Management, risk factors and prognostic impact of checkpoint-inhibitor pneumonitis (CIP) in lung cancer - A multicenter observational analysis.

Introduction: Checkpoint-inhibitor pneumonitis (CIP) represents a major immune-related adverse event (irAE) in patients with lung cancer. We aimed for the clinical characterization, diagnostics, risk factors, treatment and outcome in a large cohort of patients from everyday clinical practice.
Patients and Methods: For this retrospective analysis, 1,376 patients having received checkpoint inhibitors (CPI) in any line of therapy from June 2015 until February 2020 from three large-volume lung cancer centers in Berlin, Germany were included and analyzed.
Results: With a median follow-up of 35 months, all-grade, high-grade (CTCAE ≥ 3) and fatal CIP were observed in 83 (6.0%), 37 (2.7%) and 12 (0.9%) patients, respectively, with a median onset 4 months after initiation of CPI therapy. The most common radiologic patterns were organizing pneumonia (OP) and non-specific interstitial pneumonia (NSIP) (37% and 31%). All except 7 patients with G1-2 CIP interrupted treatment. Corticosteroids were administered to 74 patients with a median starting dose of 0.75 mg/kg. After complete restitution (n = 67), re-exposure to CPI (n = 14) led to additional irAE in 43% of the cases. Thoracic radiotherapy targeting the lung was the only independent risk factor for CIP (odds ratio 2.8, p < 0.001) and pretherapeutic diffusing capacity for carbon monoxide inversely correlated with CIP severity. Compared with patients without CIP and non-CIP irAE, CIP was associated with impaired overall survival (hazard ratios 1.23, p = 0.24 and 2.01, p = 0.005).
Conclusions: High-grade CIP accounts for almost half of all CIP cases in an allcomer lung cancer population. A continuous vigilance, rapid diagnostics and adequate treatment are key to prevent disease progression associated with impaired survival.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Frost reports consulting fees for being an advisory board member from AbbVie, Amgen, AstraZeneca, BeiGene, Berlinchemie, Boehringer Ingelheim, Bristol Myers&Squibb, Lilly, Merck Sharp&Dohme, Merck, Novartis, Pfizer, Roche, Sanofi and Takeda; Support for attending meetings and/or travel from Amgen, AstraZeneca, BMS, Janssen, Lilly and Takeda; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for the “Deutsche Gesellschaft für Pneumologie (DGP)” and the “Deutsche Krebsgesellschaft (DKG): Arbeitsgemeinschaft Internistische Onkologie, Sektion Thoraxonkologie”. Mrs. Unger has nothing to disclose. Dr. Blum has nothing to disclose. Dr. Misch has nothing to disclose. Dr. Kurz has nothing to disclose. Dr. Lüders has nothing to disclose. Dr. Olive has nothing to disclose. Dr. Raspe has nothing to disclose. Dr. Hilbrandt has nothing to disclose. Dr. Koch reports consulting fees for AstraZeneca and Roche, travel support from Boehringer Ingelheim and participation on a data safety monitoring board or advisory board for Roche and Janssen-Cilag. Dr. Böhmer reports consulting fees from Varian Medical Systems. Dr. Senger has nothing to disclose. Dr. Witzenrath reports having received research grants from the „Deutsche Forschungsgemeinschaft“, „Bundesministerium für Bildung und Forschung“, „Deutsche Gesellschaft für Pneumologie“, European Respiratory Society, Marie Curie Foundation, Else Kröner Fresenius Foundation, Capnetz Foundation, International Max Planck Research School, personal fees for lectures or consulting from: Astra Zeneca, Bayer Health Care, Berlin Chemie, Biotest, Boehringer Ingelheim, Chiesi, Gilead, Glaxo Smith Kline, Hexal, Insmed, Novartis, Noxxon, Pantherna, Roche, Teva, Vaxxilon; Patents planned, issued or pending: EPO 12181535.1: IL-27 for modulation of immune response in acute lung injury (Issued 2012), WO/2010/094491: Means for inhibiting the expression of Ang-2 (Issued 2010); PCT/EP2021/066543: A pharmaceutical combination comprising an anti-viral protonophore and a serine protease inhibitor (Issued 2021); PCT/EP2021/075627: New medical use of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (Issued 2021). Dr. Grohé reports having received research grants from AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda and Siemens; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Ariad, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda and Siemens; Participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Ariad, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda and Siemens; Dr. Bauer has nothing to disclose. Dr. Modest reports consulting fees from Amgen, Merck Serono, Servier, Pierre Fabre, BMS, MSD, Lilly, AstraZeneca, Onkowissen, Sanofi, Taiho, G1 and Transgene; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, Merck Serono, Servier, Pierre Fabre, BMS, MSD, Lilly, AstraZeneca, Onkowissen, Sanofi, Taiho, G1 and Transgene; Support for attending meetings and/or travel from Amgen. Dr. Kollmeier has nothing to disclose.
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