Association of Immune-Related Adverse Events and the Efficacy of Anti-PD-(L)1 Monotherapy in Non-Small Cell Lung Cancer: Adjusting for Immortal-Time Bias.

Abstract

The association between immune-related adverse events (irAEs) and survival outcomes in non-small cell lung cancer (NSCLC) patients treated with programmed-death-(ligand)1 [PD-(L)1] inhibitors remains controversial, partly due to variations in dealing with immortal-time bias (ITB). We retrospectively enrolled 425 advanced NSCLC patients who received anti-PD-(L)1 monotherapy between January 2016 and June 2021, stratifying them into irAE (n=127) and non-irAE (n=298) groups. The primary endpoint was to assess the impact of irAEs on progression-free survival (PFS) and overall survival (OS). Landmark (2-, 3-, 6-, and 9-month) and time-dependent Cox analyses were performed to eliminate ITB. With a median follow-up of 38.8 months, the occurrence of overall irAEs was significantly associated with superior PFS (11.2 vs. 3.4 months, p<0.0001) and OS (31.4 vs. 14.0 months, p<0.0001), which persisted in landmark and time-dependent Cox analyses. For the main organ-specific irAEs, skin, thyroid, and hepatic irAEs, respectively, showed significantly improved survival compared to the non-irAE group, whereas pneumonitis did not. Single-organ irAEs had the best outcomes compared with multi-organ or no irAE, which also held across subgroups of skin, thyroid and hepatic irAEs. Moreover, severe grade irAEs and immunotherapy discontinuation had a detrimental effect on survival, systemic steroid therapy showed little effect, while immunotherapy resumption had tolerable safety and a trend of improved survival. After adequately adjusting ITB, the occurrence of overall irAEs predicts for favorable efficacy of anti-PD-(L)1 monotherapy in NSCLC, with better outcomes observed in patients with skin, thyroid, or hepatic irAEs, particularly those with single-organ involvement.