The incidence and relative risk of PD-1/PD-L1 inhibitors-related colitis in non-small cell lung cancer: A meta-analysis of randomized controlled trials

Abstract

BackgroundThe programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors have shown encouraging merits in non-small cell lung cancer (NSCLC) patients, however, they are often related to potentially fatal immune-related adverse events (irAEs) including colitis. Considering the incidence and characteristics of immune-related colitis may have significant implications for the appropriate utilization of PD-1/PD-L1 inhibitors in clinical practice, we conduct this meta to systematically analyze the correlation between PD-1/PD-L1 inhibitors for the treatment of NSCLC and the incidence of immune-associated colitis. MethodsElectronic databases including PubMed, Embase, Cochrane Library and ClinicalTrials.gov (http://clinicaltrials.gov/) were searched up to May 2019, clinical trials reporting all grade (1–5), higher grade (3–5) colitis and grade 3–5 diarrhea were included, data were expressed as relative risk (RR), incidence, corresponding p value and 95% confidence intervals (CIs). Results9 randomized controlled trials (RCTs) were identified (7 with PD-1 inhibitors [n = 4526]) and 2 with PD-L1 inhibitors [n = 1464]). The overall incidence of PD-1/PD-L1 target agents was 1.40% for all grade colitis, 0.89% for severe colitis, 11.62% for all grade diarrhea and 1.36% for severe diarrhea. Compared with chemotherapy group, the PD-1/PD-L1 inhibitors had a significantly higher risk of all grade (RR: 3.68, p < 0.001) and high-grade (RR: 2.97, p = 0.01) colitis. Additional analysis of relative risk of diarrhea revealed that PD-1/PD-L1 treatment moderately reduce the risk of all grade diarrhea (RR: 0.64, p = 0.03), while the difference was not statistically significant in the risk of grade 3–5 diarrhea (RR: 0.83, p = 0.64). Subgroup analyses showed that the RR of all grade and higher grade colitis in PD-1 inhibitors was more significant (RR: 3.56, p = 0.001 vs RR: 2.98, p = 0.02 respectively). However, there was no appreciable difference in PD-L1 inhibitors (RR: 4.75, p = 0.15 vs RR: 2.85, p = 0.52 respectively). When compared with first-line therapy, second-line therapy associated with a higher risk of all grade colitis than first-line therapy (RR: 3.29, p = 0.006; RR: 4.69, p = 0.026). ConclusionOur meta-analysis indicates when compared with control group, the PD-1/PD-L1 inhibitors may lead to a higher risk of all grade and high grade immune-mediated colitis, but may result in a reduction in all grade diarrhea. PD-1 inhibitors in NSCLC patients, but not PD-L1 inhibitors, increase the risk of all- and high grade colitis. These results suggest that clinicians shall pay more attention to this rare but life-threatening toxic effect.