Prediction of site-specific immune-related adverse events of PD-L1 blockade in advanced non-small cell lung cancer through baseline organ-metastatic landscape: Pooled post-hoc analyses of two randomized controlled trials.

Abstract

8542 Background: The patterns of immune-related adverse events (irAEs) during immunotherapy vary among tumors of different origins. However, it remains unknown whether metastases in different organs confer varying susceptibility to irAEs in a specific tumor type. Herein, we explored the impact of the baseline organ-metastatic landscape on the irAE patterns following PD-L1 blockade in advanced non-small cell lung cancer (NSCLC). Methods: We conducted a pooled post-hoc analysis of 708 patients with advanced NSCLC who received atezolizumab from two randomized controlled trials (OAK and POPLAR). The association between the baseline metastatic status and both overall and site-specific irAEs was analyzed using multivariate logistic regression and multivariate Cox regression. The Kaplan-Meier method with the log-rank test was leveraged to compare the cumulative risk of irAEs based on organ-specific metastatic status. Results: Patients harboring different organ metastases yielded varying vulnerability of irAEs (p = 0.047). Overall, irAEs were less likely to occur in patients with bone metastases (OR = 0.52, p = 0.039) and pleural effusion metastases (OR = 0.65, p = 0.039), while more frequent in patients with brain metastases (OR = 1.96, p = 0.023). Besides, patients with bone metastases experienced a significant delayed onset of irAEs compared to those with metastases to other organs (HR = 0.65, p = 0.007). In terms of the incidence of site-specific irAEs, hepatitis (OR = 0.55, p = 0.03), hypothyroidism (OR = 0.27, p = 0.008), and rash (OR = 0.63, p = 0.039) were less frequent in patients with bone metastases, whereas pneumonia (OR = 3.25, p = 0.046), adrenal insufficiency (OR = 12.71, p = 0.019) and ocular inflammatory toxicity (OR = 21.17, p = 0.017) were more concentrated in patients with brain metastases; adrenal insufficiency was particularly prevalent in patients with adrenal metastases (OR = 15.22, p = 0.023). As for the onset of site-specific irAEs, patients with bone metastases experienced significantly later onset of hypothyroidism (HR = 0.27, p = 0.008), while those with metastases to brain (HR = 7.81, p = 0.029) and adrenal glands (HR = 12.54, p = 0.029) developed earlier onset of adrenal insufficiency; liver metastases were associated with earlier onset of hepatitis (HR = 1.8, p = 0.018) and colitis (HR = 5.49, p = 0.033). Conclusions: The baseline organ-metastatic landscape might be a predictive factor for overall and site-specific irAEs in advanced NSCLC patients received PD-L1 blockade. Our findings enhance the understanding of organ-specific immunity in immunotherapy under the metastatic setting of NSCLC and may inform personalized immunotherapy strategies.