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
1Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China 2Department of Oncology, The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China 3Wenzhou Medical University, Wenzhou, China
Correspondence
Yun Fan ,Tel: 86-571-88122091 , Fax: 86-571-88122515 , Email: fanyun@zjcc.org.cn
Received: October 11, 2023; Accepted: December 30, 2023. Published online: January 2, 2024. *Ying Yu and Ning Chen contributed equally to this work.
ABSTRACT
Purpose
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).
Materials and Methods
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.
Results
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.
Conclusion
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.
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