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

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.

Keywords: ACBP; NSCLC; acyl CoA binding protein; benzodiazepines; lung adenocarcinoma; lung squamous carcinoma; psychotropic agents.

Figure 1.

Impact of benzodiazepines on overall survival of lung cancer patient under pembrolizumab-based immunotherapy in the French national database including patients with non-small cell lung cancer that received immunotherapy. The graph compares the survival of patients after the 2 month-landmark that received benzodiazepines (orange line) or not (blue line). The number of surviving patients is indicated below the graph for selected time points.

Figure 2.

Impact of benzodiazepine and antibiotic use on overall survival of patients enrolled in the ONCOBIOTICS trial.

Figure 3.

Impact of benzodiazepine and antibiotic use on the fecal microbiota in patients enrolled in the ONCOBIOTICS trial.