For ICI monotherapy, anti-PD1 had the highest incidence of all-grade PAEs. However, there was no significant difference between anti-PD1 and anti-PDL1 in the incidence of all-grade PAEs. In addition, the incidence of ICI monotherapy varied across studies owing to the different dose regimens. Here, the risk of all-grade PAEs was dose-dependent for nivolumab, pembrolizumab, and atezolizumab, whereas no significant difference in PAEs was observed between dose groups for the other ICIs. By contrast, Wu et al. hypothesized that the incidence and intensity of PAEs induced by anti-PD1 are independent of drug dose [
26]. However, this difference may be due to the inclusion of more recent studies in our analysis and consideration of treatment-related PAE differentiation. In addition, our control group was administered the same drug. Wu et al. only included studies published until 2016, and the types of drugs in the control group were not consistent. Therefore, it is not surprising that the incidence of PAEs varied with regimens. Higher doses of nivolumab and a low dose and high frequency of atezolizumab administration in combination with targeted therapy may also be a factor affecting the risk of all-grade PAEs. Therefore, to prevent further aggravation of PAEs in patients using anti-PD1/anti-PDL1 with different usage and dosage, clinicians must focus on minor changes in these patients, including timely diagnosis and intervention.
Recently, the FDA and EMA have approved several ICIs in combination with chemotherapy or targeted therapies. In addition, some cancers already use combination therapy as the standard of care. For combination treatment regimens, we have found the following points. First, anti-PD1 plus anti-CTLA4 and plus chemotherapy had the greatest risk of PAEs, which differed significantly from the other regimens. This may be due to the increased risk of PAEs associated with drug combinations with different mechanisms of action. Association of anti-CTLA4 and anti-PD1 enhances T cell activation and proliferation. This increases the production of proinflammatory cytokines [
27]. Second, the incidence of PAEs was much higher with anti-PD1 plus anti-CTLA4 than with ICI monotherapy, but there was no significant difference in the risk of PAEs. By contrast, Nishino et al. suggested that the incidence of developing pneumonitis is higher with combination therapy than with ICI monotherapy. This may be because their study was limited to three ICI molecules, the anti-PD1 nivolumab, pembrolizumab, and the anti-CTLA4 agent ipilimumab. However, we also included atezolizumab, avelumab, durvalumab, tremelimumab, camrelizumab, cemiplimab, sintilimab, and tislelizumab. Third, the risk of all-grade PAEs was significantly lower with ICI plus chemotherapy than with dual-ICIs, and the risk of all-grade PAEs was significantly lower with anti-PD1 plus chemotherapy than with anti-PD1 monotherapy. These observations are in agreement with those of Chen et al. [
28]. A possible reason is that the traditional chemotherapy regimen primarily consists of cytotoxic drugs, which induce immunosuppression and lead to decreased immune function, thereby reducing the risk of immune-related adverse reactions [
29,
30]. Another possible factor is that the combination of pre-treated glucocorticoids in the chemotherapy regimen reduces the risk of PAEs. Glucocorticoids can not only suppress the immune system [
31,
32] but also have certain therapeutic effects on some lung diseases, including ICI-related pneumonitis [
33,
34]. However, the mechanism of how cytotoxic drugs and corticosteroids combined with ICI regulate the immune system remains unclear. More prospective studies of the mechanisms described above are essential to maximize anti-cancer benefits while minimizing the risks of PAEs. Moreover, we included the latest drug therapy combination, anti-PD1 plus anti-PDL1. Interestingly the incidence of all-grade PAEs is not low, but the risk of grade 3–4 PAEs is low. Although the underlying mechanism is still unclear, our results provide clinicians with the latest reference for PAEs of drug combinations.
Our study has several strengths as we rigorously and comprehensively searched the literature for patients with ICI-treated cancer. We included cohorts of patients worldwide, making our findings more generalizable. Additionally, several studies with relatively large sample sizes were included, which increased the statistical power of our meta-analysis. However, our study also had a few limitations, which may be methodological flaws. First, the studies we included were all RCTs; therefore, the baseline conditions of the patients were highly selected and may not reflect the real-world situation. Second, PAEs include a variety of pulmonary toxicity outcomes, and the measurement criteria of different outcomes and the number of trials by various authors lacked some transparency in each study. Finally, we did not investigate the performance of different Bayesian meta-analytic methods in rare events [
19].