Vitamin D Status Is Associated With Immune Checkpoint Inhibitor Efficacy and Immune-related Adverse Event Severity in Lung Cancer Patients: A Prospective Cohort Study

Abstract

Vitamin D (VitD) is potentially immunomodulatory, so here we aimed to explore the relationships between serum VitD levels, immune checkpoint inhibitor (ICI) efficacy, and immunerelated adverse events (irAEs). Serum 25-hydroxyvitamin D [25 (OH)D] levels were quantified before and after ICI treatment in prospectively enrolled patients with advanced lung cancers. Of 77 enrolled patients, 29 developed 42 irAEs. Baseline 25(OH)D levels of partial response (PRs) patients were significantly higher than non-PR patients (19.39 ± 7.16 vs. 16.28 ± 5.99 ng/mL, P = 0.04). The area under the curve of 25(OH)D > 15.73 ng/mL to identify PR was 0.63 (95% CI, 0.51-0.76, P = 0.047), and baseline 25(OH)D levels > 15.73 ng/mL (odds ratio: 2.93, 95% CI, 1.10-7.79, P = 0.03) and prior targeted therapy (odds ratio: 0.30, 95% CI, 0.10-0.92, P = 0.04) were independent predictors of PR as best efficacy by multivariable logistic regression. With respect to irAEs, baseline 25 (OH)D levels were higher in grade 1 irAE patients than in grade 2/3/4 irAE patients (20.07 ± 8.64 vs. 15.22 ± 2.30 ng/mL, P = 0.02). However, the area under the curve was only 0.56 (95% CI, 0.42-0.70, P = 0.39) for a baseline 25(OH)D of 20.99 ng/mL for predicting irAE occurrence. There was a direct monotonic relationship and U-shaped relationship between baseline 25(OH)D levels and ICI efficacy and irAE occurrence, respectively. Overall survival was significantly different between VitD sufficient, insufficient, and deficient patients (log-rank P = 0.01), which remained after adjustment in Cox proportional hazards regression models. Baseline 25(OH)D levels seem to be associated with ICI efficacy and prognosis, it might be helpful to assess the baseline VitD status, and supplementation with VitD might bring some benefit to enhance ICI efficacy and reduce moderate-severe irAEs.

Integrative Oncology Approaches to Supporting Immune Checkpoint Inhibitor Treatment of Solid Tumours

“…The main current IO approaches in ICI support outlined in Fig. 1 include a Mediterranean-style diet with over 20 g of fibre [12 ••, 50••], regular exercise [14], the use of live biotherapeutics [82][83][84], ensuring vitamin D repletion [13,97], and minimising PPI and antibiotic use [67,[74][75][76], with many other integrative oncology approaches under study. This area is ripe for further research, ranging from dietary intervention and dietary component studies, e.g.…”

“…Most of the research around ICIs and nutritional supplements has focused on vitamin D so far with its established immunomodulatory role [96]. A prospective study of 77 patients with advanced lung cancer showed that baseline 25-hydroxy-vitamin D levels were associated with ICI response and prognosis in terms of overall survival, with a relatively low baseline vitamin D level of 40 nmol/l and above carrying an AUC of 0.63 (p = 0.047) for partial ICI response [97]. This 25-hydroxy-vitamin D level would not be considered sufficient for osteoprotection where a minimum of 50 nmol/l is usually used a cutoff [98].…”