Liver cancer has long been one of oncology’s most stubborn challenges, and hepatocellular carcinoma (HCC) — the dominant primary liver malignancy — has historically resisted the systemic therapies that transformed other cancers. For decades, patients with unresectable or advanced disease had almost no effective drug options. That changed in 2007, when the landmark SHARP and Asia-Pacific trials established the tyrosine kinase inhibitor (TKI) sorafenib as the world’s first, and for over a decade unchallenged, systemic standard of care. A comprehensive new review published in The Lancet Regional Health – Europe, led by David J. Pinato of Imperial College London and Lorenza Rimassa of Humanitas University, now maps how dramatically — and unevenly — the European treatment landscape has evolved since then.
The TKI era delivered incremental but real gains. Lenvatinib emerged as a non-inferior first-line alternative to sorafenib, while regorafenib, cabozantinib, and the anti-VEGFR-2 antibody ramucirumab — the latter reserved for patients with alpha-fetoprotein levels of at least 400 ng/mL — extended survival after sorafenib failure. Yet the ceiling was low: median life expectancy on first-line TKI therapy rarely exceeded 12 to 13 months. Progressive liver dysfunction, clinical decompensation, and the difficulty of tolerating TKIs long-term exposed a fundamental limitation. Immune checkpoint inhibitors (ICIs) tested as monotherapy also failed to beat sorafenib in phase III studies, leaving the field at an impasse until combination immunotherapy arrived.
The turning point came with regimens that pair PD-1 pathway blockade with either VEGF inhibition or CTLA-4 inhibition. Median overall survival for untreated advanced HCC patients, once roughly six months, climbed to between 16 and 23 months in contemporary phase III trials — a leap accompanied by higher response rates, better safety profiles, and improved quality of life. Four pivotal trials now define first-line care. IMbrave150 showed atezolizumab plus bevacizumab (A + B) achieved a median overall survival of 19.2 months versus 13.4 months for sorafenib, with an objective response rate of 30% versus 11%, though six grade 5 bleeding events in the combination arm underscored the need for baseline endoscopic varices screening. HIMALAYA demonstrated that a single priming dose of tremelimumab plus monthly durvalumab (the STRIDE regimen) improved median survival to 16.4 months, with striking five-year survival of 19.6% compared with 9.4% for sorafenib.
CheckMate 9DW added a third option, combining ipilimumab induction with nivolumab maintenance against a control arm dominated by lenvatinib. Median overall survival reached 23.7 months versus 20.6 months, with a 36% response rate and a 48-month survival rate of 31% versus 18%. Notably, early deaths from hepatic events caused the survival curves to cross within the first six months, a reminder that close monitoring for liver decompensation is essential. The fourth positive trial, CARES-310, paired camrelizumab with the TKI rivoceranib and achieved the highest hazard ratio benefit (0.64) and a 23.8-month median survival — but with grade 3–4 toxicity in 81% of patients and a predominantly Asian, hepatitis B-driven population, its results are difficult to extrapolate to Europe, where alcohol-related liver disease, hepatitis C, and metabolic dysfunction-associated steatohepatitis (MASH) predominate.
Underlying liver disease aetiology was once thought to blunt immunotherapy efficacy, particularly in MASH-related HCC, but subsequent analyses have been inconsistent, and current European Society for Medical Oncology (ESMO) guidelines recommend the approved regimens regardless of aetiology. A thornier question concerns patients with Child-Pugh B liver dysfunction, who were largely excluded from phase III trials. Evidence from CheckMate 040 cohort 5 — where nivolumab achieved a 12% response rate and 7.6-month median survival in 49 Child-Pugh B7–B8 patients — and from a meta-analysis of 22 studies suggests immunotherapy is not absolutely contraindicated, though survival is markedly worse than in patients with preserved liver function. The authors stress that the cause of hepatic decline, whether tumour burden or decompensated cirrhosis, must be weighed case by case, ideally with refined tools such as the ALBI grade and within multidisciplinary team consensus.
Managing immune-related liver injury has itself become a core clinical skill. Because HCC arises on a backdrop of chronic liver disease, immune-mediated hepatotoxicity occurs earlier and more frequently than in other solid tumours, and diagnosis is complicated by the absence of specific criteria and by baseline liver test abnormalities. Most cases resolve without permanent discontinuation, but fatal hepatic toxicities have been reported, making vigilant monitoring and early multidisciplinary involvement non-negotiable elements of modern care.
What happens after first-line immunotherapy fails remains one of the field’s largest unmet needs. ESMO guidelines recommend only TKIs — sorafenib, lenvatinib, regorafenib, or cabozantinib — or ramucirumab in the second line, regardless of prior immunotherapy exposure. Observational data from the European LEVIATHAN registry favour lenvatinib over sorafenib after A + B failure (progression-free survival of 5.5 versus 2.6 months), and single-arm Asian phase II trials support regorafenib and cabozantinib in this setting. The recent IMbrave251 trial, though negative for its primary endpoint, provided the first randomised phase III benchmark for TKI monotherapy after first-line immunotherapy: 12.5-month overall survival and 4.8-month progression-free survival in the TKI-only arm. Crucially, no immunotherapy agent holds European approval in the second line — a stark contrast with the United States, where pembrolizumab and ipilimumab plus nivolumab are licensed after TKI failure. Off-label immunotherapy use in Europe therefore depends on institutional policies and is often not reimbursed, pushing costs onto hospital budgets, insurers, or patients themselves.
Access inequity emerges as the review’s most provocative theme. Although the European Medicines Agency grants EU-wide marketing authorisation, national reimbursement decisions vary enormously. Atezolizumab plus bevacizumab and the STRIDE regimen are now reimbursed in 23 and 18 European countries respectively, but ipilimumab plus nivolumab — EMA-approved in March 2025 — was, more than a year later, reimbursed in only one country, Germany. During 2016–2021, compliance with the EU’s recommended 180-day reimbursement deadline ranged from 100% in Germany to just 3% in Belgium. Molecular profiling offers little help in personalising choices: no genomic alteration in HCC reaches the top tiers of the ESMO ESCAT framework, and in the French Genomic Programme only 3 of 135 HCC patients were successfully matched to a targeted therapy. Emerging predictors — tumour immune contexture signatures, the CRAFITY score combining AFP and C-reactive protein, radiomic machine-learning models, and gut microbiome profiles — show promise but await prospective validation.
Meanwhile, European practice is quietly diverging from guidelines in the locoregional arena. Trans-arterial chemoembolization remains the standard for liver-confined intermediate-stage disease, and phase II/III trials including EMERALD-1 and LEAP-012 have shown progression-free survival gains from adding PD-1/PD-L1 blockade to TACE — though no overall survival benefit has yet been demonstrated and no European marketing authorisation exists for the combination. Selective internal radiotherapy (SIRT) with yttrium-90 microspheres, once dismissed after the negative SARAH and SIRveNIB trials, has been rehabilitated by the DOSISPHERE-01 study, which showed that personalised dosimetry delivering at least 205 Gy to the tumour significantly improves survival, even in patients with portal vein thrombosis. The prospective French PROACTIF registry of 989 patients reported 21.8-month median survival after SIRT, yet no randomised comparison with immunotherapy exists, leaving a widening gap between routine practice and guideline-endorsed standards.
The authors call for a coordinated, multi-stakeholder response: harmonised reimbursement pathways, prospective evidence for treatment sequencing, validated predictive biomarkers, broader access to clinical trials beyond academic centres through platforms such as the EU’s Clinical Trials Information System, and universal multidisciplinary review — potentially expanded through virtual networks supported by artificial intelligence. With HCC ranking thirteenth by incidence and sixth by mortality in Europe, the science has finally delivered survival gains once thought impossible. The remaining challenge, the review concludes, is no longer inventing effective treatments but ensuring that every European patient can actually receive them.
Subject of Research: Systemic and locoregional treatment paradigms for unresectable and advanced hepatocellular carcinoma in Europe
Article Title: Systemic treatment paradigms for unresectable and advanced hepatocellular carcinoma in Europe
Article References: Pinato, D. J., Alimenti, E., Lombardi, P., Vaz, J., Digklia, A., Edeline, J., Ben Khaled, N., Di Giacomo, E., Scheiner, B., Ramos, J. P., O’Kane, G. M., Cappuyns, S., Tesini, G., & Rimassa, L. (2026). Systemic treatment paradigms for unresectable and advanced hepatocellular carcinoma in Europe. The Lancet Regional Health – Europe, 70, Article 101839. https://doi.org/10.1016/j.lanepe.2026.101839
Image Credits: AI Generated
DOI: 10.1016/j.lanepe.2026.101839
Keywords: hepatocellular carcinoma, immunotherapy, atezolizumab, bevacizumab, durvalumab, tremelimumab, tyrosine kinase inhibitors, EMA, reimbursement, health inequality, locoregional therapy, biomarkers
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Nathaniel Bowman. (September 23, 2026). Immunotherapy Reshapes Advanced Liver Cancer Care in Europe, but Access Lags Behind. Scienmag. https://scienmag.com/immunotherapy-reshapes-advanced-liver-cancer-care-in-europe-but-access-lags-behind/
Nathaniel Bowman. “Immunotherapy Reshapes Advanced Liver Cancer Care in Europe, but Access Lags Behind.” Scienmag, 23 September 2026, https://scienmag.com/immunotherapy-reshapes-advanced-liver-cancer-care-in-europe-but-access-lags-behind/. Accessed 23 September 2026.
Nathaniel Bowman. “Immunotherapy Reshapes Advanced Liver Cancer Care in Europe, but Access Lags Behind.” Scienmag. September 23, 2026. https://scienmag.com/immunotherapy-reshapes-advanced-liver-cancer-care-in-europe-but-access-lags-behind/
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Tags: advanced liver cancer managementatezolizumabbevacizumabBiomarkerschallenges in liver cancer systemic therapiesdurvalumabEMAEuropean liver cancer carehealth inequalityhepatocellular carcinomahepatocellular carcinoma treatment advancesImmunotherapyimmunotherapy access disparities in Europeliver cancer immunotherapylocoregional therapynovel treatments for unresectable HCCreimbursementsorafenib and lenvatinib treatmentsurvival outcomes in liver cancersystemic therapy for liver cancertargeted therapies for liver cancertremelimumabTyrosine kinase inhibitorstyrosine kinase inhibitors in HCC
