Combination of immune checkpoint inhibitors plus chemotherapy and risk of pneumonitis: A worldwide retrospective pharmacovigilance study

e14587 Background: Pneumonitis is one of the most common fatal pulmonary adverse events that stem from immune checkpoint inhibitors (ICIs). Although the combination of ICI plus chemotherapy has become the standard first-line treatment regiments for various tumors, how the risk of pneumonitis changes during the combination treatments remains unclear. We used the World Health Organization pharmacovigilance database (VigiBase) to compare the risk of pneumonitis from the combinations of ICI plus chemotherapy with ICI in other regimens, including monotherapy. Methods: This observational, retrospective, pharmacovigilance study is a disproportionality analysis based on the individual case safety reports (ICSRs) extracted from the VigiBase from 1997 to 2020. The disproportionality analysis (known as case-non-case analysis) was conducted to compare the reporting of pneumonitis from the combination of ICI plus chemotherapy with ICI in other drug regimens, including monotherapy. The reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated. Results: From 1994 to 2020, A total of 93,623 ICI-associated ICSRs were reported in Vigibase, including 3,453 reports of pneumonitis (3.7%), among which 274 were associated with the combinations of ICI plus chemotherapy. The median time to event onset occurred about 2 months after therapy either in ICI without chemotherapy group or in the combination with chemotherapy group (61.5 days vs 74 days, respectively, p > 0.05). The ICI plus chemotherapy combination demonstrated a significant association with pneumonitis (ROR 1.35, 95% Cl 1.18-1.52). Among all the ICIs, anti-PD-1 antibodies combinations and anti-CTLA-4 antibodies combinations demonstrated a significant association with pneumonitis (PD-1+chemotherapy: 1.76, 95 % CI 1.52-2.05; CTLA-4+chemotherapy: 2.36, 95% Cl 1.67-3.35), while anti-PD-L1 antibodies plus chemotherapy combinations did not show similar association (ROR 0.37, 95% Cl 0.28-0.47). Conclusions: The combination of ICI plus chemotherapy is associated with higher risk of pneumonitis toxicity compared to other ICI-containing regimens (including ICI monotherapy) based on real-world data. The anti-PD-L1 plus chemotherapy combination has different pneumonitis profiles compared to anti-PD-1/CTLA-4 combinations. It suggests that a close monitoring for pneumonitis may be needed when using ICI plus chemotherapy combinations.[Table: see text]