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Observational Study
. 2024 Jan 2;7(1):e2352302.
doi: 10.1001/jamanetworkopen.2023.52302.

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

Sarah Cook  1 , Vanessa Samuel  1 , Daniel E Meyers  2 , Igor Stukalin  1 , Ishjot Litt  1 , Randeep Sangha  3 , Don G Morris  4 , Daniel Y C Heng  4 , Aliyah Pabani  5 , Michelle Dean  1 , Vishal Navani  4
Affiliations
Observational Study

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

Sarah Cook et al. JAMA Netw Open. .

Abstract

Importance: Immune-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.

Objective: To examine the association between irAEs and their severity with OS in patients with locally advanced or metastatic NSCLC receiving ICIs.

Design, setting, and participants: This 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.

Exposure: Developing 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 measures: The 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.

Results: Among 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 relevance: In 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Sangha reported receiving personal fees from Pfizer Inc, F. Hoffmann–La Roche AG, Eli Lilly and Company, AstraZeneca, BMS, Merck & Co Inc, AbbVie Inc, Takeda Pharmaceutical Company, Sanofi SA, H. Lundbeck A/S, Teva Pharmaceutical Industries Ltd, and Bayer AG outside the submitted work. Dr Heng reported receiving personal fees from Novartis AG, Merck & Co Inc, Pfizer Inc, BMS, Ipsen, AstraZeneca, Exilexis Inc, and Eisai outside the submitted work. Dr Pabani reported receiving grant funding from BMS and ACF Pharmaceuticals and personal fees from Canadian Agency for Drugs and Technologies in Health, AstraZeneca, F. Hoffmann–La Roche AG, Merck & Co Inc, and Pfizer Inc outside the submitted work. Dr Navani reported receiving personal fees from Pfizer Inc, AstraZeneca, Ipsen, Janssen Pharmaceuticals, and Novotech and nonfinancial support from Sanofi SA and EMD Serono outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Relative Frequency and Type of Clinically Meaningful Immune-Related Adverse Event by Agent Received
Figure 2.
Figure 2.. Median Overall Survival for Patients With Metastatic Non–Small Cell Lung Cancer
Analysis includes patients who survived to at least 12 weeks. A, Full cohort of patients who did or did not develop an immune-related adverse event (irAE) (median OS, 23.7 [95% CI, 19.3-29.1] vs 9.8 months [95% CI, 8.7-11.4 months]; P < .001). B, Patients hospitalized compared with those treated as outpatients for irAEs (median OS, 20.8 [95% CI, 11.7-30.6] vs 25.6 [95% CI, 20.1-29.8] months; P = .33).
Figure 3.
Figure 3.. Median Time to Next Treatment for Patients With Metastatic Non–Small Cell Lung Cancer
Analysis includes patients who survived to at least 12 weeks. A, Full cohort of patients who did or did not develop an immune-related adverse event (irAE) (median time to next treatment, 18.0 [95% CI, 15.6-22.9] vs 7.3 [95% CI, 6.6-8.4] months; P < .001). B, Patients hospitalized compared with those treated as outpatients for irAEs (median time to next treatment, 15.3 [95% CI, 9.6-24.8] vs 15.9 [95% CI, 13.6-18.0] months; P = .67).
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