Evaluation of rare but severe immune related adverse effects in PD-1 and PD-L1 inhibitors in non-small cell lung cancer: a meta-analysis

Background: Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitor therapy is showing marked efficacy in advanced non-small cell lung cancer (NSCLC). Meanwhile, it is concomitant with distinctive immune-related adverse effects. We aim to describe the incidence of pneumonitis and other rare but severe immune-related adverse effects (IRAEs), as well as treatment related deaths. In addition, we analyze the differences in incidence of pneumonitis between PD-1 and PD-L1 inhibitors and standard-of-care chemotherapy.

Methods: PubMed was searched up to 24 March 2017 for clinical trials of PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab, avelumab and durvalumab) in treatment of NSCLC. Besides, references of relevant articles were screened.

Results: Finally, 22 trials were included in our study, 14 with data of pneumonitis, 19 with other severe IRAEs or treatment related deaths and 5 with control groups. Incidence of all-grade pneumonitis was 2.9% (95% CI, 2.0-4.8%) and grade 3 or higher pneumonitis 2.0% (95% CI, 1.0-2.0%). Incidence of all-grade pneumonitis in PD-1 and PD-L1 inhibitor therapy (n=1,313) was significantly higher than that in chemotherapy (n=918) (OR=2.35, 95% CI, 1.32-4.20, P=0.004), but had no significance in grade 3-5 pneumonitis. Incidence of cardiorespiratory arrest (n=537) was 1.0% (95% CI, 0-2.0%), cardiac failure (n=214) 2.0% (95% CI, 1.0-5.7%), myocardial infarction (n=402) 1.0% (95% CI, 0-3.8%), stroke (n=135) 2.0% (95% CI, 0-13.0%), disease progression (n=391) 1.0% (95% CI, 0-2.9%), pancreatitis (n=700) 1.0% (95% CI, 0-2.0%) and severe skin reactions (n=836) 2.0% (95% CI, 1.0-3.8%). Incidence of treatment related deaths was 0.7%.

Conclusions: Immune related adverse effects can on occasion be life-threatening even though usually rare. Incidence of pneumonitis in PD-1 and PD-L1 inhibitors was significantly higher than that in chemotherapy. More studies should be conducted to investigate the incidence of these rare but life-threatening IRAEs.