Surrogate Endpoints for Overall Survival in Advanced Hepatocelluar Carcinoma in the Era of Immunotherapy: A Trial Level Meta-Analysis
Bibliographic record
Abstract
Background: Systemic therapy containing immune checkpoint inhibitors (ICIs) has become the standard of care for patients with advanced hepatocellular carcinoma (HCC). A prior analysis from the pre-ICI era demonstrated a moderate correlation between progression-free survival (PFS) and overall survival (OS). We performed a literature-based meta-analysis to include randomized phase III trials (RCTs) of ICIs to evaluate surrogate endpoints for OS in advanced HCC. Methods: RCTs evaluating systemic therapies in advanced HCC published/presented between 2007 and 2024 were identified through a systemic literature search. Hazard ratios (HRs) for OS and PFS were extracted. The change in the overall response rates (ΔORR) was calculated as the difference between experimental and control arms. Pearson correlation and mixed-effects meta-regression analyses were performed. Strength of correlation was determined using the criteria from the Institute for Quality and Efficiency in Health Care (IQWIG). Surrogate threshold effect (STE) was determined for each comparison when possible. Subgroup analysis was performed. A p < 0.05 was considered to be statistically significant. Results: In total, 21 1st-line and 12 2nd-line RCTs were included. Of 1st-line RCTs, 48% evaluated ICIs either alone or in combination. There was a weak correlation between HR-PFS and HR-OS (n = 18, r = 0.64, 95% confidence interval (CI): 0.25–0.85, p = 0.004) and no correlation between ΔORR and HR-OS (n = 21, r = 0.42, 95% CI: −0.01 – 0.72, p = 0.06). The STE for HR-PFS was 0.68. Subgroup analyses revealed a moderate correlation between HR-PFS and HR-OS in 1st-line RCTs enrolling fewer patients with nonviral etiology (n = 9, r = 0.75, 95% CI: 0.17–0.94, p = 0.02). There was, however, a strong correlation between HR-PFS and HR-OS in 2nd-line RCTs (n = 10, r = 0.90, 95% CI: 0.61–0.98, p < 0.001). The STE for HR-PFS in 2nd-line RCTs was 0.87. Conclusion: The correlation between HR-PFS and HR-OS is weak in 1st-line RCTs in advanced HCC where OS remains the most appropriate endpoint. There is a strong association between HR-PFS and HR-OS for 2nd-line RCTs, suggesting that PFS is a suitable surrogate endpoint in that setting.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.027 | 0.038 |
| Meta-epidemiology (narrow) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.017 | 0.074 |
| Bibliometrics | 0.004 | 0.004 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.004 | 0.002 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".