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Hepatocellular carcinoma — clinical trials landscape

TL;DR — The HCC trial portfolio has shifted from single-agent kinase inhibition toward immune combinations, perioperative therapy, TACE/systemic integration, personalized radiation, biomarker-guided detection, and cell/vaccine approaches. Landmark completed trials form a clear genealogy—SHARP (NCT00105443), REFLECT (NCT01761266), IMbrave150 (NCT03434379), HIMALAYA (NCT03298451), and CheckMate 9DW (NCT04039607)—but they do not provide head-to-head ranking of current first-line options. Active studies are moving checkpoint therapy before and after surgery, into transplant-adjacent settings, and alongside TARE/TACE. Surveillance trials are testing abbreviated MRI against ultrasound and prospective blood-marker cohorts, while prevention trials finally target cirrhosis/MASLD populations. Trial eligibility remains narrower than real-world HCC because Child-Pugh B/C disease, decompensation, transplant, autoimmunity, and poor performance are commonly excluded.

All 49 previously cited identifiers were re-fetched from ClinicalTrials.gov API v2 on 2026-10-25. No status, results-availability, or last-update change was found against the 2026-10-18 snapshot. Two additional records were fetched: KEYNOTE-937 (NCT03867084) and CARES-009 (NCT04521153). Status is a dated registry snapshot.

Landmark completed phase 3 genealogy

Trial NCT Comparison Published anchor What changed
SHARP NCT00105443 Sorafenib vs placebo Llovet 2008, PMID 18650514 First systemic OS benefit
REFLECT NCT01761266 Lenvatinib vs sorafenib Kudo 2018, PMID 29433850 Non-inferior TKI alternative
RESORCE NCT01774344 Regorafenib vs placebo after sorafenib Bruix 2017, PMID 27932229 Validated second line after tolerated sorafenib
IMbrave150 NCT03434379 Atezolizumab-bevacizumab vs sorafenib Finn 2020, PMID 32402160 IO/VEGF first-line standard
HIMALAYA NCT03298451 Tremelimumab-durvalumab/durvalumab vs sorafenib Abou-Alfa 2022, PMID 38319892 Dual-IO first-line option
CheckMate 9DW NCT04039607 Nivolumab-ipilimumab vs lenvatinib/sorafenib Yau 2025, PMID 40349714 OS 23.7 vs 20.6 months; additional dual-IO first-line option
IMbrave050 NCT04102098 Adjuvant atezolizumab-bevacizumab vs surveillance Qin 2023, PMID 37871608; Yopp 2026, PMID 41580093 Initial RFS signal not sustained; benefit–risk does not support use
EMERALD-1 NCT03778957 TACE + durvalumab ± bevacizumab Sangro 2025, PMID 39798579 Positive PFS for TACE + IO/VEGF
LEAP-012 NCT04246177 TACE + lenvatinib-pembrolizumab vs TACE control Kudo 2025, PMID 39798578 Positive PFS; registry-posted final OS no different (HR 0.98, 95% CI 0.76–1.26)
KEYNOTE-937 NCT03867084 Adjuvant pembrolizumab vs placebo after resection or ablation Registry results posted 2026-04-24; no PubMed primary retrieved 2026-10-25 RFS HR 1.06 (95% CI 0.88–1.26), p=0.7190; OS HR 1.08 (0.81–1.43); 959 enrolled
CARES-009 NCT04521153 Perioperative camrelizumab-rivoceranib vs surgery alone Wang 2025, PMID 41125112 EFS 42.1 vs 19.4 months, HR 0.59 (0.41–0.85); China, open-label phase 2/3

ClinicalTrials.gov listed SHARP, REFLECT, RESORCE, IMbrave150, CheckMate 9DW, IMbrave050, and LEAP-012 as completed on 2026-08-30. HIMALAYA and EMERALD-1 were active, not recruiting, reflecting ongoing follow-up or registry maintenance despite primary publication. Change on 2026-10-11: LEAP-012 is now listed as terminated ("Business Reasons"; primary completion 2025-08-19, study completion 2026-03-26). Its results, first posted on 2026-09-03, give final OS of 40.4 versus 40.8 months (HR 0.98, 95% CI 0.76–1.26) with PFS unchanged at HR 0.66 (NCT04246177). This is a registry posting, not a peer-reviewed report; see locoregional therapy.

Additional published trials checked on 2026-10-25

Trial Registry status Publication and boundary
TORCH (NCT02435953) Completed; no posted registry results Abstract: PFS HR 0.47 and OS HR 0.50 for TACE-ablation vs TACE; two Chinese centres; open full text still unavailable (Lyu 2026, PMID 42530948)
EMERALD-3 (NCT05301842) Active, not recruiting; last updated 2026-10-16; no posted registry results Abstract: STRIDE + lenvatinib + TACE PFS HR 0.70, OS HR 0.84 (p=0.18). Erratum PMID 42805209 exists; correction text unread (Kudo 2026, PMID 42636832)
RAD-18-TAcE (NCT04803019) Unknown; last posted update 2021-03-19 Full-text trial report available (Mosconi 2026, PMID 42265476); registry staleness must not be interpreted as active recruitment
KEYNOTE-937 (NCT03867084) Completed; results first posted 2026-04-24 Registry-posted null adjuvant pembrolizumab; no PubMed primary on 2026-10-25
CARES-009 (NCT04521153) Active, not recruiting; last updated 2025-05-11; no posted registry results Published EFS benefit for perioperative camrelizumab-rivoceranib (Wang 2025, PMID 41125112); historical recovery this sweep

Current portfolio by disease phase

Disease phase Active direction Scientific question
Prevention Aspirin or metabolic intervention in cirrhosis/MASLD Can HCC incidence be reduced before cancer?
Surveillance Abbreviated MRI, biomarker cohorts, risk modeling Can early detection improve without excessive harm?
Neoadjuvant IO ± anti-VEGF/TKI before resection Does pathologic response predict recurrence benefit?
Adjuvant IO/TKI after high-risk cure Can micrometastatic recurrence be prevented?
Transplant bridge/downstage TARE/TACE ± IO Can tumor be controlled without rejection risk?
Intermediate TACE/TARE plus systemic therapy Which tumors need combined local-systemic control?
Advanced New checkpoints, bispecifics, vaccines, cell therapy Can response deepen beyond current combinations?
Resistance Post-IO TKI, microbiome, adaptive platforms What reverses primary/acquired resistance?

Surveillance and prevention trials

NCT Status at retrieval Design signal Why it matters
NCT04965259 Active, not recruiting ELEGANCE high-risk prospective early-detection cohort Longitudinal biospecimens and marker validation
NCT05486572 Recruiting PREMIUM: ultrasound+AFP versus abbreviated MRI+AFP every six months 4,700-person RCT powered for HCC mortality through planned 2031 completion
NCT06658782 Recruiting Abbreviated MRI versus ultrasound surveillance Direct modality comparison in high-risk people
NCT07010588 Not yet recruiting Ultrasound versus abbreviated MRI with/without hepatobiliary phase Compares practical MRI strategies
NCT07291141 Recruiting MRI versus ultrasound in cirrhosis Detection plus body composition/decompensation risk
NCT07529262 Not yet recruiting Phase 3 aspirin prevention in cirrhosis Hard prevention endpoint rather than association
NCT07495995 Not yet recruiting Phase 2 SAMe prevention in MASLD cirrhosis Etiology-specific chemoprevention
NCT04172779 Not yet recruiting Erlotinib HCC chemoprevention Repurposed pathway intervention

The critical design distinction is whether a study measures test accuracy, stage shift, or mortality. Better sensitivity does not guarantee net benefit.

Perioperative and adjuvant wave

NCT Status Intervention Boundary
NCT05440864 Recruiting Durvalumab-tremelimumab in resectable HCC Pathologic response and surgical timing
NCT04658147 Active, not recruiting Perioperative nivolumab ± relatlimab Small early-phase feasibility
NCT05701488 Active, not recruiting SIRT + tremelimumab-durvalumab for resectable HCC Local radiation plus IO before surgery
NCT06089382 Not yet recruiting Phase 3 sintilimab-lenvatinib after resection with PVTT Very-high-risk adjuvant population
NCT06498622 Recruiting Donafenib-envafolimab after high-risk cure Adjuvant combination
NCT07350824 Not yet recruiting MRD prediction and adjuvant PD-1 Non-randomized two-cohort design per registry; cannot test whether MRD-guided treatment improves outcomes
NCT06311929 Recruiting Phase 4 precision adjuvant therapy Real-world strategy evaluation
NCT03867084 Completed; results posted 2026-04-24 KEYNOTE-937 adjuvant pembrolizumab vs placebo Registry RFS HR 1.06 (0.88–1.26); no journal primary retrieved
NCT04521153 Active, not recruiting CARES-009 perioperative camrelizumab-rivoceranib Published EFS HR 0.59 (Wang 2025, PMID 41125112)

Perioperative trials face special bias: pathologic response is available only to patients reaching surgery, and immune toxicity can delay or prevent definitive treatment.

Locoregional-systemic integration

NCT Status Strategy
NCT03778957 Active, not recruiting EMERALD-1: TACE + durvalumab ± bevacizumab
NCT04246177 Terminated (business reasons; results posted 2026-09-03) LEAP-012: TACE + lenvatinib-pembrolizumab
NCT05301842 Active, not recruiting EMERALD-3: STRIDE ± lenvatinib + TACE
NCT02435953 Completed TORCH: TACE then thermal ablation
NCT05063565 Active, not recruiting TheraSphere + durvalumab-tremelimumab
NCT04605731 Active, not recruiting Durvalumab-tremelimumab after radioembolization
NCT06999694 Recruiting Proton radiotherapy + tremelimumab-durvalumab
NCT07059494 Recruiting Atezolizumab-bevacizumab + Y-90 for transplant pathway
NCT01918683 Active, not recruiting TACE ± SBRT as transplant bridge

Combined trials must report liver decompensation and transplant consequences alongside PFS.

Resistance and adaptive strategies

NCT Status Hypothesis
NCT04770896 Active, not recruiting Atezolizumab plus lenvatinib/sorafenib after atezolizumab-bevacizumab
NCT05690048 Recruiting Fecal microbiota transfer to overcome atezolizumab-bevacizumab resistance
NCT07328009 Recruiting Personalized adaptive platform
NCT07310173 Recruiting AST-3424 in AKR1C3-high HCC
NCT06109272 Active, not recruiting (89 enrolled) Livmoniplimab-budigalimab
NCT06954467 Recruiting JS207 + JS007 first line

Adaptive platforms can test multiple hypotheses efficiently, but small molecular strata and changing standards complicate control arms.

Cell and vaccine therapies

NCT Status Platform Key concern
NCT06044506 Recruiting Autologous natural-killer cells Persistence and manufacturing
NCT07123545 Recruiting Autologous neoantigen-specific T cells Turnaround and personalized product
NCT04147078 Recruiting Personalized dendritic-cell vaccine after surgery Antigen selection and recurrence endpoint
NCT06676982 Recruiting CD19 CAR-T in advanced HCC Biological rationale and off-tumor effects need clarity

HCC cell therapy must navigate antigen heterogeneity, an immunosuppressive liver, cirrhosis, and on-target injury to normal tissue.

Trial-population gap

Common exclusions create evidence gaps:

  • Child-Pugh B/C or active decompensation;
  • uncontrolled varices or recent bleeding;
  • solid-organ transplant;
  • active autoimmune disease;
  • severe cardiovascular or renal disease;
  • poor ECOG performance;
  • mixed HCC-cholangiocarcinoma;
  • limited access to trial centres.

These exclusions protect safety and endpoint interpretability but limit real-world transportability.

Endpoints and pitfalls

Endpoint Strength Pitfall
Overall survival Patient-important and integrative Subsequent therapy and competing liver death
PFS Earlier readout Imaging timing and uncertain OS translation
Recurrence-free survival Relevant after cure Does not distinguish delayed recurrence from cure
Objective response Useful for conversion/downstaging Criteria and confirmation vary
Pathologic response Direct tissue effect Only resected patients assessed
Time to deterioration/QoL Patient-centered Missing data and open-label bias
Child-Pugh/ALBI worsening Liver preservation Tumor, toxicity, and infection confounded

Live registry snapshot and denominator discipline

Portfolio Registered status on 2026-08-30 Planned enrollment Interpretation
HIMALAYA (NCT03298451) Active, not recruiting 1,324 Published efficacy does not require the registry to be “completed”; long-term follow-up remains active
CheckMate 9DW (NCT04039607) Completed 732 Registry enrollment differs from the 668 randomized patients in the global publication (Yau 2025, PMID 40349714)
IMbrave050 (NCT04102098) Completed 668 Updated RFS HR 0.90 (95% CI 0.72–1.12); initial benefit was not sustained (Yopp 2026, PMID 41580093)
EMERALD-1 (NCT03778957) Active, not recruiting 724 PFS publication precedes final registry closure and mature OS
LEAP-012 (NCT04246177) Terminated (2026-10-11; was completed on 2026-08-30) 480 Registry-posted final OS: HR 0.98 (95% CI 0.76–1.26), median 40.4 vs 40.8 months; PFS benefit without OS benefit
IMbrave251 (NCT04770896) Active, not recruiting 557 Tests continuation/change of pathway after atezolizumab-bevacizumab
ELEGANCE detection cohort (NCT04965259) Active, not recruiting 2,002 Large prospective biomarker cohort, not a randomized mortality trial
PREMIUM surveillance RCT (NCT05486572) Recruiting 4,700 HCC-mortality endpoint; estimated completion September 2031
Adaptive platform (NCT07328009) Recruiting 350 Efficiently tests multiple hypotheses but requires contemporaneous controls
AspiRe HCC prevention (NCT07529262) Not yet recruiting 890 Phase 3 prevention ambition; no efficacy inference until enrollment and results
MRD-guided adjuvant study (NCT07350824) Not yet recruiting 276 Registry allocation is NON_RANDOMIZED (active monitoring vs adjuvant PD-1 cohorts), so it cannot validate MRD-triggered treatment
KEYNOTE-937 (NCT03867084) Completed; results posted 2026-04-24 959 Registry-posted adjuvant pembrolizumab RFS HR 1.06 (0.88–1.26); no PubMed primary on 2026-10-25
CARES-009 (NCT04521153) Active, not recruiting 294 Published perioperative EFS benefit (Wang 2025, PMID 41125112); registry last updated 2025-05-11
EMERALD-3 (NCT05301842) Active, not recruiting 760 Abstract PFS benefit without significant OS; erratum unread (Kudo 2026, PMID 42636832)

Registry status must not be confused with evidence status. “Recruiting” does not mean promising, “completed” does not mean positive, and a planned sample is not an analyzed sample. Conversely, an active-not-recruiting registry can have a practice-changing primary publication while survival follow-up continues.

What earlier trial generations teach

A systematic review of randomized HCC trials from 2002–2020 showed that positive evidence accumulated unevenly across disease stages and that many apparently plausible interventions failed at phase 3 (Haber 2021, PMID 34126063). STORM is the canonical adjuvant warning: sorafenib activity in advanced disease did not prevent recurrence after cure, and molecular analyses found prognostic signals without a validated predictive subgroup that rescued the negative trial (Pinyol 2019, PMID 30108162). By contrast, adjuvant cytokine-induced killer cells showed recurrence benefit in a randomized setting but did not become a globally standardized platform because manufacturing, replication, and evolving comparators matter (Lee 2015, PMID 25747273).

Conversion and neoadjuvant studies introduce denominator risk. A single-arm lenvatinib-plus-PD-1 phase 2 can report resection among responders, but the meaningful denominator is everyone who started conversion therapy and the endpoints include progression that closes surgery, operative delay, pathologic response, recurrence, and OS (Zhang 2023, PMID 37730273). In neoadjuvant cabozantinib-nivolumab, 5 of 15 patients had a pathologic response; spatial analysis revealed different resistance and recurrence programs, but 15 patients cannot validate a surrogate endpoint (Zhang 2023, PMID 37723590).

Early-phase innovation: signal versus proof

Platform Early evidence Missing proof
TACE plus lenvatinib Prospective multicentre single-arm phase 2 in selected Child-Pugh A intermediate HCC Randomized attribution and OS (Kudo 2024, PMID 38344448)
TACE then pembrolizumab PETAL phase 1b: 15 patients; no dose-limiting synergistic toxicity, treatment-related events in 93% Comparative efficacy and decompensation risk (Pinato 2024, PMID 38578610)
Personalized neoantigen vaccine plus pembrolizumab Phase 1/2 demonstrated feasibility and immune/clinical signals Manufacturing scalability, randomized benefit, and biomarker-defined responders (Yarchoan 2024, PMID 38584166)
GPC3 CAR-T Phase-1 trials established feasibility and antitumor activity Persistence, antigen escape, on-target liver injury, and controlled efficacy (Shi 2020, PMID 32371538)
Perioperative checkpoint therapy CARES-009 improved EFS versus surgery alone (HR 0.59); earlier studies showed pathologic responses OS maturity, transport outside China, and whether neoadjuvant exposure (not the full perioperative package) caused the benefit (Wang 2025, PMID 41125112; Llovet 2024, PMID 38424197)

Highest-value portfolio gaps

  1. Head-to-head first-line IO combinations.
  2. Randomized sequencing after IO-combination failure.
  3. Child-Pugh B-specific trials with liver and cancer endpoints.
  4. Completion of a modern surveillance mortality trial outside HBV; PREMIUM is recruiting but has no outcome data (NCT05486572).
  5. Risk-enriched non-cirrhotic MASLD surveillance.
  6. Prospective biomarker-treatment interaction.
  7. Transplant-safe perioperative IO strategies.
  8. Patient-reported outcomes that separate tumor and cirrhosis burden.

Open questions

  • LEAP-012's registry-posted final OS shows no gain (NCT04246177), and EMERALD-3's abstract OS is likewise non-significant (Kudo 2026, PMID 42636832). Will EMERALD-1's PFS gain translate into OS, and do TACE-combination trials need OS rather than PFS as their primary endpoint?
  • Which MRD assay is ready to randomize adjuvant treatment? NCT07350824 is registered as non-randomized.
  • Can microbiome intervention reverse IO resistance reproducibly (NCT05690048)?
  • Will abbreviated MRI improve HCC mortality and net benefit, not merely detection, in PREMIUM and the companion modality trials (NCT05486572; NCT06658782; NCT07010588)?
  • How can decompensated patients be studied safely without excluding the population most unlike pivotal trials?

References

  1. Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. PMID 18650514
  2. Kudo M, et al. Lenvatinib versus sorafenib in unresectable HCC. Lancet. 2018;391:1163-1173. PMID 29433850
  3. Bruix J, et al. Regorafenib after sorafenib (RESORCE). Lancet. 2017;389:56-66. PMID 27932229
  4. Finn RS, et al. Atezolizumab plus bevacizumab in unresectable HCC. N Engl J Med. 2020;382:1894-1905. PMID 32402160
  5. Abou-Alfa GK, et al. Tremelimumab plus durvalumab in unresectable HCC. NEJM Evid. 2022;1:EVIDoa2100070. PMID 38319892
  6. Yau T, et al. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW). Lancet. 2025;405:1851-1864. PMID 40349714
  7. Qin S, et al. IMbrave050. Lancet. 2023;402:1835-1847. PMID 37871608
  8. Sangro B, et al. EMERALD-1. Lancet. 2025;405:216-232. PMID 39798579
  9. Kudo M, et al. LEAP-012. Lancet. 2025;405:203-215. PMID 39798578
  10. Haber PK, et al. Evidence-based management of HCC: systematic review of randomized trials, 2002–2020. Gastroenterology. 2021;161:879-898. PMID 34126063
  11. Pinyol R, et al. Molecular predictors and prognostic factors in the phase 3 STORM adjuvant trial. Gut. 2019;68:1065-1075. PMID 30108162
  12. Lee JH, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for HCC. Gastroenterology. 2015;148:1383-1391.e6. PMID 25747273
  13. Zhang W, et al. Lenvatinib plus anti-PD-1 antibodies as conversion therapy: phase 2 trial. J Immunother Cancer. 2023;11. PMID 37730273
  14. Kudo M, et al. TACE plus lenvatinib in intermediate HCC: TACTICS-L phase 2 trial. Liver Cancer. 2024;13:99-112. PMID 38344448
  15. Pinato DJ, et al. Pembrolizumab following TACE: PETAL phase 1b study. Clin Cancer Res. 2024;30:2433-2443. PMID 38578610
  16. Llovet JM, et al. Adjuvant and neoadjuvant immunotherapies in HCC. Nat Rev Clin Oncol. 2024;21:294-311. PMID 38424197
  17. Zhang S, et al. Spatial transcriptomics of neoadjuvant cabozantinib-nivolumab identifies resistance and recurrence mechanisms. Genome Med. 2023;15:72. PMID 37723590
  18. Yarchoan M, et al. Personalized neoantigen vaccine and pembrolizumab in advanced HCC: phase 1/2 trial. Nat Med. 2024;30:1044-1053. PMID 38584166
  19. Shi D, et al. Glypican-3 CAR-T therapy for advanced HCC: phase 1 trials. Clin Cancer Res. 2020;26:3979-3989. PMID 32371538
  20. Yopp A, et al. Updated data from IMbrave050: adjuvant atezolizumab plus bevacizumab for high-risk hepatocellular carcinoma. J Hepatol. 2026;84:1102-1111. PMID 41580093
  21. Lyu N, et al. Transarterial Chemoembolization Plus Thermal Ablation in Unresectable Hepatocellular Carcinoma: The Phase 3 TORCH Randomized Clinical Trial. JAMA Oncol. 2026;12:980-989. PMID 42530948
  22. Kudo M, et al. Durvalumab and tremelimumab, with or without lenvatinib, combined with transarterial chemoembolisation in participants with embolisation-eligible hepatocellular carcinoma (EMERALD-3): a global, randomised, open-label, sponsor-blinded, phase 3 study. Lancet Oncol. 2026;27:1077-1093. PMID 42636832
  23. Wang Z, et al. Perioperative camrelizumab plus rivoceranib versus surgery alone in patients with resectable hepatocellular carcinoma at intermediate or high risk of recurrence (CARES-009): a randomised phase 2/3 trial. Lancet. 2025;406:2089-2099. PMID 41125112
  24. Correction to Lancet Oncol 2026; 27: 1077-93. Lancet Oncol. 2026;27:e450. PMID 42805209
  25. Mosconi C, et al. Transarterial Embolization Alone Versus Drug-Eluting Microspheres Chemoembolization for Hepatocellular Carcinoma (RAD-18-TAcE): A Multicenter Randomized Clinical Trial. Cardiovasc Intervent Radiol. 2026;49:2052-2061. PMID 42265476