Landmark analysis of overall survival (OS) by objective response (OR) in previously treated patients (pts) with advanced hepatocellular carcinoma (aHCC): Post hoc analysis of the randomized, phase 3 KEYNOTE-240 study.
Bibliographic record
Abstract
e16122 Background: Studies have shown that OR is prognostic of OS in pts with HCC. KEYNOTE-224 (NCT02702414) evaluated pembrolizumab (pembro; anti–PD-1) in sorafenib (sora)-treated pts with aHCC and showed an ORR of 17% that was durable in responders receiving pembro, ultimately leading to FDA approval. In KEYNOTE-224, a landmark analysis showed that OR in pembro-treated pts was prognostic of longer OS. The KEYNOTE-240 (NCT02702401) study evaluated pembro + best supportive care (BSC) vs placebo (pbo) + BSC in sora-treated pts with aHCC. Although clinical benefit was observed in KEYNOTE-240 with pembro vs pbo, prespecified statistical significance criteria for OS and PFS were not met. This post hoc analysis of KEYNOTE-240 was performed to determine whether OR at landmark is prognostic of longer survival after landmark time. Methods: Eligible pts were aged ≥18 y, had confirmed aHCC, and experienced progression during or after sora treatment or intolerance to sora. Landmark analyses of OS according to OR at 6, 12, and 18 wk after randomization were performed on the pembro arm to evaluate the association between survival after the landmark with response achieved before the landmark. OR was assessed by blinded independent central review per RECIST v1.1. Responders at each landmark were defined as pts with any response assessment of CR or PR before the landmark date; all other pts were defined as nonresponders. HR and 95% CI for survival after the landmark were calculated from the Cox proportional hazards model using Efron method of tie handling, with responder status as a single covariate. Analysis was performed on the ITT population. Results: As of Jan 2, 2019, median time from randomization to data cutoff was 21.2 mo (range 13.4-30.4) for pembro. In the pembro arm, 51 pts (18.3%) had a best OR of CR or PR and 6 pts (4.4%) in the pbo arm had a best OR of PR (no CR) (excluded from landmark analyses). OS after landmark time was longer for responders than nonresponders at the wk 6, 12, and 18 time points (Table). The HR for OS after landmark time for responders vs nonresponders was 0.37 (95% CI 0.18-0.75), 0.39 (95% CI 0.23-0.66), and 0.37 (95% CI 0.21-0.63) at wk 6, 12, and 18, respectively. Conclusions: This post hoc analysis showed that pts with sora-treated aHCC who achieved OR by landmark time with pembro have longer OS after the landmark time, confirming the prognostic association between OR with pembro and OS observed in KEYNOTE-224. Clinical trial information: NCT02702401. [Table: see text]
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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 | 0.006 | 0.003 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.004 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 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".