costs associated with novel therapies. In this context, the push of the EASL-AASLD-ILCA consensus statement for harmonised and solid clinical trial end points partly addresses the issue of how regulatory bodies evaluate the cost/benefit ratio of each drug. Indeed, it tries to provide a globally homogeneous scientific ground not only for study designs, but also, indirectly, for the interpretation of the strength of the evidence generated in clinical trials.⁷⁴ Ultimately, it offers local authorities a standardised decisional framework, which could lead to more harmonised decisions on drug reimbursement at an international level.

As therapeutic options continue to grow at fast pace and multiple sequences of loco-regional and systemic treatment move from clinical trials to routine practice, collaborative efforts from multiple stakeholders including regulatory authorities, healthcare professionals, patients and pharmaceutical industry should be aimed at harmonizing pathways of approval and implementation of novel treatments.^58,59 Furthermore, given the increasing complexity of treatment decisions, it is essential that all patients are discussed within an MDT where all relevant specialties are represented, ensuring that every patient receives a tailored and optimal treatment sequence.

MDT discussions are essential in the management of HCC, particularly for patients with Child-Pugh B liver dysfunction or other complex clinical features, where available evidence and guidelines may not fully guide treatment decisions. By integrating expertise from multiple specialties, MDTs support individualized, patient-centred care. However, access to dedicated HCC MDTs remains uneven across Europe because of financial, organizational and workforce constraints. Virtual MDT networks supported by digital technologies and artificial intelligence could expand access to specialist expertise, reduce disparities, and facilitate real-world evidence generation and quality improvement. Recent Italian data support this approach.

Reducing disparities in access to clinical trials across Europe - particularly beyond major academic centres - remains a key priority to increase patient exposure to experimental innovative therapies. In this regard, centralised efforts such as the Clinical Trials Information System (CTIS) represent a significant step forward; such platforms aim to streamline regulatory processes and may, in time, enable a more efficient and equitable distribution of studies across diverse geographical regions. Equally, continued appraisal of post-registration “real-world” data following approval of novel therapies represents an important aspect of research, which may provide useful efficacy and safety benchmarks outside clinical studies, helping to consolidate trial results into everyday clinical practice.

Conclusion

The therapeutic landscape for advanced unresectable HCC has undergone meaningful expansion in recent years, and further progress is anticipated as novel agents move through regulatory and reimbursement pipelines. Yet access to these innovations — including immunotherapy-based combinations — remains markedly uneven across Europe, generating clinically significant disparities in the standard of care available to patients. Bridging these gaps demands a coordinated, multi-stakeholder response involving regulatory bodies, payers, scientific societies, and policymakers, with the shared goal of streamlining approval, reimbursement, and real-world implementation of effective treatment strategies. Ultimately, reducing inequities in treatment access is not merely a governance priority but a prerequisite for meaningful improvements in patient outcomes across the continent.

Key recommendations.

Evidence and treatment selection

• •Generate prospective evidence to define optimal treatment sequencing after first-line immunotherapy.
• •Develop and prospectively validate predictive biomarkers to guide treatment selection.
• •Clarify the positioning of locoregional therapies relative to systemic treatment through comparative evidence.

Access to treatment

• •Promote timely and consistent reimbursement of approved HCC therapies across European countries.
• •Reduce between-country and within-country disparities in access to systemic and locoregional therapies.
• •Facilitate access to clinical trials beyond large academic centres to broaden opportunities for patients to receive novel therapies.

Coordination

• •Strengthen collaboration among clinicians, regulators, payers, scientific societies, patients and industry to harmonise HCC care across Europe.

Contributors

Concept and design: DJP, LR.

Acquisition of data: All authors.

Analysis and interpretation of data: All authors.

Drafting of the manuscript: DJP.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: N/A.

Obtained funding: DJP.

Administrative, technical, or material support: N/A.

Study supervision: N/A.

Editor note

The Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations.

Declaration of interests

DJP received lecture fees from Bayer Healthcare, Astra Zeneca, EISAI, Bristol Myers-Squibb, Roche, Boston Scientific, Ipsen; consulting fees for Mina Therapeutics, Galapagos, Parabilis, Boeringer Ingelheim, Ewopharma, EISAI, Ipsen, Roche, H3B, Astra Zeneca, DaVolterra, Mursla, Terumo, Avammune Therapeutics, Starpharma, LiFT Biosciences, Exact Sciences; travel expenses from Bristol Myers-Squibb, Roche, Bayer Healthcare, Astra Zeneca; received research funding (to institution) from MSD, GSK, BMS.

JV received consulting fees from AstraZeneca, Madrigal and Eisai; lecture fees from AstraZeneca; travel expenses from AstraZeneca; research grants (to Institution) from Eisai.

JE declares: Consulting fees from: MSD, Eisai, BMS, AstraZeneca, Bayer, Roche, Ipsen, Basilea, Merck Serono, Incyte, Servier, Beigene, Taiho, Boston Scientific, Guerbet, Jazz; Lectures, presentations fees from: AstraZeneca, Roche, Servier, Boston Scientific, Jazz; DSMB participation for: Captor therapeutics; Research funding (institutional) from: BMS, Beigene, Boston Scientific, Exeliom biosciences, SUMMIT, AstraZeneca, Servier, Jazz, Taiho, Revolution Medicine.

BS received grant support from AstraZeneca, Eisai, Roche and Ipsen, speaker honoraria from AstraZeneca and Eisai as well as travel support from AstraZeneca and Roche.

GT received grant support from COST Action 22125 (Precision-BTC-Network) and speaking fees from AstraZeneca.

NBK received consulting fees from AstraZeneca, Boston Scientific and Roche; lecture fees from AstraZeneca, Ipsen, Roche, Boston Scientific, Sirtex, GSK; travel expenses/meeting attendance support from AstraZeneca, Eisai and Roche; institutional research funding from AstraZeneca and Roche. NBK reports non-financial interests as programme committee member of the German Association for the Study of the Liver and UEG Digestive Disease Mechanisms, and institutional drug support from Genentech.

LR received consulting fees from AbbVie, AstraZeneca, Basilea, Bayer, BMS, Boehringer Ingelheim, Boston Scientific, Eisai, Elevar Therapeutics, Exelixis, Genenta, Guerbet, Hengrui, Incyte, Ipsen, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, Biologix, BMS, Eisai, Guerbet, Incyte, Ipsen, Roche, Servier, CORE2ED, eChinaHealth, Medscape, PeerVoice, VJOncology, Vumedi; travel expenses from AstraZeneca, Servier; research grants (to Institution) from AbbVie, Agios, AstraZeneca, BeiGene, BMS, Exelixis, Fibrogen, Incyte, Ipsen, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, TransThera Sciences, Zymeworks.

SC received travel expenses/meeting attendance support from Servier, Merck, Ipsen, Astra Zeneca, Gilead, Roche; consulting fees from Roche; AD received consulting fees from AstraZeneca, BMS, Boehringer Ingelheim, Boston Scientific, Eisai, Guerbet, Incyte, Roche, Servier, BeOne; travel expenses from AstraZeneca, Servier; lecture fees from AstraZeneca, Servier, BeOne.

GK received consulting fees from AstraZeneca, Roche, Sevier; lecture fees from Roche and Regeneron; travel expenses/meeting attendance support from Takeda, MSD, Novartis; research grants (to Institution) from Astrazeneca; Advisory Board: Zymeworks.

EA received lecture fees from Roche, Gilead.