Grade 3-4 Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer (NSCLC) Patients Are Correlated with Better Outcome: A Real-Life Observational Study

Simple Summary Immune checkpoint inhibitors (ICIs) recently became a standard treatment for advanced non-small-cell lung cancers (NSCLCs). Immune-related adverse events (irAEs) could occur in 10 to 80% of treated patients but were reported to associate with a better prognosis in clinical trials. However, the prognostic role of Grade 3-4 irAEs, occurring in 2 to 18% of cases, has not been specifically addressed in a real-life setting yet. In this observational study, we highlighted an association between high-grade irAEs and better outcomes in advanced NSCLC patients who received ICI treatment. Actually, a significantly longer overall survival was observed in patients with high-grade irAEs compared to the no-irAEs group. This observation thus suggests a direct link between anti-tumor efficacy and the level of immune activation leading to high-grade irAEs. Background: Immune checkpoint inhibitors (ICIs) have been a major advance in treating non-small-cell lung cancer (NSCLC). Programmed cell death protein-1/programmed death-ligand 1 blockade enhances immune function, mediating anti-tumor activity, yet causing immune-related adverse events (irAEs). We investigated the prognostic role of Grade 3-4 irAEs on overall survival (OS). Methods: This observational study recruited advanced NSCLC patients who received ICIs at Bichat-Claude Bernard University Hospital and in a community hospital, Saint-Joseph Foundation (Paris), between 1 January 2016 and 31 December 2019. Immunotherapy as a single-agent or double-drug combination was applied in the first and later lines. Univariable and multivariable analyses were instrumental in evaluating the prognostic impact of irAEs. Results: Overall, 201 consecutive ICI-treated patients were enrolled. High-grade irAEs (Grades 3-4) occurred in 36 patients (17.9%), including 11 (30.5%) cases of pneumonitis, 8 (22.2%) of colitis, 4 (11.1%) hepatic, 3 (8.3%) dermatological, 2 (5.5%) neurological events, and 2 cases (5.5%) of poly-arthralgia. The median OS was 10.4 +/- 1.36 months (95% CI:7.7-13.1), being significantly higher in patients with high-grade irAEs than those without, 27.8 months vs. 8.1 months, respectively (HR = 2.5; p < 0.0001). Multivariable analysis revealed an independent association between high-grade irAEs and longer OS (HR = 0.29, 95% CI: 0.2-0.6, p < 0.0001). Conclusions: Our real-life study confirms that high-grade irAEs predict longer OS in advanced NSCLC.