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Multicenter Study
. 2020 Dec 1;6(12):1952-1956.
doi: 10.1001/jamaoncol.2020.5012.

Multisystem Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors for Treatment of Non-Small Cell Lung Cancer

Bairavi Shankar  1   2 , Jiajia Zhang  1   2 , Abdul Rafeh Naqash  3   4 , Patrick M Forde  1   2 , Josephine L Feliciano  1   2 , Kristen A Marrone  1   2 , David S Ettinger  1   2 , Christine L Hann  1   2 , Julie R Brahmer  1   2 , Biagio Ricciuti  5   6 , Dwight Owen  7 , Yukihiro Toi  8 , Paul Walker  3 , Gregory A Otterson  7 , Sandip H Patel  7 , Shunichi Sugawara  8 , Jarushka Naidoo  1   2   9
Affiliations
Multicenter Study

Multisystem Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors for Treatment of Non-Small Cell Lung Cancer

Bairavi Shankar et al. JAMA Oncol. .

Abstract

Importance: The spectrum of individual immune-related adverse events (irAEs) from anti-programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) has been reported widely, and their development is associated with improved patient survival across tumor types. The spectrum and impact on survival for patients with non-small cell lung cancer (NSCLC) who develop multisystem irAEs from ICIs, has not been described.

Objective: To characterize multisystem irAEs, their association with survival, and risk factors for multisystem irAE development.

Design, setting, and participants: This retrospective cohort study carried out in 5 academic institutions worldwide included 623 patients with stage III/IV NSCLC, treated with anti-PD-(L)1 ICIs alone or in combination with another anticancer agent between January 2007 and January 2019.

Exposures: Anti-PD-(L)1 monotherapy or combinations.

Main outcomes and measures: Multisystem irAEs were characterized by combinations of individual irAEs or organ system involved, separated by ICI-monotherapy or combinations. Median progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Differences in PFS and OS between irAE groups were assessed by multivariable models. Risk for multisystem irAE was estimated as odds ratios by multivariable logistic regression.

Results: The 623 patients included in the study were mostly men (60%, n = 375) and White (77%, n = 480). The median (range) age was 66 (58-73) years, and 148 patients (24%) developed a single irAE, whereas 58 (9.3%) developed multisystem irAEs. The most common multisystem irAE patterns in patients receiving anti-PD-(L)1 monotherapy were pneumonitis thyroiditis (n = 7, 14%), hepatitis thyroiditis (n = 5, 10%), dermatitis pneumonitis (n = 5, 10%), and dermatitis thyroiditis (n = 4, 8%). Favorable Eastern Cooperative Oncology Group (ECOG) performance status (PS) (ECOG PS = 0/1 vs 2; adjusted odds ratio [aOR], 0.27; 95% CI, 0.08-0.94; P = .04) and longer ICI duration (aOR, 1.02; 95% CI, 1.01-1.03; P < .001) were independent risk factors for development of multisystem irAEs. Patients with 1 irAE and multisystem irAEs demonstrated incrementally improved OS (adjusted hazard ratios [aHRs], 0.86; 95% CI, 0.66-1.12; P = .26; and aHR, 0.57; 95% CI, 0.38-0.85; P = . 005, respectively) and PFS (aHR, 0.68; 95% CI, 0.55-0.85; P = .001; and aHR, 0.39; 95% CI, 0.28-0.55; P < .001, respectively) vs patients with no irAEs, in multivariable models adjusting for ICI duration.

Conclusions and relevance: In this multicenter cohort study, development of multisystem irAEs was associated with improved survival in patients with advanced NSCLC treated with ICIs.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Owen receives research funding to his institution from BMS, Merck, Genentech, Palobiofarma, and AbbVie, and is a consultant or on an advisory board for theMednet.org and Astra Zeneca. No disclosure is directly relevant to the research here. Dr Toi receives research funding to his institution or is a consultant for Ono Pharmaceutical, Bristol Myers Squibb, MSD, and Astra Zeneca. No disclosure is directly relevant to the research herein. Dr Sugawara receives research funding to his institution or is a consultant for Ono Pharmaceutical, Bristol Myers Squibb, MSD, Astra Zeneca, Chugai Pharma, Nippon Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly and Company, Novartis, and Kyowa Hakko Kirin. No disclosure is directly relevant to the research herein. Dr Ettinger is a consultant or on an advisory board for Alkermes Inc, Astra Zeneca, BeyondSpring Pharmaceuticals, Bristol Myers Squibb, and Guardant Health Inc. No disclosure is directly relevant to the research herein. Dr Otterson receives research funding to his institution from Astra Zeneca, BMS, Genentech, Pfizer, Merck, Revolution Medicine, and Takeda, and is a consultant for BMS, Guardant Health, Astra Zeneca, Novocure, and Gilead. No disclosure is directly relevant to the research herein. Dr Forde receives research funding, to his institution from Astra Zeneca, Bristol Myers Squibb, Kyowa, Novartis, and Corvus, and is a consultant for AbbVie, Astra Zeneca, and Bristol Myers Squibb. No disclosure is directly relevant to the research herein. Dr Brahmer is a consultant or on an advisory board for Amgen, BMS, Genentech/Roche, Eli Lilly and Company, GlaxoSmithKline, Merck, and Sanofi, and receives research funding to her institution from Astra Zeneca, BMS, Genentech/Roche, Merck, RAPT Therapeutics Inc, and Revolution Medicines. She is also on the Data and Safety Monitoring Board/Committee for GlaxoSmithKline and Sanofi. No disclosure is directly relevant to the research herein. Dr Hann receives research funding to her institution from AbbVie, Astra Zeneca, BMS, Amgen, and Genentech/Roche. She is on an advisory board for AbbVie, Ascentage, Astra Zeneca, BMS, and Genentech/Roche. No disclosure is directly relevant to the research herein. Dr Walker was a consultant for Genentech Speaker’s Bureau and Biodesix at the time of data collection for this study. He currently owns stock in Circulogene. No disclosure is directly relevant to the research herein. Dr Naidoo receives research funding, to her institution from Astra Zeneca and Merck. She is a consultant for Astra Zeneca, Bristol Myers Squibb, Merck, and Roche/Genentech. No disclosure is directly relevant to the research herein. Dr Feliciano receives research funding to her institution from Astra Zeneca and BMS. She is a consultant for Astra Zeneca, BMS, Merck, Genentech, Takeda, and Eli Lilly and Company. No disclosure is directly relevant to the research herein.

Figures

Figure.
Figure.. Progression-Free Survival and Overall Survival in Patients With NSCLC Treated With Anti–Programmed Cell Death 1 and Programmed Cell Death Ligand 1 Immunotherapy
A, Progression-free survival, and (B) overall survival in patients with NSCLC treated with anti–programmed cell death 1 and programmed cell death ligand 1 immunotherapy. irAE Indicates immune-related adverse events; NSCLC, non–small cell lung cancer.
See this image and copyright information in PMC

Comment in

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