Abstract
Background and ObjectiveAlthough anti-programmed cell death protein 1 (PD-1) antibodies have exerted remarkable anticancer activity in non-small cell lung cancer (NSCLC), it remains a challenge to identify patients who can benefit from these treatments. Immune-related adverse events (irAEs) may be associated with improved clinical outcomes after immune checkpoint inhibition. However, no conclusive evidence of this correlation has been summarized in patients with NSCLC receiving PD-1 inhibitors. We performed a systematic review and meta-analysis to evaluate the association between irAEs induced by anti-PD-1 antibodies and clinical outcomes in patients with NSCLC.MethodsVarious databases were searched from their inception to January 9, 2021, followed by screening of eligible studies. Hazard ratios were used for the pooled analysis of overall survival (OS) and progression-free survival (PFS), while odds ratios (ORs) were utilized to pool objective response rates (ORRs) and disease control rates (DCRs). A random-effects model was applied to all analyses.ResultsA total of 26 cohorts, including 8,452 patients with NSCLC receiving anti-PD-1 antibodies, were enrolled in the study. Significantly improved OS (HR: 0.51; 95% CI: 0.44-0.60; P < 0.01) and PFS (HR: 0.50; 95% CI: 0.43-0.58; P < 0.01) were found to be correlated with irAEs. In addition, patients with NSCLC who developed irAEs after PD-1 inhibition demonstrated better responses to therapies, confirmed by pooled ORs of ORRs (OR: 3.41; 95% CI: 2.66-4.35; P < 0.01) and DCRs (OR: 4.08; 95% CI: 2.30-7.24; P < 0.01). Furthermore, subgroup analysis suggested that both skin and endocrine irAEs are closely correlated with a reduced risk of death, whereas pulmonary irAEs showed no association with longer OS.ConclusionsIn patients with NSCLC treated with anti-PD-1 therapies, the presence of irAEs was strongly correlated with better survival and response, suggesting its potential role as a predictive biomarker for outcomes after PD-1 inhibition.
Highlights
In recent decades, immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1), programmed deathligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment landscape for patients with advanced cancer [1]
For objective response rates (ORRs) analyses, we found that Immune-related adverse events (irAEs) were significantly related to higher rates of objective responses to PD-1 blockade (OR: 3.41; 95% confidence intervals (CIs): 2.66–4.35; P < 0.01; Figure 3A) with moderate heterogeneity (I2 = 56%, P < 0.01; Figure 3A)
The analysis revealed that skin (HR: 0.41; 95% CI: 0.32–0.52; P < 0.01) and endocrine (HR: 0.41; 95% CI: 0.33–0.51; P < 0.01) irAEs were significantly associated with longer overall survival (OS), whereas pulmonary irAEs showed no correlation (HR: 0.98; 95% CI: 0.53–1.83; P = 0.96) (Figure 4A)
Summary
Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1), programmed deathligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment landscape for patients with advanced cancer [1]. Several predictive approaches have recently been developed for NSCLC treatment, including biomarkers of PD-L1 expression [6, 7], tumorinfiltrating lymphocytes [8], and tumor mutation burden [9]. While these biomarkers were developed primarily to focus on the histological or molecular features of the tumor, evidence for predictive capacity of other clinical characteristics is unclear. Anti-programmed cell death protein 1 (PD-1) antibodies have exerted remarkable anticancer activity in non-small cell lung cancer (NSCLC), it remains a challenge to identify patients who can benefit from these treatments. We performed a systematic review and meta-analysis to evaluate the association between irAEs induced by anti-PD-1 antibodies and clinical outcomes in patients with NSCLC
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