Benzodiazepines interfere with the efficacy of pembrolizumab-based cancer immunotherapy. Results of a nationwide cohort study including over 50,000 participants with advanced lung cancer
Bibliographic record
Abstract
We previously reported that elevated levels of diazepam binding inhibitor (DBI), also called ‘endozepine’ because it acts as an endogenous benzodiazepine equivalent on the gamma-aminobutyric acid type A receptor, constitutes a potential risk factor for the diagnosis of non-small cell lung cancer (NSCLC). Antibody-mediated neutralization of DBI improved the immunosurveillance of NSCLC in preclinical models with and without immunotherapy targeting programmed cell death protein 1 (PD-1). A pilot study in a small French-Canadian cohort (n = 205) suggested that benzodiazepine (BZD) use correlates with reduced progression-free survival in NSCLC patients receiving PD-1/PD-L1 blockade. Here, we report a retrospective analysis of the nation-wide French registry of advanced NSCLC patients treated with pembrolizumab. Among the eligible NSCLC patients surviving ≥2 months after treatment initiation (n = 31,479), 37.7% (n = 11,878) received at least two prescriptions of benzodiazepines within 90 days before to 30 days after treatment initiation. Compared to non-users (n = 19,601), BZD users had significantly reduced overall survival (hazard ratio = 1.08, 95% CI: 1.04–1.12, p < 0.001), an effect that persisted after correction using inverse probability of treatment weighting (IPTW) on sociodemographic, clinical, oncologic, and comedication variables. In a subset of 556 patients from the ONCOBIOTICS study, benzodiazepine use was associated with signs of intestinal dysbiosis and alterations in the TOPOSCORE, a prognostic marker linked to poorer outcomes in cancer patients receiving immunotherapy. We conclude that benzodiazepine use may be an independent negative prognostic factor for NSCLC patients under pembrolizumab-based immunotherapy. Future studies must determine whether withdrawal of benzodiazepines or neutralization of DBI improves the clinical response to immunotherapy.
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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 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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".