Abstract CT023: Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 biomarker analyses
Bibliographic record
Abstract
Abstract Background: CheckMate 649, a randomized phase 3 study in advanced GC/GEJC/EAC, showed superior overall survival (OS) and an acceptable safety profile with 1L NIVO + chemo vs chemo, leading to approval in multiple countries. We present exploratory efficacy analyses by baseline tumor mutational burden (TMB) and gene expression signatures (GES) from CheckMate 649. Methods: Whole exome sequencing of baseline tumor tissue and matching blood was performed to derive TMB. TMB-high (H) was defined as ≥ 199 mutations/exome (Chang et al. Mol Diagn Ther 2019). RNA sequencing of baseline tumor tissue was performed to assess GES. GES included a 4-gene inflammatory (inflam) (Lei et al. Clin Cancer Res 2021), a proprietary 12-gene epithelial mesenchymal transition (EMT), 6-gene angiogenesis (angio) (McDermott et al. Nat Med 2018), and other stroma- and angiogenesis-related signatures. Results: Of 1581 patients (pts) randomized to receive NIVO + chemo or chemo, 685 (43%) were evaluable for TMB (NIVO + chemo 45%, chemo 41%), and 809 (51%) were evaluable for GES (NIVO + chemo 53%, chemo 49%). In pts with PD-ligand (L)1 combined positive score (CPS) ≥ 5, OS benefit with NIVO + chemo vs chemo was seen in TMB-H pts (HR 0.44), which accounted for 10% of this population, and non-TMB-H pts (HR 0.75) (Table). Similar results were observed when excluding MSI-H pts and will be presented. OS benefit was observed across multiple GES subgroups, although low EMT and angio signature tertiles were associated with greater OS benefit (Table). Similar results were observed with other stroma- and angiogenesis-related GES for all randomized pts and pts with PD-L1 CPS < 5 which will be presented. Conclusions: Although the magnitude of benefit was higher in TMB-H and EMT/angio-low pts, OS benefit with NIVO + chemo vs chemo was observed regardless of TMB, inflam, EMT, and angio GES status. Table PD-L1 CPS ≥ 5 TMB (N = 451) GES (N = 513) Inflam EMT Angio All evaluable HR (95% CI) 0.71 (0.58-0.87) 0.72 (0.59-0.87) High, n (%) 43 (10) 171 (33) 171 (33) 171 (33) HR (95% CI) 0.44 (0.21-0.93) 0.65 (0.45-0.93) 0.88 (0.64-1.22) 0.86 (0.61-1.20) Medium, n (%) - 171 (33) 171 (33) 171 (33) HR (95% CI) - 0.65 (0.47-0.91) 0.80 (0.57-1.12) 0.69 (0.50-0.97) Low, n (%) 408 (90) 171 (33) 171 (33) 171 (33) HR (95% CI) 0.75 (0.61-0.93) 0.77 (0.55-1.07) 0.57 (0.41-0.80) 0.62 (0.44-0.86) All randomized TMB (N = 685) GES (N = 809) Inflam EMT Angio All evaluable HR (95% CI) 0.79 (0.67-0.93) 0.78 (0.67-0.91) High, n (%) 57 (8) 270 (33) 270 (33) 270 (33) HR (95% CI) 0.48 (0.25-0.93) 0.70 (0.53-0.93) 0.88 (0.68-1.15) 0.91 (0.70-1.19) Medium, n (%) - 269 (33) 269 (33) 269 (33) HR (95% CI) - 0.83 (0.64-1.08) 0.84 (0.65-1.10) 0.79 (0.61-1.03) Low, n (%) 628 (92) 270 (33) 270 (33) 270 (33) HR (95% CI) 0.83 (0.70-0.99) 0.75 (0.58-0.97) 0.68 (0.52-0.88) 0.66 (0.51-0.86) HR data are NIVO + chemo vs chemo. Citation Format: Ming Lei, Yelena Y. Janjigian, Jaffer A. Ajani, Markus Moehler, Xuya Wang, Lin Shen, Marcelo Garrido, Carlos Gallardo, Kensei Yamaguchi, Lucjan Wyrwicz, Tomasz Skoczylas, Arinilda Bragagnoli, Tianshu Liu, Mustapha Tehfe, Elena Elimova, Mingshun Li, Valerie Poulart, Yu Wang, Parul Doshi, Kohei Shitara. Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 biomarker analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT023.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.003 |
| Science and technology studies | 0.002 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 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 teacher head, 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".