Across 46 unique European CTIS hepatocellular carcinoma (HCC) Phase II and Phase III trials, overall survival (OS) and objective response / response endpoints are the most frequently measured endpoint families, each appearing in 38 of 46 trials (82.6%). Phase II-containing trials are response-led, with ORR/response used as a primary endpoint in 23 of 30 trials (76.7%), while Phase III-containing trials are survival-led, with OS primary in 11 of 19 trials (57.9%).
OS and ORR/response each appear in 38 of 46 trials (82.6%). Safety/tolerability follows in 35 of 46 trials (76.1%), and PFS/progression timing appears in 31 of 46 trials (67.4%).
European HCC protocols are built around the classic oncology efficacy stack: OS, response, PFS, safety, and DoR. QoL/PRO endpoints are present but remain secondary-supportive rather than primary-defining.
ORR/response is the leading primary endpoint family, used in 26 of 46 trials (56.5%). Secondary endpoint sets are broader: ORR/response appears in 31 trials (67.4%), OS in 30 (65.2%), PFS/progression timing in 28 (60.9%), and safety/tolerability in 27 (58.7%).
HCC Phase II/III endpoint architecture uses primary endpoints to establish a focused efficacy thesis, then uses secondary endpoints to capture survival durability, safety burden, patient experience, PK, and biomarker support.
Among 30 Phase II-containing trials, ORR/response is primary in 23 (76.7%) and safety/tolerability is primary in 12 (40.0%). Among 19 Phase III-containing trials, OS is primary in 11 (57.9%), ahead of ORR/response in 5 (26.3%).
| Endpoint family | Phase II-containing | Phase III-containing |
|---|---|---|
| ORR / response | 23/30 (76.7%) | 5/19 (26.3%) |
| OS | 5/30 (16.7%) | 11/19 (57.9%) |
| Safety / tolerability | 12/30 (40.0%) | 3/19 (15.8%) |
| PFS / progression timing | 4/30 (13.3%) | 4/19 (21.1%) |
| RFS / recurrence timing | 4/30 (13.3%) | 3/19 (15.8%) |
Phase II HCC trials are optimized for signal detection and dose-expansion decisions, while Phase III trials shift toward survival endpoints that support confirmatory EU regulatory and reimbursement positioning.
The largest analyzable settings were general HCC (15 trials), advanced/unresectable/metastatic HCC (13), multi-cancer baskets including HCC (8), resectable/high-risk/early HCC (4), and intermediate/locoregional HCC (3). Advanced disease was universally response-measured: ORR/response appeared in 13 of 13 trials (100.0%).
| Setting | Trials | Most frequent measured endpoints |
|---|---|---|
| General HCC | 15 | OS 14/15; ORR/PFS 11/15 each |
| Advanced / unresectable / metastatic | 13 | ORR 13/13; safety 12/13; PFS 11/13 |
| Multi-cancer basket including HCC | 8 | ORR and safety 6/8 each; PK and OS 5/8 each |
| Resectable / high-risk / early | 4 | RFS, ORR, and safety 4/4 each |
| Intermediate / locoregional | 3 | PFS/progression and OS 3/3 each |
| Paediatric / hepatoblastoma-HCC | 2 | EFS/FFS, OS, response, safety used across both trials |
| Post-transplant HCC | 1 | ACR, PFS, OS, ORR, DoR, QoL, safety, DSA |
Advanced HCC trials are response-and-PFS heavy, while resectable or high-risk settings pull recurrence-free survival into the core endpoint strategy. Basket trials add more PK and safety weight because HCC is one cohort within broader solid-tumour development.
Monoclonal antibody-containing trials were the largest modality group at 34 of 46 trials (73.9%). In this group, OS and ORR/response each appeared in 30 of 34 trials (88.2%), and PFS/progression plus safety each appeared in 25 of 34 (73.5%).
The HCC CTIS dataset is dominated by immunotherapy and combination-development logic. Small-molecule trials lean more toward OS as a primary endpoint, while antibody and peptide/protein-containing trials more often retain ORR and safety as primary signal endpoints.
RECIST-family imaging criteria appear in 24 of 46 trials (52.2%). CTCAE safety grading appears in 15 trials (32.6%), investigator assessment in 14 (30.4%), and independent central review or independent review facility assessment in 10 (21.7%).
| RECIST / iRECIST / mRECIST | 24/46 (52.2%) |
| CTCAE safety grading | 15/46 (32.6%) |
| Investigator assessment | 14/46 (30.4%) |
| PK concentration parameters | 11/46 (23.9%) |
| EORTC / FACT-Hep PRO instruments | 10/46 (21.7%) |
| Independent central review / IRF | 10/46 (21.7%) |
Endpoint measurement is imaging-led but not uniformly centralized. This creates operational demand for RECIST-capable imaging workflows, CTCAE safety capture, and selective BICR/IRF vendor support in EU HCC submissions.
By first CTIS authorization year, 33 of 46 trials (71.7%) were authorized in 2024, 8 (17.4%) in 2025, and 5 (10.9%) in 2026. Median time from initial CTIS submission to first authorization was 68 days overall.
For EU HCC clinical operations, CTIS planning should account for endpoint package complexity, especially when protocols include RECIST imaging, BICR/IRF, PK, PROs, and safety grading across multiple Member States.