The Impact of Beta Blockers on Survival Outcomes in Patients With Non-small-cell Lung Cancer Treated With Immune Checkpoint Inhibitors

Abstract

Background: Beta blockers have been associated with anti-tumorigenic effects, potentially by reducing adrenergic-mediated stress responses. Preclinical studies have additionally shown that beta blockade may enhance the efficacy of cancer immunotherapy. We investigated patients with lung cancer who concomitantly used beta blockers and immune checkpoint inhibitors (ICIs), with the hypothesis that beta blockade would positively impact clinical outcomes.

Patients and methods: We retrospectively reviewed the health records of 109 patients who were treated at Northwestern University from January 2014 through August 2018 with ICIs for non-small-cell lung cancer (NSCLC). Comparisons of overall survival and progression-free survival (PFS) were performed using Kaplan-Meier analysis with log-rank test, and a univariate regression analysis was performed with a Cox proportional hazards model.

Results: Among 109 patients treated with ICIs for NSCLC, 28 of them were concomitantly prescribed beta blockers. Use of beta blockers was associated with increased PFS, with a hazard ratio of 0.58 and 95% confidence interval of 0.36 to 0.93. There was not a significant increase in overall survival among patients who took beta blockers (hazard ratio, 0.66; 95% confidence interval, 0.38-1.17). In a regression model, beta blockers were identified as predictive of PFS, as were non-squamous histology, tumor programmed death-ligand 1 positivity, and lower line of treatment.

Conclusions: Our data suggests beta blocker use may be associated with improved PFS among patients treated with ICIs for NSCLC. This was a small study, and these findings should be further validated in prospective clinical studies.

Keywords: Adrenergic; Antidepressant; Immunotherapy; NSCLC; Stress response.

Figure 1.. Survival outcomes in association with beta blocker use.

(A) Use of beta blockers and immune checkpoint blockade was associated with longer PFS but (B) not OS in a Kaplan-Meier analysis. (C) Similar analysis performed showed difference in PFS but (D) not OS for the subset of patients with selective beta blockers. (E) There was no difference in PFS or (F) OS between patients who started beta blockers within 3 months of starting immunotherapy or prior to 3 months. (G) There was no statistically significant difference in PFS among patients with intracranial metastases, but (H) there was improved OS with beta blocker use.

Figure 2.. Survival outcomes in association with other stress-related medications.

Kaplan Meier plots showing no differences in (A) PFS or (B) OS between patients taking and not taking antidepressant medications. Similar results were obtained when categorizing by (C-D) selective serotonin reuptake inhibitors use and (E-F) benzodiazepine use.