Correlation between immune-related adverse events and the efficacy of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: systematic review and meta-analysis

PD-1/PD-L1 inhibitors were established as an important component in the field of immunotherapy for non–small cell lung cancer (NSCLC). Many retrospective studies have demonstrated that immune checkpoint inhibitors (ICIs) dramatically improved long-term survival in treated patients with advanced NSCLC [1‐3]. Compared to anticancer therapies, the ICIs may cause immune-related adverse events (irAEs) because of nonspecific immune activation [4]. Regarding the mechanisms of ICIs, while immune cells attack tumor cells, it also promotes the immune system to attack normal tissues and organs. IrAEs can involve almost every organ of the body, but the skin, gastrointestinal tract, pulmonary and endocrine are the most common organs [5]. Despite the good clinical efficacy, but in the clinical treatment, the development of irAEs greatly limits the application of ICIs in many cancer patients.

Several studies reported the occurrence of irAEs could improve survival outcomes with advanced NSCLC [6, 7], but in the other reports, the correlation has not been investigated [8]. Therefore, it is still controversial whether the presence of irAEs is the predictive factors of the ICI response in advanced NSCLC. A systematic review has supported the relationship between irAEs occurrence and the curative effect of ICIs in all solid malignancies [9]. To explore the associations of the development of irAEs and the curative effect in advanced NSCLC, we conducted a meta-analysis of published data. The predictive effects of different irAEs types, irAEs grades and the impact on outcome were analyzed.

We all know that the immune system plays a very important role in the progression and treatment of cancer. PD-1/PD-L1 receptor blocker by inhibiting the escape of cancer cells from host T-cells which has become a new immunotherapy for malignant [36]. The application of immunotherapy, especially of PD-1/PD-L1 inhibitors, provides unprecedented curative effect for the treatment of NSCLC. However, in the process of activating host T cells against malignant antigen tissues, inhibition checkpoint blocking may also attacks on other tissues [37]. Consequently, with the promotion of monotherapy and combination therapy, unpredictable efficacy and inevitable irAEs are two problems which increasingly obvious. At present, whether the occurrence of irAEs is related to the treatment of ICI remains controversial. This study provides a more comprehensive and widespread analysis of the relationship between irAEs and the treatment efficacy of ICI.

In the analysis, we found that compared with patients who were without irAEs, patients who developed irAEs experienced a longer OS and PFS. In addition, the correlation was very stable, and there was no significant change in a sensitivity analysis. So far, the machine-processed between irAEs and survival benefits is not fully clear. The most promising hypotheses for this phenomenon could be the Antigen mimicry theory between tumor and healthy tissue [26]. Immune checkpoint is an important part of the molecular mechanism of maintaining peripheral immune tolerance. The release of antigens by ICI therapy is considered as one of the prime mechanisms that can trigger irAEs [38]. Thus, the development of irAEs indicates that irAEs have a strong immune response to both tumor and healthy tissues, thereby predicting a better therapeutic response. The results indicated that irAEs might be a predictive factor of durable efficacy in NSCLC.

The stratified analysis based on irAEs types. The results indicate that endocrine irAEs, skin irAEs and gastrointestinal irAEs have favorable results. However, no significant associations were found between the hepatobiliary irAEs, pulmonary irAEs and favorable results in NSCLC. Previous study have suggested that among the patients treated with immune checkpoint inhibitors, 14%–47% of the patients will have skin reactions, the severity of these reactions varies from mild to widespread, and 1%–3% of the patients will have this reaction [39]. About 4%–10% or more NSCLC patients who were treated with nivolumab have rashes and itching [40]. According to the report, Pembrolizumab leads to cutaneous reactions in about 9%–27% of patients [41]. ASO et al. [42] found that early skin reactions within 6 weeks seem to be related to the efficacy of ICI therapy which had better ORR and PFS than patients without skin reaction. Thyroid dysfunction is the most common endocrine irAEs. The mechanism of thyroid dysfunction during immunotherapy is not well understood. The investigators hypothesized that thyroid toxicity occur because of either humoral immunity or deterioration of low-level autoimmunity during anti-PD-1/PD-L1 antibody therapy [13]. Zhou et al. [9] found that the favorable results remained insignificant for endocrine and gastrointestinal irAEs might be explained by heterogeneity which is inconsistent with our study. According to hepatobiliary irAEs and pulmonary irAEs, considering that tumors of respiratory and hepatobiliary systems are the most commonly involved in anti-PD-1/PD-L1 therapy, it may increase mortality and lead to undesirable results [43].

Regarding the subgroup analyses based on irAEs grades, there was significant prognostic value on low-grade irAEs. The prognostic value was also significant on severe-grade irAEs for FPS. But no significant associations were found between the severe-irAEs and favorable OS on severe-grade irAEs. First, fewer patients are considered to have grade 3 or higher grade, it does not have sufficient capacity to determine any correlation. Second, because patients with severe irAEs may be life-threatening, glucocorticoid therapy is required to save lives which inhibit the effect of ICI and promote the growth of tumor [44]. Therefore, accurate assessment of tumor response is considered more difficult.

Our meta-analysis has some limitations that need to be improved. First of all, our study only includes published studies, and many unpublished data are not included, and we excluded several studies because they did not report HR values and other reasons. Therefore, publication bias is hard to avoid, Egger’s test indicated the existence of publication bias in the results of OS. But, the trim and fill method and Begg’s test further prove the stability. Second, there existed significant heterogeneity in the OS analysis, which might result from irAEs types and irAEs grades. To reduce the effect of heterogeneity, we analyzed each type and grade of irAEs. Third, due to limited resources, subgroup analysis was not performed according to the anti PD-1 and PD-L1 antibody types. Due to the lack of detailed analysis of tumor staging, class of ICIs, combination therapy and treatment line, which may influence the results of our study. Finally, because our study included a limited number of studies, therefore, the statistical ability is weak in the evaluation of the correlation between the irAEs development and the survival benefit of anti-PD-1/PD-L1 antibody, especially in stratified analyses.

In conclusion, our study further demonstrated that the development of irAEs with anti-PD-1/PD-L1 antibody therapy is related to better survival benefits in patients with NSCLC, especially endocrine, gastrointestinal, skin and low-grade irAEs. With the rapid development of immunotherapy, it will become very important to find the indicators to predict the efficacy. Our results suggest that irAEs may be a potential prognostic factor for efficacy. However, due to the small number of studies, some results are limited. Therefore, it is necessary to conduct further large-scale research.