• Bairavi Shankar, Jiajia Zhang, Abdul Rafeh Naqash, Patrick M Forde, Josephine L Feliciano, Kristen A Marrone, David S Ettinger, Christine L Hann, Julie R Brahmer, Biagio Ricciuti, Dwight Owen, Yukihiro Toi, Paul Walker, Gregory A Otterson, Sandip H Patel, Shunichi Sugawara, and Jarushka Naidoo.
• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland.
• JAMA Oncol. 2020 Dec 1; 6 (12): 1952-1956.

ImportanceThe 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.ObjectiveTo characterize multisystem irAEs, their association with survival, and risk factors for multisystem irAE development.Design, Setting, And ParticipantsThis 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.ExposuresAnti-PD-(L)1 monotherapy or combinations.Main Outcomes And MeasuresMultisystem 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.ResultsThe 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 RelevanceIn 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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