Toxicity spectrum of immunotherapy in advanced lung cancer: A safety analysis from clinical trials and a pharmacovigilance system

Background With the increased use of immune checkpoint inhibitors (ICIs) in advanced lung cancer, adverse events (AEs), particularly immune-related AEs (irAEs), have garnered considerable interest. We conducted a compre-hensive assessment of the toxicity profile in advanced lung cancer using multi-source medical data. Methods First, we systematically searched the PubMed, Embase, and Cochrane Library databases (from inception to 10 August 2021) for relevant randomised controlled trials (RCTs) involving ICI-based treatments for advanced lung cancer. The primary outcomes were treatment-related AEs and irAEs, including events that were assigned grade 1-5 and 3-5. The secondary outcomes were grade 5 AEs and irAEs (grade 1-5 and grade 3-5) in specific organs. Network comparisons were conducted for 11 treatments, including chemotherapy (CT), ICI monotherapy (three regimens: programmed death-1 receptor [PD-1] inhibitors, programmed death ligand-1 [PD-L1] inhibitors, and cytotoxic T lym-phocyte-associated antigen [CTLA-4] inhibitors), dual-ICI combination therapy (two regimens), and treatment using one or two ICI drugs administered in combination with CT (five regimens). We also conducted a disproportionality analysis by extracting reports of various irAEs associated with ICIs from the FDA Adverse Event Reporting System (FAERS) database. The reporting odds ratios and fatality proportions of different irAEs were calculated and com-pared. PROSPERO: CRD42021268650. Findings Overall, 41 RCTs involving 23,121 patients with advanced lung cancer were included. Treatments contain-ing chemotherapy increased the risk of treatment-related AEs compared to ICI-based regimens without chemother-apy. Concerning irAEs, PD-L1 + CTLA-4 + CT was associated with the highest risk of grade 1-5 irAEs, followed by two regimens of dual ICI combination, three regimens of ICI monotherapy, and three regimens of one ICI com-bined with CT. For 3-5 irAEs, CTLA-4 accounted for most AEs. Detailed comparisons of ICI-based treatment options provided irAE profiles based on specific organs/systems and AE severity. Insights from the FAERS database revealed that signals corresponding to pneumonitis, colitis, thyroiditis, and hypophysitis were observed across all ICI regimens. Further analyses of the outcomes indicated that myocarditis (163 of 367, 44.4%), pneumonitis (1610 of 4497, 35.8%), and hepatitis (290 of 931, 31.1%) had high fatality rates. Interpretation Included RCTs showed heterogeneity in a few clinical factors, and reports derived from the FAERS database might have involved inaccurate data. Our results can be used as a basis for improving clinical treatment strategies and designing preventive methods for ICI treatment in advanced lung cancer.

Automated summary

The use of immune checkpoint inhibitors (ICIs) in advanced lung cancer can lead to adverse events, particularly immune-related adverse events (irAEs). This study comprehensively assessed the toxicity profile in advanced lung cancer patients using multi-source medical data. The findings revealed that ICI-based regimens with chemotherapy increased the risk of treatment-related adverse events compared to those without chemotherapy. PD-L1 + CTLA-4 + CT combination therapy was associated with the highest risk of grade 1-5 irAEs. Myocarditis, pneumonitis, and hepatitis had high fatality rates. The results can be used to improve clinical treatment strategies for ICI treatment in advanced lung cancer.