Evaluation of RNA-sequencing (RNA-seq) signatures with pembrolizumab (pembro) in patients (pts) with renal cell carcinoma (RCC) from KEYNOTE-427 cohort A.
Bibliographic record
Abstract
729 Background: We evaluated the association (assoc) of baseline RNA-seq–based signatures with response/resistance to pembro from the phase 2 KEYNOTE-427 study (NCT02853344) in pts with advanced clear cell RCC enrolled in cohort A (n = 110). Methods: In pembro-treated pts with RNA-seq and clinical data (N = 78), we analyzed the assoc of signatures (18-gene tumor T-cell–inflamed GEP; 10 non–T-cell–inflamed GEP canonical signatures [angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFβ, WNT]) quantifying the TME with clinical outcomes. Canonical signatures were derived from 2 databases (TCGA, Moffit) using an algorithm that included genes based on their correlation to reference signatures in the literature. Signature definitions were finalized before linking to the clinical data, and significance was prespecified at 0.10 given the potential for limited power. Canonical signatures were also analyzed through regression testing of response and the residuals of consensus signatures after adjusting for T-cell–inflamed GEP and IMDC scores in the model. P values were adjusted for multiplicity. Database cutoff date for clinical data: March 12, 2019. Results: Pt characteristics for this analysis were similar to those of the overall cohort A population. T-cell–inflamed GEP was statistically significantly assoc with ORR ( P = 0.021) but not PFS ( P = 0.116). When adjusting for PD-L1 expression (CPS by IHC) and IMDC scores, T-cell–inflamed GEP remained statistically significantly assoc with ORR ( P = 0.059). The angiogenesis signature was not assoc with response. PD-L2 RNA-seq expression was not assoc with response with multiplicity-adjusted P values. Like PD-L1 IHC, PD-L2 RNA-seq expression moderately correlated with T-cell–inflamed GEP and did not show independent predictive value when adjusted for T-cell–inflamed GEP and IMDC scores. Conclusions: RNA-seq–based, T-cell–inflamed GEP was assoc with ORR in pts with clear cell RCC receiving first-line pembro monotherapy; no canonical signatures showed statistical significance. Future directions for these data include whole exome sequencing analysis. Clinical trial information: NCT02853344.
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How this classification was reachedexpand
Direct model labels (unvalidated)
Per-model category and study-design labels from the labeling rounds. They are machine output, unvalidated, and the disagreement between models ships as data. No study design here is MEDLINE-validated yet.
| Model arm | Categories | Study design | Confidence |
|---|---|---|---|
| gemma | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Observational | low |
| gpt | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Observational | low |
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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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, unvalidatedLabeled directly by 2 models reading the full record.
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".