Association between beta-catenin (<i>CTNNB1</i>) mutations and clinical outcomes of pembrolizumab in advanced hepatocellular carcinoma (aHCC): Exploratory analyses from KEYNOTE-240.
Bibliographic record
Abstract
4109 Background: CTNNB1 mutations ( CTNNB1mut) occur in approximately 30% of HCC tumors and may result in constitutive activation of CTNNB1, leading to the transcription of genes that regulate cell survival and proliferation via the WNT pathway. This exploratory analysis of the global randomized phase 3 KEYNOTE-240 study (NCT02702401) of second-line pembrolizumab + best supportive care (BSC) versus placebo + BSC investigated the association between clinical outcomes and circulating tumor DNA (ctDNA)-derived CTNNB1mut status in patients with aHCC. Methods: The analysis population includedpatients with previously treated aHCC who were enrolled in KEYNOTE-240 and had available pretreatment cycle 1 day 1 ctDNA data. The presence of ctDNA in plasma as well as ctDNA-derived CTNNB1was evaluated using the Guardant Health G360 LDT assay. CTNNB1 was also measured in tissue using whole exome sequencing (WES) of tumor and matched germline from blood for a subset of patients with available data. One objective of this analysis was to evaluate the concordance between ctDNA- and WES-derived CTNNB1mut status by positive percent agreement (PPA) and negative percent agreement (NPA) with Wilson CIs using WES as the gold standard. Another objective was to evaluate the association between ctDNA-derived CTNNB1mut status and clinical outcomes (PFS, OS, and ORR) using 1-sided (pembrolizumab; hypothesized negative association) or 2-sided (placebo; no hypothesized direction of association) nominal P-values for Cox proportional hazard regression (PFS; OS) and logistic regression (ORR) adjusted for ECOG performance status. Significance was prespecified at P = 0.05. The database cutoff date was January 2, 2019. Results: Overall, 361 of 413 patients (87%) had evaluable CTNNB1 mutation data from ctDNA; of these, 137 (38%) had CTNNB1mut tumors per ctDNA. Two patients had a ctDNA burden of 0. A total of 41 patients had evaluable CTNNB1mutation data from both ctDNA and WES. Concordance was high between the assays, with agreement in 95% (39 of 41) of the evaluable samples. Of the 41 patients with both ctDNA and WES data available, 13 were CTNNB1mut by both assays, 26 were wild type by both assays, and 2 were wild type by ctDNA and CTNNB1mut by WES. PPA was 86.7% (Wilson CI, 62.1-96.3) and NPA was 100% (Wilson CI, 87.1-100). There was no association between ctDNA-derived CTNNB1mut status and PFS, OS, or ORR with pembrolizumab ( P =0.525, 0.558, and 0.132, respectively) or with placebo ( P = 0.295, 0.387, and 0.717, respectively). Conclusions: ctDNA-derived CTNNB1mut status was highly concordant with WES-derived CTNNB1mut status in patients with aHCC. There was no association observed between ctDNA-derived CTNNB1mut status and clinical outcomes with pembrolizumab or placebo in patients with aHCC enrolled in KEYNOTE-240 . Clinical trial information: NCT02702401 .
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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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".