Impact of concomitant medication on clinical outcomes in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors: A retrospective study

Abstract

Background: It has recently been suggested that concomitant medication may affect the clinical outcome of patients treated with immune checkpoint inhibitors (ICIs). However, only a few studies on the impact of concomitant medication on immune-related adverse events (irAEs) have previously been reported. Here, we aimed to determine the impact of concomitant medication on the efficacy and safety of ICIs.

Methods: We retrospectively analyzed the data of 300 patients treated with nivolumab or pembrolizumab for advanced non-small cell lung cancer (NSCLC) between January 2016 and July 2018. Multivariate logistic regression analysis was used to assess the effect of concomitant medication on treatment response or irAEs. A multivariate Cox proportional hazards model was used to evaluate concomitant medication-related factors associated with time-to-treatment failure or overall survival (OS).

Results: A total of 70 patients responded to treatment and 137 experienced irAEs. The response rate and incidence of irAEs in patients treated with ICIs were not significantly associated with concomitant medication. Multivariate analysis showed that the use of opioids was an independent factor (time-to-treatment failure: hazard ratio 1.39, p = 0.021, OS: hazard ratio 1.54, p = 0.007).

Conclusions: The efficacy and safety of nivolumab or pembrolizumab in the treatment of patients with advanced NSCLC were not significantly influenced by concomitant medication. However, opioid usage might be associated with shorter OS in patients treated with these ICIs. Further mechanistic investigations should explore whether these associations are purely prognostic or contribute to ICI resistance.

Keywords: concomitant medication; immune checkpoint inhibitors; immune-related adverse events; non-small cell lung cancer; opioids.

FIGURE 1

Kaplan–Meier curves of time‐to‐treatment failure (TTF) with or without concomitant medication. TTF was not significantly different with (red lines) or without (blue lines) each concomitant medication. (a) TTF with or without statins (median TTF: 1.9 vs. 2.8 months, log‐rank p = 0.118); (b) TTF with or without fibrates (median TTF: 7.5 vs. 2.5 months, log‐rank p = 0.638); (c) TTF with or without dipeptidyl peptidase‐4 (DPP‐4) inhibitors (median TTF: 2.1 vs. 2.6 months, log‐rank p = 0.796); (d) TTF with or without metformin (median TTF: 2.5 vs. 2.5 months, log‐rank p = 0.954); (e) TTF with or without angiotensin receptor blockers (ARBs) (median TTF: 2.8 vs. 2.4 months, log‐rank p = 0.767); (f) TTF with or without corticosteroids (median TTF: 1.2 vs. 2.6 months, log‐rank p = 0.682); (g) TTF with or without antibiotics (median TTF: 1.2 vs. 2.6 months, log‐rank p = 0.122); (h) TTF with or without probiotics (median TTF: 1.5 vs. 2.6 months, log‐rank p = 0.274); (i) TTF with or without nonsteroidal anti‐inflammatory drugs (NSAIDs) (median TTF: 1.8 vs. 3.3 months, log‐rank p = 0.144); (j) TTF with or without proton pump inhibitors (PPIs) (median TTF: 1.9 vs. 3.5 months, log‐rank p = 0.018); (k) TTF with or without opioids (median TTF: 1.8 vs. 3.5 months, log‐rank p = 0.003); (l) TTF with or without laxatives (median TTF: 1.6 vs. 3.2 months, log‐rank p = 0.023); (m) TTF with or without vitamin D (median TTF: 1.9 vs. 2.8 months, log‐rank p = 0.304)

FIGURE 2

Kaplan–Meier curves of overall survival (OS) with or without concomitant medication. OS was not significantly different with (red lines) or without (blue lines) each concomitant medication. (a) OS with or without statins (median OS: 10.5 vs. 11.7 months, log‐rank p = 0.775); (b) OS with or without fibrates (median OS: No data vs. 11.7 months, log‐rank p = 0.626); (c) OS with or without dipeptidyl peptidase‐4 (DPP‐4) inhibitors (median OS: 13.8 vs. 11.3 months, log‐rank p = 0.505); (d) OS with or without metformin (median OS: 12.9 vs. 11.7 months, log‐rank p = 0.516); (e) OS with or without angiotensin receptor blockers (ARBs) (median OS: 15.9 vs. 10.9 months, log‐rank p = 0.343); (f) OS with or without corticosteroids (median OS: 2.3 vs. 11.8 months, log‐rank p = 0.386); (g) OS with or without antibiotics (median OS: 9.3 vs. 12.0 months, log‐rank p = 0.225); (h) OS with or without probiotics (median OS: 9.7 vs. 11.7 months, log‐rank p = 0.471); (i) OS with or without nonsteroidal anti‐inflammatory drugs (NSAIDs) (median OS: 8.8 vs. 15.9 months, log‐rank p = 0.014); (j) OS with or without proton pump inhibitors (PPIs) (median OS: 7.9 vs. 19.6 months, log‐rank p < 0.001); (k) OS with or without opioids (median OS: 5.7 vs. 15.9 months, log‐rank p < 0.001); (l) OS with or without laxatives (median OS: 5.6 vs. 17.3 months, log‐rank p = 0.001); (m) OS with or without vitamin D (median OS: 11.7 vs. 11.3 months, log‐rank p = 0.919)