With the rapid expansion of the indications of ICIs, oncologists increasingly encounter several clinical issues involving irAEs. Most irAEs were mild to moderate but severe ones can result in death [10–12, 16]. A meta-analysis revealed the fatality rate of irAEs was up to 0.8%ཞ1.7% [17]. Although irAEs covered spectrum of damage, CIP was one of the most threatening with high mortality [13]. Consequently, it is put on agenda to screen high-risk fators of fatal CIP.
To the best of our knowledge, this study firstly provided the most elaborate spectrum and susceptible factors of fatal CIP based on widespread databases. The overall incidence was 0.96%, which was analogous to that of the SUSPECT trial (the real world) [18]. And the occurrence of fatal CIP were significantly higher in hematologic malignancy group (compared with the solid tumors group), and in ≥ 2 line treatment group (compared with the first line treatment group). While the frequency in phase Ⅲ trial group was remarkably lower compared with that in phase Ⅰ/Ⅱ trial group, and tended to be descended in ICIs plus chemotherapy and ICI monotherapy (compared with PD-(L)1 plus CLA-4 inhibitors group).
Why did participants enrolled in the phase Ⅰ/Ⅱ trial possess a higher incidence than phase Ⅲ trial? The possible interpretation was that the design of phase Ⅲ trial was optimized based on the experience of phase Ⅰ/Ⅱ trial, and to facilitate the contraction of incidence of CIP. We also found that the majority of first line treatment group fell into phase Ⅲ trial group (40/58), which partly addressed the issue that why incipient patients less likely to suffered from a fatal CIP. However, no significant difference occurred between first line treatment and ≥ 2 line treatment after controlling for primary tumors, treatment approaches, and trial phase.
Furthermore, the univariate meta-regression analysis showed PD-(L)1 plus CTLA-4 inhibitors tended to generate a higher incidence of fatal CIP, compared with ICI monotherapy or ICIs plus chemotherapy. Previous study found that PD-(L)1 plus CTLA-4 inhibitors was more likely to bring out CIP, with a relative risk of 3.47 for any-grade CIP and 3.48 for severe CIP [19]. The mechanism may have been attributed to synergistic rather than additive side effects [18, 20]. Thereby, the application of combined ICIs may elevate the risk of fatal CIP in exchange for a better clinical outcome. Before a combined ICIs is meted out, several factors must be considered: the general situation, previous treatment, and type of malignancy of the patients.
Interestingly, fatal CIP appeared to occur more frequently in patients with hematologic malignancy than in those with solid tumors. The reason remains to be elucidated. Whereas, the trials comprising hematologic malignancy was only 6 cohorts with 233 participants. Hence, it should be cautious to explicate the result.
However, this study confronted a flaw that our study was single arms meta analysis, for the controlled trials were unavailable, although we had comprehensively searched the articles.