Comedications Associated with Immune-Related Adverse Events from Immune-Checkpoint Inhibitors

Abstract

Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment but are responsible for various immune-related adverse events (irAE). The impact of non-anticancer medications (comedications) on irAE occurrence remains largely unexplored. The objective of this study was to assess comedications associated with an increased reporting of irAE with ICIs. In this pharmacovigilance study, all individual case safety reports (ICSRs) involving ICIs reported in the World Health Organization international pharmacovigilance database Vigibase up to January 2024 were extracted. All suspect or interacting comedications were analyzed individually and as drug classes using Anatomical Therapeutic Chemical classification level 4. The primary outcome was the reporting odds ratio (ROR) of irAE in patients who received both an ICI and the comedication of interest, compared with ICI-treated patients who did not receive that comedication. Among 169,753 ICSRs involving an ICI, a total of 314,366 comedications were recorded, with 8,122 identified as "suspect or interacting." Analysis shows an increased reporting of nephritis with proton pump inhibitors (PPI) (ROR = 29.62 [95% CI = 18.61-47.14]) and with non-steroidal anti-inflammatory drugs (ROR = 10.47 [95% CI = 4.15-26.41]), myositis with statins (ROR = 9.41 [95% CI = 3.50-25.30]), ketoconazole with hepatitis (ROR = 20.49 [95% CI = 1.53-274.17]) and autoimmune bullous disease with dipeptyl-peptidase-4 inhibitors (ROR = 46.42 [95% CI = 11.71-184.05]), among others. Various drugs, including PPI (ROR = 8.61 [95% CI = 3.48-21.26]), some anti-infectives (sulfamethoxazole, ROR = 31.31 [95% CI = 13.32-73.61], clavulanic acid, ROR = 18.12 [95% CI = 4.77-68.89]), allopurinol (ROR = 57.11 [95% CI = 11.27-289.39]) or levetiracetam (ROR = 14.91 [95% CI = 2.15-103.64]) were associated with serious cutaneous adverse reactions. Complementary analysis showed higher ROR in the ICI population versus without ICI for the association of nephritis with ibuprofen (ROR_ICI = 27.82 vs. ROR_{VigiBaseWithoutICI} = 3.56, ROR_ratio = 7.81 [95% CI = 1.23-49.50]) and myocarditis with influenza vaccine (ROR_ICI = 22.74 vs. ROR_{VigiBaseWithoutICI} = 0.66, ROR_ratio = 34.45 [95% CI = 1.66-723.24]), suggesting a synergistic toxicity. This study identified multiple comedications associated with an increased reporting of specific irAE. Some of them might be synergistic warranting further investigation.

Figure 1

Reporting Odds ratios for ATC level 4 & 5 for “suspect or interacting” comedications and corresponding ROR_ratio. The figure displays the reporting odds ratios (ROR, left) for ATC (Anatomical Therapeutic Chemical) classification level 4 and 5 comedications, significantly associated with irAEs. Only irAE‐comedication tandems with statistically significant associations are represented. Excluded comedications: used as irAE occurrence treatment, mainly co‐reported with other over‐reported drugs, and ATC level 4 with the same signal as ATC level 5 (Figure S1 ). ROR_ratio (right) is computed using the ratio of the ROR of comedication and irAE within the ICI database (ROR represented on the left) and the ROR of the same adverse events within all VigiBase excluding reported with ICI. Each value used for the calculation of the ROR_ratio is available in Table S3 .