Systemic Therapy for Unresectable Hepatocellular Carcinoma: Current Landscape and Future Directions
Abstract
1. Introduction
2. Molecular Pathways and Mutations in Hepatocellular Carcinoma Pathogenesis
2.1. Genomic Alterations
2.2. Structural Variations and Viral Integration
2.3. Key Dysregulated Pathways
2.4. Immune Evasion and Tumor Microenvironment
2.5. Epigenetic and Non-Coding RNA Alterations
2.6. Metabolic Reprogramming
2.7. Cancer Stem Cells and the Tumor Microenvironment
2.8. Clinical Implications and Therapeutic Challenges
3. Systemic Therapy for HCC
3.1. First-Line Therapies
3.2. Second-Line Therapies
3.3. Third-Line Therapies
3.4. Emerging Therapies
4. Discussion
Author Contributions
Funding
Conflicts of Interest
References
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Pathway | Gene/Mutation | Function | Targetable |
---|---|---|---|
Telomerase Activation | TERT promoter mutations/HBV integration | Reactivates telomerase, bypasses senescence | Imetelstat (telomerase inhibitor) in trials; no approved therapy yet [40] |
DNA Damage Response | P53 (R249S hotspot), BRCA1/2 | Impairs DNA repair, apoptosis; BRCA loss causes genomic instability | PARP inhibitors (olaparib) in trials for BRCA+ HCC; no direct TP53 therapies [41] |
Wnt/β-catenin | CTNNB1, AXIN1, APC | Wnt activation, proliferation, chemoresistance | Porcupine inhibitors (LGK974) and β-catenin disruptors in preclinical [42] |
Chromatin Remodeling | ARID1A, ARID2, SMARCA4 | Impaired epigenetic control, chromatin instability | HDAC inhibitors (panobinostat) and EZH2 inhibitors in trials [43] |
JAK/STAT | JAK1, IL6ST, STAT3 amplification | STAT3 activation, inflammation, immune evasion | STAT3 antisense oligonucleotides (AZD9150) and JAK inhibitors (ruxolitinib) [44,45] |
RTK (MET, FGFR, EGFR) | MET amp, FGF19 amp, EGFR mutations | Proliferation, angiogenesis, metastasis | MET inhibitors (tepotinib), [46] FGFR inhibitors (pemigatinib), EGFR (erlotinib) [47,48] |
PI3K/Akt/mTOR | PTEN loss, PIK3CA, AKT1 mutations | Growth, metabolic reprogramming | mTOR inhibitors (everolimus), [49] AKT inhibitors (ipatasertib) in trials [50] |
TGF-β | SMAD4 inactivation, TGFBR2 mutations | EMT, metastasis, immunosuppression in late stages | Galunisertib (TGF-βR1 inhibitor) [51] & fresolimumab (antibody) in trials [52] |
Immune Checkpoints | PD-L1/PD-1, CTLA-4, LAG3, TIM3 | T-cell exhaustion, immune evasion | Approved: nivolumab (PD-1), ipilimumab (CTLA-4); LAG3 inhibitors in trials [53] |
Epigenetic Regulation | CDKN2A, RASSF1A hypermethylation | Silences tumor suppressors, promotes cell cycle progression | Hypomethylating agents (azacitidine) and HDAC inhibitors in trials [54] |
Metabolic Reprogramming | HIF-1α, c-MYC, IDH1/2, PKM2 | Aerobic glycolysis, glutamine dependency, lipid synthesis | IDH1 inhibitors (ivosidenib), PKM2 modulators in trials [55] |
Cancer Stem Cell | EpCAM, CD133, CD47, NANOG, ALDH1A1 | Self-renewal, therapy resistance, immune evasion | Anti-CD47 (magrolimab) and ALDH inhibitors in early trials [56] |
Tumor Microenvironment | YAP/TAZ, CAFs, HIF-1α, CXCL12 | CSC niche, angiogenesis, immune suppression | YAP/TAZ inhibitors (verteporfin) [57], CXCR4 antagonists (plerixafor) in preclinical [58] |
Hedgehog Signaling | SMO, GLI1/2 mutations | Stemness, desmoplasia, tumor-stroma crosstalk | Glasdegib (SMO inhibitor) in phase I/II trials [59] |
Notch Signaling | NOTCH1/2/3, JAG1 overexpression | Differentiation blockade, angiogenesis | Gamma-secretase inhibitors (AL101) in preclinical [60] |
RAS/RAF/MEK/ERK | KRAS/NRAS, BRAF V600E | Proliferation, survival, metastasis | MEK inhibitors (trametinib) in trials for BRAF-mutant HCC [61] |
VEGF/VEGFR | VEGFA amp, VEGFR2 mutations | Angiogenesis, immune suppression | Approved: sorafenib, lenvatinib, ramucirumab (VEGFR2) [62] |
Ferroptosis | GPX4 downregulation, SLC7A11 loss | Lipid peroxidation-driven cell death | Ferroptosis inducers (erastin, sulfasalazine) in preclinical [63] |
Autophagy | ATG5/7, BECN1 mutations | Stress adaptation, chemoresistance | Chloroquine/hydroxychloroquine in trials with chemo [64] |
Ubiquitin-Proteasome | FBXW7 mutations | Stabilizes oncoproteins (c-MYC, mTOR) | Proteasome inhibitors (bortezomib) in early trials [65] |
Genetic Alteration/Pathway | Association with Unresectable HCC |
---|---|
TP53 Mutation (p53 pathway) | TP53-mutated tumors show high rates of vascular invasion and poor prognosis, often being advanced. |
RAS/RAF/MAPK Pathway | Activation of RAS/MAPK (e.g., KRAS mutation or FGF19–FGFR4 amplification) is linked to extrahepatic metastasis and aggressive disease. |
PI3K/Akt/mTOR Pathway | Frequently active in HCC (~50%); drives proliferation, motility, and angiogenesis, thereby facilitating tumor progression. |
TGF-β Signaling | Elevated TGF-β activity promotes EMT, invasion, and metastasis; associated with vascular invasion in HCC. |
VEGF/VEGFR (Angiogenesis) | High VEGF levels correlate with microvascular invasion and metastasis in advanced HCC. |
Immune Checkpoints (PD-1/PD-L1, CTLA-4) | PD-L1 overexpression is tied to vascular invasion and advanced stage in HCC. |
Tumor Microenvironment (CAFs, TAMs) | Pro-tumor stroma secretes factors (TGF-β, etc.) that enhance HCC invasion and spread. |
Hedgehog Signaling | Hh pathway activation is associated with worse prognosis and more advanced, invasive HCC. |
Hippo Pathway (YAP activation) | YAP overexpression correlates with poor survival, intrahepatic metastases, and vascular invasion. |
Epigenetic Alterations (e.g., ARID1A) | Mutations like ARID1A are linked to larger tumors with microvascular invasion. |
Trial Name | Type of Trial | Primary Outcomes | Secondary Outcomes | Patient Population | Number of Patients | Key Findings |
---|---|---|---|---|---|---|
IMbrave150 [70] | Randomized Controlled Trial, Open-label | Overall Survival (OS), Progression-Free Survival (PFS) | Objective Response Rate (ORR), Safety, Patient-Reported Outcomes (PROs) | Unresectable HCC, no prior systemic therapy, Child–Pugh class A, ECOG PS 0-1 | 501 (336 atezolizumab + bevacizumab, 165 sorafenib) | Atezolizumab + bevacizumab significantly improved OS (HR 0.66, p < 0.001) and PFS (HR 0.65, p < 0.001) compared to sorafenib. ORR was 29.8% for atezolizumab + bevacizumab vs. 11.3% for sorafenib. |
HIMALAYA [73] | Randomized Controlled Trial, Open-label | Overall Survival (OS) | Objective Response Rate (ORR), Safety, Patient-Reported Outcomes (PROs) | Unresectable HCC, no prior systemic therapy, Child–Pugh class A, ECOG PS 0-1 | 1171 (393 STRIDE, 389 durvalumab, 389 sorafenib) | STRIDE regimen (tremelimumab + durvalumab) significantly improved OS (HR 0.78, p = 0.0035) compared to sorafenib. ORR was 20.1% for STRIDE vs. 5.1% for sorafenib. Durvalumab monotherapy was noninferior to sorafenib for OS (HR 0.86, 95.67% CI, 0.73–1.03). |
SHARP [76] | Randomized Controlled Trial, Double-blind | Overall Survival (OS) | Time to Progression (TTP), Disease Control Rate (DCR), Safety | Advanced HCC, Child–Pugh class A, ECOG PS 0-2 | 602 (299 sorafenib, 303 placebo) | Sorafenib significantly improved OS (HR 0.69, p < 0.001) compared to placebo. Median OS was 10.7 months for sorafenib vs. 7.9 months for placebo. |
REFLECT [77] | Randomized Controlled Trial, Open-label | Overall Survival (OS) | Progression-Free Survival (PFS), Objective Response Rate (ORR), Safety | Unresectable HCC, no prior systemic therapy, Child–Pugh class A, ECOG PS 0-1 | 954 (478 lenvatinib, 476 sorafenib) | Lenvatinib was non-inferior to sorafenib for OS (HR 0.92, 95% CI, 0.79–1.06). Median OS was 13.6 months for lenvatinib vs. 12.3 months for sorafenib. |
CELESTIAL [78] | Randomized Controlled Trial, Double-blind | Overall Survival (OS) | Progression-Free Survival (PFS), Objective Response Rate (ORR), Safety | Advanced HCC, previously treated with sorafenib, Child–Pugh class A, ECOG PS 0-1 | 707 (470 cabozantinib, 237 placebo) | Cabozantinib significantly improved OS (HR 0.76, p = 0.005) compared to placebo. Median OS was 10.2 months for cabozantinib vs. 8.0 months for placebo. |
RESORCE [79] | Randomized Controlled Trial, Double-blind | Overall Survival (OS) | Progression-Free Survival (PFS), Objective Response Rate (ORR), Safety | Advanced HCC, previously treated with sorafenib, Child–Pugh class A, ECOG PS 0-1 | 573 (379 regorafenib, 194 placebo) | Regorafenib significantly improved OS (HR 0.63, p < 0.001) compared to placebo. Median OS was 10.6 months for regorafenib vs. 7.8 months for placebo. |
REACH [80] | Randomized Controlled Trial, Double-blind | Overall Survival (OS) | Progression-Free Survival (PFS), Objective Response Rate (ORR), Safety | Advanced HCC, previously treated with sorafenib, Child–Pugh class A, ECOG PS 0-1 | 565 (283 ramucirumab, 282 placebo) | Ramucirumab did not significantly improve OS compared to placebo (HR 0.87, p = 0.14). |
REACH-2 [81] | Randomized Controlled Trial, Double-blind | Overall Survival (OS) | Progression-Free Survival (PFS), Objective Response Rate (ORR), Safety | Advanced HCC, previously treated with sorafenib, AFP ≥ 400 ng/mL, Child–Pugh class A, ECOG PS 0-1 | 292 (197 ramucirumab, 95 placebo) | Ramucirumab significantly improved OS (HR 0.71, p = 0.0199) compared to placebo. Median OS was 8.5 months for ramucirumab vs. 7.3 months for placebo. |
CheckMate-040 [82] | Phase I/II, Open-label | Safety, Objective Response Rate (ORR) | Overall Survival (OS), Progression-Free Survival (PFS) | Advanced HCC, previously treated with sorafenib, Child–Pugh class A, ECOG PS 0-1 | 262 (48 nivolumab, 214 nivolumab + ipilimumab) | Nivolumab showed an ORR of 14.3% and a median OS of 15.1 months. Nivolumab + ipilimumab showed an ORR of 32% and a median OS of 22.8 months. |
CheckMate-459 [83] | Randomized Controlled Trial, Open-label | Overall Survival (OS) | Progression-Free Survival (PFS), Objective Response Rate (ORR), Safety | Advanced HCC, no prior systemic therapy, Child–Pugh class A, ECOG PS 0-1 | 743 (371 nivolumab, 372 sorafenib) | Nivolumab did not significantly improve OS compared to sorafenib (HR 0.85, p = 0.0752). Median OS was 16.4 months for nivolumab vs. 14.7 months for sorafenib. |
CheckMate-9DW [85] | Randomized Controlled Trial, Open-label | Overall Survival (OS) | Progression-Free Survival (PFS), Objective Response Rate (ORR), Safety | Advanced HCC, no prior systemic therapy, Child–Pugh class A, ECOG PS 0-1 | 668 (335 nivolumab + ipilimumab, 333 lenvatinib or sorafenib) | Nivolumab + ipilimumab significantly improved OS (HR 0.79, p = 0.0180) compared to sorafenib. Median OS was 23.7 months for nivolumab + ipilimumab vs. 20.6 months for lenvatinib or sorafenib. |
KEYNOTE-224 [87] | Phase II, Open-label | Objective Response Rate (ORR) | Overall Survival (OS), Progression-Free Survival (PFS), Safety | Advanced HCC, previously treated with sorafenib, Child–Pugh class A, ECOG PS 0-1 | 104 (104 pembrolizumab) | Pembrolizumab showed an ORR of 17% and a median OS of 13.9 months. |
KEYNOTE-240 [88] | Randomized Controlled Trial, Double-blind | Overall Survival (OS), Progression-Free Survival (PFS) | Objective Response Rate (ORR), Safety | Advanced HCC, previously treated with sorafenib, Child–Pugh class A, ECOG PS 0-1 | 413 (278 pembrolizumab, 135 placebo) | Pembrolizumab did not significantly improve OS (HR 0.78, p = 0.0209) or PFS (HR 0.72, p = 0.0002) compared to placebo (statistically significant but did not meet the primary endpoint) |
KEYNOTE-394 [89] | Randomized Controlled Trial, Double-blind | Overall Survival (OS) | Progression-Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR) | Advanced HCC, previously treated with sorafenib, Child–Pugh class A, ECOG PS 0-1 | 453 (300 pembrolizumab, 153 placebo) | Pembrolizumab significantly improved median OS compared to placebo (14.6 vs. 13.0 months (HR 0.79, p = 0.0180) as well as PFS and ORR. |
Trial | Therapy | Overall Survival (Months) | Progression-Free Survival (Months) | Objective Response Rate (%) |
---|---|---|---|---|
IMbrave150 [70] | Atezolizumab + Bevacizumab | 19.2 | 6.8 | 27.3 |
HIMALAYA [73] | Tremelimumab + Durvalumab | 16.4 | 3.8 | 20.1 |
SHARP [76] | Sorafenib | 10.7 | 5.5 | 2.0 |
REFLECT [77] | Lenvatinib | 13.6 | 7.4 | 24.1 |
CELESTIAL [78] | Cabozantinib | 10.2 | 5.2 | 4.0 |
RESORCE [79] | Regorafenib | 10.6 | 3.1 | 11.0 |
REACH [80] | Ramucirumab | 9.2 | 2.8 | 4.6 |
REACH-2 [81] | Ramucirumab | 8.5 | 2.8 | 4.6 |
CheckMate-040 [82] | Nivolumab | 15.0 | 4.0 | 15.0–20.0 |
CheckMate-459 [83] | Nivolumab | 16.4 | 3.7 | 15.0 |
CheckMate-9DW [85] | Nivolumab + Ipilimumab | 23.7 | 9.1 | 36.0 |
KEYNOTE-224 [87] | Pembrolizumab | 12.9 | 4.9 | 17.0 |
KEYNOTE-240 [88] | Pembrolizumab | 13.9 | 3.0 | 18.3 |
KEYNOTE-394 [89] | Pembrolizumab | 14.6 | 2.6 | 12.7 |
NCT Number | Study Title | Study Status | Interventions | Primary Outcome Measures | Enrollment | Study Type | Study Design | Start Date | Completion Date |
---|---|---|---|---|---|---|---|---|---|
NCT06261138 | Survival Analysis: TACE vs. Combination Therapy in HCC | Completed | DRUG: Transarterial chemoembolization|OTHER: Systemic treatment | Progression-free survival (PFS) per mRECIST: The duration from treatment initiation to PD in patients who cannot undergo surgery, or to the date of postoperative relapse in patients who receive surgery, or death for any reason, whichever occurs first (according to mRECIST), 12–48 months | 279 | Observational | Observational Model: Time Perspective: p | 1 February 2019 | 31 October 2023 |
NCT05630937 | Study on Safety and Efficacy of NMS-01940153E in Adult Patients With Unresectable Hepatocellular Carcinoma (HCC) Previously Treated With Systemic Therapy | Completed | DRUG: NMS-01940153E | Drug-related dose limiting toxicities (DLTs) (phase I), Cycle 1 (28 days); objective response rate (ORR) (phase II), within two years | 31 | Interventional | Allocation: NA|Intervention Model: SEQUENTIAL|Masking: NONE|Primary Purpose: TREATMENT | 13 November 2020 | 6 August 2024 |
NCT00812175 | Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of Its Treatment With Sorafenib | Completed | DRUG: Sorafenib (Nexavar, BAY43-9006) | The safety of Nexavar in all patients with unresectable HCC who are candidates for systemic therapy and in whom a decision to treat with Nexavar has been made under real-life practice conditions, at each follow-up visit, every 2–4 months on average | 3371 | Observational | Observational Model: Time Perspective: p | January 2009 | April 2012 |
NCT06680258 | A Study of TPST-1120 With Atezolizumab Plus Bevacizumab in Patients With Unresectable or Metastatic HCC Not Previously Treated With Systemic Therapy | NOT_YET_RECRUITING | DRUG: TPST-1120|BIOLOGICAL: Atezolizumab|BIOLOGICAL: Bevacizumab | Overall survival (OS), defined as the time from randomization to death from any cause up to 60 months; the time from randomization to death from any cause up to 60 months | 740 | Interventional | Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: QUADRUPLE (PARTICIPANT, CARE_PROVIDER, INVESTIGATOR, OUTCOMES_ASSESSOR)|Primary Purpose: TREATMENT | 29 March 2025 | December 2029 |
NCT00901901 | Nexavar-Tarceva Combination Therapy for First Line Treatment of Patients Diagnosed With Hepatocellular Carcinoma | Completed | DRUG: Sorafenib (Nexavar, BAY43-9006)|DRUG: Erlotinib (Tarceva)|DRUG: Placebo | Overall survival (OS): Overall survival (OS) was defined as the time from date of randomization to death due to any cause; from randomization of the first patient until 34 months or date of death of any cause whichever came first | 732 | Interventional | Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: DOUBLE (PARTICIPANT, INVESTIGATOR)|Primary Purpose: TREATMENT | 21 May 2009 | 23 May 2018 |
NCT00988741 | Trial of ARQ 197 in Patients With Unresectable Hepatocellular Carcinoma (HCC) Who Have Failed One Prior Systemic Therapy | Completed | DRUG: ARQ 197|DRUG: Placebo | Evaluate time to progression among all patients treated with ARQ 197 compared to placebo. Patients will be evaluated every 6 weeks until unacceptable toxicity, disease progression or another discontinuation criterion is met | 107 | Interventional | Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: QUADRUPLE (PARTICIPANT, CARE_PROVIDER, INVESTIGATOR, OUTCOMES_ASSESSOR)|Primary Purpose: TREATMENT | September 2009 | March 2012 |
NCT06796803 | Camrelizumab Combined with Rivoceranib and Hepatic Arterial Infusion Chemotherapy (HAIC) As Conversion Therapy for Potentially Resectable Hepatocellular Carcinoma(HCC) | Not_Yet_Recruiting | DRUG: camrelizumab combined with rivoceranib and HAIC|DRUG: camerlizumab + rivoceranib | R0 rate: R0 rate defined as the proportion of patients who accomplish the complete resection of tumor with pathologically confirmed negative margin, 24 months|OS, Overall survival (OS) after randomization, defined as the time from randomization to death from any cause, 24 months | 398 | Interventional | Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: TREATMENT | 20 February 2025 | 28 February 2030 |
NCT02989922 | A Study to Evaluate SHR-1210 in Subjects With Advanced HCC | Completed | BIOLOGICAL: SHR-1210 | Objective response rate: Tumour responses were evaluated by the independent review committee (IRC) according to RECIST 1.1. The primary endpoints were the proportion of patients with an IRC-assessed objective response (defined as the percentage of patients whose best overall response was confirmed complete or partial response); approximate 3 years|6-month overall survival rate, 6-month overall survival rate (defined as cumulative overall survival rate from the date of the first dose to 6 months), from the date of the first dose to 6 months | 220 | Interventional | Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: TREATMENT | 15 November 2016 | 3 March 2020 |
NCT05917431 | Phase 2 Study of SBRT Plus Tislelizumab and Regorafenib in Unresectable or Oligometastatic HCC | Recruiting | COMBINATION_PRODUCT: SBRT plus tislelizumab and regorafenib | PFS, progression-free survival, from the date of treatment beginning until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months | 39 | Interventional | Allocation: NA|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: TREATMENT | June 2023 | 30 December 2026 |
NCT04732286 | A Study of Atezolizumab in Combination With Bevacizumab in Spanish Patients With Unresectable or Unsuitable for Locoregional Treatments Hepatocellular Carcinoma Not Previously Treated With Systemic Therapy | Completed | DRUG: Atezolizumab|DRUG: Bevacizumab | Incidence of treatment discontinuations of atezolizumab and/or bevacizumab due to adverse events of grade ≥ 3, Initiation of study treatment up to approximately 3 years | 100 | Interventional | Allocation: NA|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: TREATMENT | 4 May 2021 | 26 April 2024 |
NCT05733598 | Study of RP2 in Combination With Second-line Therapy in Patients With Locally Advanced Unresectable or Metastatic HCC | Recruiting | BIOLOGICAL: RP2|BIOLOGICAL: Bevacizumab|BIOLOGICAL: Atezolizumab | Overall response rate per modified RECIST 1.1. The proportion of patients achieving a BOR of CR or PR per RECIST 1.1 as modified for use in this study among those that are evaluable for response., From Day 1 up to 3 years after first RP2 dose of last patient | 30 | Interventional | Allocation: NA|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: TREATMENT | 1 August 2024 | 1 July 2028 |
NCT01755767 | Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma (HCC) Who Have Been Treated With One Prior Therapy | Completed | DRUG: Tivantinib|DRUG: Placebo | Median overall survival (OS) following treatment with tivantinib 120 mg BID compared to placebo group in participants with MET diagnostic-high inoperable hepatocellular carcinoma (HCC) treated with one prior systemic therapy. Overall survival (OS) is defined as the time from randomization to the date of death. The rate of OS (percentage of participants still alive) was determined only in the tivantinib 120 mg BID cohort, within 36 months. Overall survival (OS) rate at different time points following treatment with tivantinib 120 mg BID compared to placebo group in participants with MET diagnostic-high inoperable hepatocellular carcinoma (HCC) treated with one prior systemic therapy. Overall survival (OS) is defined as the time from randomization to the date of death. The rate of OS (percentage of participants still alive) was determined only in the tivantinib 120 mg BID cohort, within 36 months | 383 | Interventional | Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: QUADRUPLE (PARTICIPANT, CARE_PROVIDER, INVESTIGATOR, OUTCOMES_ASSESSOR)|Primary Purpose: TREATMENT | 27 December 2012 | 31 July 2017 |
NCT00355238 | A Phase II Open Label Study of BMS-582664 in Locally Advanced or Metastatic Hepatocellular Cancer | Completed | DRUG: brivanib (active) | Progression-free survival (PFS) rate at 6 months per Independent Response Review Committee (IRRC) in Cohort A. The percent of participants who have not progressed or died prior to 6 months from the date of their first dose. Participants who have neither progressed nor died but had their last tumor assessment prior to 6 months will not be categorized as progression free and will not be included. Tumor response was measured by the IRRC using mWHO criteria. Progression is defined as a 25% or more increase in the sum of all index lesion areas taking as reference the smallest sum recorded at or following baseline, from first dose up to approximately 6 months after first dose. The number of participants experiencing adverse events (AEs): An adverse event (AE) is defined as any new untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have to have a causal relationship with this treatment, from first dose up to 30 days post last dose (up to approximately 34 months) | 137 | Interventional | Allocation: NA|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: TREATMENT | 31 December 2006 | 30 April 2010 |
NCT04487067 | A Study of Atezolizumab (Tecentriq) in Combination With Bevacizumab to Investigate Safety and Efficacy in Patients With Unresectable Hepatocellular Carcinoma Not Previously Treated With Systemic Therapy-Amethista | Completed | DRUG: Atezolizumab|DRUG: Bevacizumab | Number of participants with Grade 3–5 NCI CTCAE v.5 Bleeding/Haemorrhage, up to approximately 48 months | 152 | Interventional | Allocation: NA|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: TREATMENT | 25 August 2020 | 13 August 2024 |
NCT06109272 | A Study to Assess the Dose, Adverse Events, and Change in Disease Activity of Livmoniplimab as an Intravenous (IV) Solution in Combination With Budigalimab as an IV Solution in Adult Participants With Hepatocellular Carcinoma (HCC) | Active_Not_Recruiting | DRUG: Livmoniplimab|DRUG: Budigalimab|DRUG: Durvalumab|DRUG: Atezolizumab|DRUG: Bevacizumab|DRUG: Tremelimumab | Stage 1: Best overall response (BOR) per investigator: BOR is defined as a participant achieving confirmed complete response (CR) or confirmed partial response (PR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as determined by investigators at any time prior to subsequent anticancer therapy, through study completion, up to approximately 56 Months. Stage 2: Overall survival (OS): OS is defined as the time from randomization until death from any cause, through study completion, up to approximately 56 Months | 660 | Interventional | Allocation: RANDOMIZED|Intervention Model: SEQUENTIAL|Masking: NONE|Primary Purpose: TREATMENT | 11 January 2024 | September 2030 |
NCT06117891 | An Observational Study to Learn More About How Well a Treatment Works When Given After Treatment With Atezolizumab and Bevacizumab or Another Similar Combination of Drugs in Adults With Liver Cancer That Cannot be Treated With Surgery | Recruiting | DRUG: Atezolizumab|DRUG: Bevacizumab|DRUG: Durvalumab|DRUG: Tremelimumab | Overall survival (OS): OS is defined as the time (days) from start of second-line systemic treatment to the date of death, due to any cause. Patients alive or lost to follow-up will be censored at their last date of follow-up; approximately 36 months | 300 | Observational | Observational Model: Time Perspective: p | 27 November 2023 | 1 February 2027 |
NCT03764293 | A Study to Evaluate SHR-1210 in Combination With Apatinib as First-Line Therapy in Patients With Advanced HCC | Completed | DRUG: SHR-1210|DRUG: Apatinib|DRUG: Sorafenib | Overall survival (OS): OS was defined as the time from randomization to death from any cause, up to approximately 3 years. Progression-free survival (PFS): Evaluated by the Blinded Independent Review Committee (BIRC) based on RECIST v1.1, PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) by tumor image evaluation or death from any cause, whichever occurs first as determined by BIRC according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions and the sum of diameters must also demonstrate an absolute increase of \>/ = 5 millimeters (mm), or a measurable increase in a non-target lesion, or the appearance of new lesions, up to approximately 3 years | 543 | Interventional | Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: TREATMENT | 10 June 2019 | 14 June 2023 |
NCT06788353 | Prospective Collection of Therapeutic Efficacy and Safety Data in Patients with Unresectable Hepatocellular Carcinoma | Recruiting | Not Provided | Progression-free survival, defined as the time from commencement of enrollment to progression of disease or death throughout the trial. Patients who withdraw or are lost to follow-ups will be treated as censored data, and the last date of known living without progression will be used as the last survival time. Patients whose diseases have not progressed at ending of this study will be treated as censored data, and the last date of known living without progression will be used as the last survival time, 24 months | 500 | Observational | Observational Model: Time Perspective: p | 1 March 2023 | 1 March 2027 |
NCT03439891 | Sorafenib and Nivolumab in Treating Participants With Unresectable, Locally Advanced or Metastatic Liver Cancer | Completed | BIOLOGICAL: Nivolumab|DRUG: Sorafenib | Maximum tolerated dose (MTD) (Part 1 Only): MTD is defined as the dose in which 1 or more dose limiting toxicities (DLTs) are reported by study participants in Part 1 within the first cycle of treatment. Participants in Part 1 must receive at least 2 doses of nivolumab and at least 75% of sorafenib doses within 28 days (1 cycle), or experience a qualifying DLT event to be evaluable, 28 days. Proportion of participants With grade 3 or higher treatment-related adverse events (Part 2 Only): All adverse events (AEs) will be summarized based on proportion of total participants in Part 2 to evaluate the safety of the treatment combination in participants with Child–Pugh B7-9 liver function as measured by proportion of participants with an AE of toxicity grade \> = 3 as graded by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and assessed as at least possibly related to sorafenib, nivolumab, or the combination of therapies, up to 2 years | 16 | Interventional | Allocation: NON_RANDOMIZED|Intervention Model: SEQUENTIAL|Masking: NONE|Primary Purpose: TREATMENT | 16 April 2018 | 30 November 2023 |
NCT05717738 | Combined TACE, TKI/Anti-VEGF and ICIs as Conversion Therapy for Advanced Hepatocellular Carcinoma | Recruiting | PROCEDURE: TACE|DRUG: Lenvatinib|DRUG: Anti-PD-1 monoclonal antibody|DRUG: Bevacizumab Biosimilar IBI305 plus sintilimab|DRUG: Bevacizumab plus Atezolizumab|DRUG: apatinib plus camrelizumab|DRUG: Sorafenib|DRUG: Donafenib|DRUG: Regorafenib | Number of patients amendable to curative surgical interventions: Number of patients amendable to curative surgical interventions defined as number of patients receiving curative surgical resection, transplantation, or ablation after successful down-sizing of tumor(s) by intervention., from the date of first treatment to the date of last treatment, an average of 3 years | 300 | Observational | Observational Model: Time Perspective: p | 20 January 2022 | 31 December 2024 |
NCT05713994 | Combined HAIC, TKI/anti-VEGF and ICIs As Conversion Therapy for Unresectable Hepatocellular Carcinoma | Recruiting | PROCEDURE: HAIC|DRUG: Bevacizumab plus Atezolizumab|DRUG: Bevacizumab Biosimilar IBI305 plus sintilimab|DRUG: Lenvatinib|DRUG: Sorafenib|DRUG: Donafenib|DRUG: Regorafenib|DRUG: apatinib plus camrelizumab|DRUG: Anti-PD-1 monoclonal antibody | Number of patients amendable to curative surgical interventions: Number of patients amendable to curative surgical interventions defined as number of patients receiving curative surgical resection, transplantation, or ablation after successful down-sizing of tumor(s) by intervention., from the date of first treatment to the date of last treatment, an average of 3 years | 300 | Observational | Observational Model: Time Perspective: p | 19 May 2020 | 30 December 2025 |
NCT03782207 | A Study Investigating the Outcomes and Safety of Atezolizumab Under Real-World Conditions in Patients Treated in Routine Clinical Practice | Active_Not_Recruiting | DRUG: Atezolizumab | Overall survival (OS): Time from index date until date of death from any cause. Index date is the date of administration of the first ever dose of atezolizumab for each patient, index date up to approximately 6 years. OS at 2 years: Percentage of participants alive 2 years after initiation of atezolizumab treatment, after index date up to 2 years | 2756 | Observational | Observational Model: Time Perspective: p | 7 February 2019 | 31 July 2016 |
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Philippi, Z.; Reddy, K.D.; Malik, S.; Al-Khalil, Z.; Dbouk, N. Systemic Therapy for Unresectable Hepatocellular Carcinoma: Current Landscape and Future Directions. Int. J. Mol. Sci. 2025, 26, 5994. https://doi.org/10.3390/ijms26135994
Philippi Z, Reddy KD, Malik S, Al-Khalil Z, Dbouk N. Systemic Therapy for Unresectable Hepatocellular Carcinoma: Current Landscape and Future Directions. International Journal of Molecular Sciences. 2025; 26(13):5994. https://doi.org/10.3390/ijms26135994
Chicago/Turabian StylePhilippi, Zachary, Keerthi D. Reddy, Sheza Malik, Zeina Al-Khalil, and Nader Dbouk. 2025. "Systemic Therapy for Unresectable Hepatocellular Carcinoma: Current Landscape and Future Directions" International Journal of Molecular Sciences 26, no. 13: 5994. https://doi.org/10.3390/ijms26135994
APA StylePhilippi, Z., Reddy, K. D., Malik, S., Al-Khalil, Z., & Dbouk, N. (2025). Systemic Therapy for Unresectable Hepatocellular Carcinoma: Current Landscape and Future Directions. International Journal of Molecular Sciences, 26(13), 5994. https://doi.org/10.3390/ijms26135994