Exploratory biomarker analysis of the phase 3 KEYNOTE-604 study of pembrolizumab plus etoposide for extensive-stage SCLC.
Bibliographic record
Abstract
8503 Background: In the phase 3 KEYNOTE-604 study of extensive-stage small-cell lung cancer (ES-SCLC; NCT03066778), first-line pembrolizumab (pembro) plus etoposide and platinum (EP) significantly improved PFS vs placebo (pbo) plus EP (HR, 0.75; P = 0.0023), with favorable OS (significance threshold not met; HR, 0.80; P = 0.0164). PFS/OS were similar regardless of PD-L1 CPS. In this exploratory analysis, tumor mutational burden (TMB), 18-gene T cell–inflamed gene expression profile (Tcell inf GEP) and SCLC transcriptional subtypes were assessed as correlates of survival. Methods: Patients (pts) eligible for this analysis of KEYNOTE-604 had previously untreated ES-SCLC with evaluable pretreatment tumor samples. TMB was assessed by whole-exome sequencing (WES) of tumor and matched normal DNA. RNA-seq was used to determine Tcell inf GEP and SCLC transcriptional subtypes (ASCL1, POU2F3, NEUROD1, YAP1, or inflamed). Associations of TMB, Tcell inf GEP, and SCLC subtype with OS were analyzed using an adjusted Cox proportional hazards model. 1-sided (pembro + EP) and 2-sided (pbo + EP) P values were calculated for TMB and Tcell inf GEP (prespecified α = 0.05); 2-sided P values were calculated for SCLC subtype (multiplicity-adjusted, α = 0.10). Clinical utility was assessed using prespecified cutoffs of ≥175 mut/exome for TMB and the first tertile for Tcell inf GEP. Clinical data cutoff date was Dec 2, 2019. Results: Of 453 pts randomized in KEYNOTE-604 (ITT), 318 had WES data (pembro + EP, n = 167; pbo + EP, n = 151), and 316 had RNA-seq data (pembro + EP, n = 159; pbo + EP, n = 157). High TMB was positively associated with OS in the pbo + EP group ( P = 0.005) but not the pembro + EP group ( P = 0.450). There was a positive association between higher Tcell inf GEP and OS in the pembro + EP ( P = 0.003) and pbo + EP ( P < 0.005) groups. SCLC subtypes were not associated with OS in either group (pembro + EP, P = 0.960; pbo + EP, P = 0.999). Clinical benefit of pembro + EP over pbo + EP was demonstrated for TMB <175 mut/exome, but not for TMB ≥175 mut/exome. Pembro + EP benefit over pbo + EP was consistent across Tcell inf GEP subgroups. Conclusions: In this exploratory analysis of biomarker subgroups of KEYNOTE-604, TMB and SCLC subtypes were not associated with OS in the pembro + EP group in pts with ES-SCLC. While Tcell inf GEP was positively associated with OS in both treatment groups, no additional OS benefit was observed with pembro + EP. Further research is warranted to better identify predictive biomarkers to immunotherapy. Clinical trial information: NCT03066778 . [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 | 0.004 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".