Immune checkpoint inhibitors such as PD-1/PD-L1 inhibitors have become crucial choices for patients with advanced malignant tumors, but the irAEs associated with them may lead to treatment interruption or fatal disease (8–10). Early prediction and correct treatment are particularly critical for irAEs management.
The correlation between irAE and PD-1/PD-L1 inhibitors response in advanced malignant tumors has long been controversial. A recent meta-analysis of 30 included studies showed that irAEs were significantly associated with PFS and OS of PD-1/PD-L1 inhibitors in advanced malignant tumors, especially in endocrine, cutaneous and low-grade irAEs, but objective remission rates were not discussed (26). This study showed no statistical difference in ORR and DCR between irAEs group and No-irAEs group, which was the same as some research results (22, 23), while the correlation between irAEs and PFS was not directly obtained. In view of the immortal time bias of irAEs and the intersection points in the overall analysis, we used landmark analysis, where the irAEs group showed a survival advantage after PFS 120 days. The reason is related to the initial time of irAEs. Studies have shown that most irAEs appear within 3 months after the beginning of treatment, while serious adverse reactions such as immune associated pneumonia appear within two months(27). Combined with our clinical data, some patients terminate treatment early due to severe adverse reactions such as immune-related myocardial injury and immune-related pneumonia.
Peripheral blood markers such as baseline NLR and PLR showed predictive value not only in the efficacy of PD-1/PD-L1 inhibitors in advanced malignant tumors (28–33), but also in the possibility of predicting the occurrence risk of irAEs(12–14). Moreover, eosinophils in peripheral blood were also associated with irAEs(14–16). This study assessed the predictive value of baseline NLR, PLR and eosinophils to the risk of irAEs, and found that the incidence of irAEs in the baseline Low-NLR group and the baseline High-AEC group was significantly higher than that in the High-NLR group and the Low-AEC group. Previous studies showed that higher baseline NLR predicted poor efficacy of PD-1/PD-L1 inhibitors, which indirectly suggested the possibility of a positive correlation between irAEs and efficacy. Meanwhile, although univariate logistic analysis showed that both baseline Low-NLR and baseline High-AEC were risk factors for irAEs, confound factors such as tumor type, treatments and treatment lines were further included, and multivariate logistic analysis only showed that AEC was an independent influence factor for irAEs. Although studies have shown that baseline PLR can be used as an independent predictor of irAEs in the treatment of advanced non-small cell lung cancer with immune checkpoint inhibitors(12), and our multivariate analysis also found that baseline PLR may be superior to NLR, its predictive value may still be much lower than that of baseline AEC. We speculate that baseline AEC may have higher irAEs occurrence risk prediction value than baseline NLR and PLR. To our knowledge, this is the first comparison of the predictive value of baseline NLR, baseline PLR, and baseline AEC for irAEs.
ECOG PS is intimately related to irAEs, and irAEs is more likely to occur in good ECOG, which is the same as previous research results (20). We balanced the confounding factors such as tumor type, treatments and treatment lines, but good ECOG still showed positive correlation with irAEs, which was an independent predictor of irAEs. In addition, studies have suggested that the treatment lines are also related to irAEs, and second-line treatment and above is more likely to occur irAEs(20), which is different from our results. It is worth noting that we found that the incidence of irAEs in immunotherapy combined with targeted therapy is relatively low, and currently there is no other data to support it, so further large sample size, single tumor species and prospective studies are needed for verification.
Of course, there are a few limitations in this study. On the one hand, we conducted a single-center retrospective study. On the other hand, we underestimated the influence of the use of hormones or immunosuppressants and irAEs classification, etc. Therefore, multi-center, prospective studies are needed to validate our results.