Science and Research

Therapeutic and Prognostic Implications of Immune-Related Adverse Events in Advanced Non-Small-Cell Lung Cancer

INTRODUCTION: PD-(L)1 inhibitors have improved prognosis of non-small-cell lung cancer (NSCLC), but can also cause immune-related adverse events (irAEs) that complicate management. METHODS: We analyzed NSCLC patients receiving PD-(L)1 inhibitors from 2012 to 2020 in a German academic center. RESULTS: IrAE showed comparable frequencies in stage IV (198/894 or 22%) vs. III (14/45 or 31%, p = 0.15), after anti-PD-(L)1 monotherapy vs. chemoimmunotherapy (139/483 vs. 58/213, p = 0.75), and across treatment lines. In stage IV, irAE occurred after 3.1 months in median, affected multiple organs (median 2) in 27/894 patients and were associated with PD-L1 positivity (25 vs. 14%, p = 0.003), lower neutrophil-to-lymphocyte ratios (29 vs. 17%, p < 0.001 for NLR dichotomized at 5), better ECOG status (26 vs. 18% for 0 vs. 1, p = 0.004), but not related to age, sex, smoking and palliative radiotherapy. Two hundred thirty two irAEs occurred mostly in endocrine glands (4.9%), lungs (4.4%), the musculoskeletal system (4.2%), colon (4.1%), liver (3.7%), and skin (2.6%), while pneumonitis was most frequent with durvalumab following definitive chemoradiation (16% or 7/45, p < 0.01). IrAE severity was grade 1 in 11%, 2 in 41%, 3 in 36%, and 4 in 11% events, while two were lethal (<1%, myocarditis and pneumonitis). Therapy was suspended in 72%, while steroids were initiated in 66% and complemented by other immunosuppressants in 6%, with longest treatment duration for rheumatic events (mean >3 months), and average cumulative prednisone doses >700 mg for all organs, except for skin. Patients developing irAE had longer progression-free (PFS) and overall survival (OS) in multivariable 12/14-week landmark analyses including ECOG status, treatment line, treatment type, PD-L1 TPS, and NLR (median PFS 17 vs. 10 months, HR = 0.68, p = 0.009; median OS 37 vs. 15 months, HR = 0.40, p < 0.001), regardless of grade. OS was longest with skin (95% at 2 years) and shortest with pneumonitis, hepatitis, neurologic, and cardiologic irAE (38, 37, 28, and 0% at 2 years, p < 0.001). CONCLUSIONS: Approximately one-fourth of immunotherapy-treated NSCLC patients develop irAEs, most of which necessitate treatment suspension and steroids. Despite more frequent occurrence with PD-L1 positive tumors, lower NLR, and better ECOG PS, irAEs are independently associated with longer survival, especially when affecting the skin. Lethality is below 1%.
  • Daniello, L.
  • Elshiaty, M.
  • Bozorgmehr, F.
  • Kuon, J.
  • Kazdal, D.
  • Schindler, H.
  • Shah, R.
  • Volckmar, A. L.
  • Lusky, F.
  • Diekmann, L.
  • Liersch, S.
  • Faehling, M.
  • Muley, T.
  • Kriegsmann, M.
  • Benesova, K.
  • Stenzinger, A.
  • Thomas, M.
  • Christopoulos, P.

Keywords

  • immune-checkpoint inhibitors
  • immune-related adverse events
  • immunotherapy
  • lethality
  • prognosis
  • treatment interruption
  • funding from AstraZeneca and Celgene. DK: advisory board and speaker’s honoraria
  • from AstraZeneca, BMS, Pfizer. RS: research funding from BMS. KB: research funding
  • from Novartis and Abbvie, speaker’s honoraria/advisory board/travel grants from
  • Abbvie, BMS, Gilead/Galapagos, Janssen, Lilly, Medac, MSD, Mundipharma, Novartis,
  • Pfizer, Roche, UCB. AS: advisory board honoraria from BMS, AstraZeneca,
  • ThermoFisher, Novartis, speaker’s honoraria from BMS, Illumina, AstraZeneca,
  • Novartis, ThermoFisher, MSD, Roche, and research funding from Chugai. MT: advisory
  • board honoraria from Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie,
  • Boehringer, speaker’s honoraria from Lilly, MSD, Takeda, research funding from
  • AstraZeneca, BMS, Celgene, Novartis, Roche and travel grants from BMS, MSD,
  • Novartis, Boehringer. PC: research funding from AstraZeneca, Novartis, Roche,
  • Takeda, and advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim,
  • Chugai, Novartis, Pfizer, Roche, Takeda. The remaining authors declare that the
  • research was conducted in the absence of any commercial or financial relationships
  • that could be construed as a potential conflict of interest.
Publication details
DOI: 10.3389/fonc.2021.703893
Journal: Front Oncol
Pages: 703893 
Work Type: Original
Location: TLRC
Disease Area: LC
Partner / Member: Thorax
Access-Number: 34268127

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