Adverse events of immunotherapy in non-small cell lung cancer: A systematic review and network meta-analysis

Immune checkpoint inhibitors have yielded significant treatment progress in non-small cell lung cancer (NSCLC), while some special adverse events (AEs) named immune-related adverse events (irAEs) were observed in clinical trials. We aimed to systematically assess the incidences of AEs in immunotherapy of NSCLC. We searched randomized controlled trials (RCTs) in PubMed/MEDLINE, Embase, Cochrane, and ClinicalTrail.gov before May 2021, and grouped arms into 10 treatment categories. We extracted AEs as serious (grade 3–5) or others (grade1-2) from all systems, and we pooled their incidences by random effects model. For arm-based pair-wise comparisons, we employed Bayesian network meta-analysis. Meta-regression was used to assess the contribution of coefficients. Totally 23,322 patients from 52 RCTs were included. The overall incidences of serious AEs were 37.0% in chemotherapy arm, 33.0% in PD1 arm, and 37.0% in PDL1 arm, while in combined groups it was 47.0% in PDL1_Chemo arm, 43.0% in PD1_CTLA4 arm, and 48.0% in ICI_Target arm. The incidence of each serious AE was less than 4% in monotherapy, and slightly higher in combined groups. In network meta-analysis, the immunotherapeutic groups presented a significant higher incidence rank in colitis, hepatobiliary disorders, pneumonitis, and rash compared with chemotherapy. There was a significantly positive correlation between the occurrence of serious hepatitis (p < 0.0001) and PFS in PDL1 arm, likewise serious pneumonitis (p = 0.0049) and rash (p < 0.0001) in PD1 arm. The overall incidences of AEs were similar in immune monotherapy compared with chemotherapy in NSCLC. Some irAEs were more common in immune therapy and their frequencies were positively associated with clinical efficacy.