Immune-Related Adverse Events and Survival Among Patients With Metastatic NSCLC Treated With Immune Checkpoint Inhibitors

Abstract

ImportanceImmune-related adverse events (irAEs) secondary to immune checkpoint inhibitor (ICI) therapy reportedly improve overall survival (OS) in patients with non–small cell lung cancer (NSCLC). However, studies have been small and the association between irAE severity and OS remains poorly defined.ObjectiveTo examine the association between irAEs and their severity with OS in patients with locally advanced or metastatic NSCLC receiving ICIs.Design, Setting, and ParticipantsThis retrospective observational cohort study included patients with NSCLC receiving ICIs between March 1, 2014, and November 30, 2021, with follow-up until March 31, 2023. Data analysis was completed April 26, 2023. The Alberta Immunotherapy Database, a provincial, multicenter cohort, was used to capture data from patients receiving ICIs in Alberta, Canada. Participants included 803 patients 18 years or older who received at least 1 cycle of ICI (alone or with chemotherapy), agnostic to treatment line.ExposureDeveloping an irAE mandating delay or discontinuation of ICI therapy and/or systematic corticosteroids for management of toxic effects (hereinafter referred to as clinically meaningful irAEs).Main Outcomes and MeasuresThe primary outcome was association between irAEs and OS according to Kaplan-Meier analysis. Clinically meaningful irAEs were identified. Patients with poor prognosis (survival <3 months) who may have died prior to irAE development were excluded from OS analysis, mitigating immortal time bias. Adjusted Cox proportional hazards regression analyses ascertained variables associated with OS.ResultsAmong the 803 patients included in the analysis, the median age of patients with irAEs was 69.7 (IQR, 63.1-75.2) years and the median age of those without irAEs was 67.5 (IQR, 60.4-73.3) years, with comparable sex distribution (139 of 295 men [47.1%] and 156 of 295 women [52.9%] with irAEs vs 254 of 505 men [50.3%] and 251 of 505 women [49.7%] without irAEs). Mitigating immortal time bias (n = 611), irAEs were associated with OS (median OS with irAEs, 23.7 [95% CI, 19.3-29.1] months; median OS without irAEs, 9.8 [95% CI, 8.7-11.4] months; P < .001). No OS difference was associated with treatment in hospital vs as outpatients for an irAE (median OS, 20.8 [95% CI, 11.7-30.6] vs 25.6 [95% CI, 20.1-29.8] months; P = .33). Developing irAEs remained associated with OS in the total cohort after Cox proportional hazards regression with known prognostic characteristics (hazard ratio, 0.53 [95% CI, 0.40-0.70]; P < .001).Conclusions and RelevanceIn this cohort study of 803 patients with locally advanced or metastatic NSCLC receiving ICIs, developing a clinically meaningful irAE was associated with improved OS. This association was not compromised by hospitalization for severe toxic effects. Whether and how ICI therapy resumption after an irAE is associated with OS warrants further study.

Characterization of Pre- and Post-treatment Soluble Immune Mediators and the Tumor Microenvironment in NSCLC Patients Receiving PD-1/L1 Inhibitor Monotherapy

“…Since irAEs re ect immune activation by ICI administration and are associated with therapeutic e cacy, we analyzed their association with the pre-and on-treatment biomarkers identi ed in the present study [13,14]. Our analysis revealed that pre-treatment biomarkers were not associated with development of irAE, whereas posttreatment changes in CCL23 were associated with the development of irAE.…”

“…We also analyzed the association and correlation between possible predictors of the therapeutic e cacy of ICI monotherapy and pre-and on-treatment biomarkers. Based on previous reports, irAE development, PD-L1 expression, CD8 + TIL density, peripheral blood cell count and proportion, and NLR were selected for examination [1][2][3][13][14][15][16][17].…”

Effects of immune checkpoint inhibitor associated endocrinopathies on cancer survival

“…A growing body of evidence suggests that development of irAEs is associated with improvements in progression-free survival, overall survival and overall disease response rate (10)(11)(12)(13). Studies have demonstrated shared T cell receptor sequences and/or upregulated organ-specific transcripts between tumors and non-malignant tissues affected by irAEs, which suggest that irAEs and the anti-tumor immune response to ICIs could be mechanistically linked (14).…”

Moving from conventional to adaptive risk stratification for oropharyngeal cancer

“…It is also important to note, that immunotherapy in the form of existing ICIs, is not quite as benign as was initially hoped. Significant levels of immunotherapy-related adverse events (irAEs) have been reported in non-small cell lung cancer (NSCLC) ( 68 , 69 ), melanoma ( 70 ) and HNSCC ( 71 ) especially when multiple ICIs are combined. Particularly problematic is the consistent observation that ICI toxicity and effectiveness are extremely correlated suggesting a substantial hurdle to ICI deployment for HNSCC particularly when combined with other toxic regimens/treatments.…”