Real-World Outcomes of Immunotherapy in Second- or Later-Line Non-Small Cell Lung Cancer with Actionable Genetic Alterations

SIMPLE SUMMARY: This study focused on actionable genetic alterations (AGAs) subtypes and pathologic or genetic biomarkers influencing the efficacy of immune checkpoint inhibitor (ICI) therapy in a real-world setting. In advanced non-small cell lung cancer (NSCLC) patients, the response to ICI monotherapy varies among AGAs. In previous studies, while patients with KRAS, BRAF, and MET exhibited favorable efficacy, it did not appear in patients with EGFR, ALK, ROS1, or RET. In this study, ICI monotherapy benefits differed across AGA subtypes but reaffirmed that KRAS, MET, and BRAF patients experienced longer benefits in the second- or later-line therapy. PD-L1 was a positive predictive biomarker, but not TMB. Co-existing STK11 with KRAS and TP53 with MET mutation were negatively correlated with ICI responses. Despite the limitation of a small sample size for some rare mutations, this study can still provide valuable insights that may guide clinical decision making and further research to validate the findings. ABSTRACT: Introduction: While the efficacy of immune checkpoint inhibitors (ICIs) in treating non-small cell lung cancer (NSCLC) patients with actionable genetic alterations (AGAs) is modest, certain patients demonstrate improved survival. Thus, this study aimed to evaluate the benefits of ICIs in NSCLC patients with diverse AGAs and verify the predictive biomarkers of ICI efficacy. Methods: From January 2018 to July 2022, this study compared the progression-free survival (PFS) of NSCLC patients with different AGAs treated with ICI monotherapy as second- or later-line therapy at Samsung Medical Center. To ascertain the predictors of ICIs efficacy, we adjusted ICIs’ effects on PFS in terms of clinical and molecular biomarkers. Results: EGFR (46.0%) was the most prevalent mutation in 324 patients. In multivariate analysis, PD-L1 positivity (tumor proportion score (TPS) ≥ 1%) (HR = 0.41) and the use of steroids for immune-related adverse events (HR = 0.46) were positive factors for ICI therapy in the AGAs group. Co-existing mutation of STK11 with KRAS mutation (HR = 4.53) and TP53 with MET mutation (HR = 9.78) was negatively associated with survival. Conclusions: The efficacy of ICI treatment varied across AGA subtypes, but patients with KRAS, MET, and BRAF mutations demonstrated relatively long-duration benefits of ICI therapy. PD-L1 was a significant positive predictive biomarker in all AGA groups.