Rate and Risk Factors of Recurrent Immune Checkpoint Inhibitor-Related Pneumonitis in Patients With Lung Cancer

Haitao Tao; Fangfang Li; Dongxiao Wu; Shiyu Ji; Qingyan Liu; Lijie Wang; Bo Liu; Francesco Facchinetti; Tracy L. Leong; Francesco Passiglia; Yi Hu


Transl Lung Cancer Res. 2022;11(3):381-392. 

In This Article

Abstract and Introduction


Background: Immune checkpoint inhibitors (ICIs) have become standard treatments for lung cancer patients. Immune checkpoint inhibitor-related pneumonitis (CIP) was the leading cause of death among ICIs-related adverse events (irAEs). Recurrent episodes of CIP without rechallenge of ICIs were reported in several cases and maybe a unique feature of CIP. Knowledge gaps remain regarding the rate and risk factors associated to CIP's recurrence.

Methods: Data from 1,102 lung cancer patients receiving ICIs treatment between January 2016 and January 2021 were retrospectively collected and analyzed. CIP was diagnosed according to typical clinical features and/or new typical imaging changes. Recurrence of CIP (CIP-R) was defined as recurrent CIP after initial CIP improved after proper treatment. Logistic regression was used to assess risk factors associated with CIP recurrence.

Results: Eighty out of 1,102 (7.26%) patients were diagnosed with CIP. Twenty of those 78 (25.64%) patients suffered CIP-R, 2 patients died and were therefore excluded from the denominator. The median onset of initial pneumonitis for patients without and with recurrence was 3.49 months [interquartile range (IQR), 0.26–31.93 months] and 2.78 months (IQR, 1.22–20.93 months), respectively (P=0.48). The median interval duration between initial CIP and CIP-R was 1.54 months (IQR, 0.98–16.70 months). Recurrence of CIP was more common in males (P=0.03), squamous histology (P=0.016), and in patients who received chest radiotherapy (P=0.049). The duration of prednisolone equivalent dose ≥15 mg/day in CIP-R was significantly shorter, at 3.71 weeks (2.86–6.57 weeks) compared with 6.36 weeks in those without recurrence (IQR, 3.12–9.86 weeks) (P=0.001). Non-squamous histology [odds ratio (OR), 0.182; 95% confidence interval (CI): 0.038–0.860; P=0.031] and prolonged administration of prednisolone equivalent dose ≥15 mg/day for more than 4 weeks (OR, 0.082; 95% CI: 0.02–0.342; P=0.001) were independently associated with a decreased odds of CIP-R development.

Conclusions: CIP-R in a real-world lung cancer cohort is not uncommon, both in patients with and without rechallenge of ICIs. A duration of prednisolone equivalent dose ≥15 mg/day of at least 4 weeks during the tapering process of corticosteroids were recommend in patients with CIP.


Immune checkpoint inhibitors (ICIs) have become standard treatments for lung cancer, including the first- and second-line therapy of advanced non-small cell lung cancer (NSCLC) without driver mutations, the first-line therapy of extensive-stage small cell lung cancer (SCLC) and the consolidative therapy of unresectable stage III NSCLC after concurrent chemoradiotherapy.[1–5] However, despite clinical benefits characterized by a significant increase of long-term survival, ICIs use is associated with a wide spectrum of immune-related adverse events (irAEs) whose pathogenetic mechanisms are still largely unknown.[6]

Although clinical trials suggest a rare incidence of immune checkpoint inhibitor-related pneumonitis (CIP) (approximately 4–6%), restrictive enrollment criteria may underestimate the true incidence in clinical practice.[7,8] Indeed, the incidence of CIP reported in real-world lung cancer cohorts ranges from 5% to 19%.[9,10] CIP is a serious adverse event in ICIs treated patients, and is the leading cause of death among the different irAEs, with an overall mortality rate of approximately 0.45%.[11,12] However, the inflammatory characteristics of CIP that result in morbidity and mortality are also associated with enhanced programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitor efficacy in NSCLC.[13]

Although irAE is generally reversible after appropriately corticosteroids treatment, several retrospective studies have reported recurrence of CIP (CIP-R).[14–18] Nishino et al. first reported that a patient with lung cancer receiving anti-PD-1 treatment experienced recurrent pneumonitis in absence of ICIs-rechallenge after a documented resolution, named a "pneumonitis flare".[14] Asher et al. reported three patients with melanoma who experienced unprovoked CIP-R after complete resolution without ICIs-rechallenge, named a "unprovoked recurrent pneumonitis".[16] Dolladille et al. reported a 28.8% recurrence rate of the same irAEs after a rechallenge with the same ICIs, and pneumonitis was associated with a higher recurrence rate compared with other irAEs.[17] Recurrent CIP seem to be not uncommon, CIP-R occurred without rechallenge of ICIs maybe a unique feature of CIP, which was similar to the durable and persisted response after ICIs discontinuation.[14] However, there is limited information on patients of CIP-R in recent research, especially regarding unprovoked recurrent pneumonitis.

The aim of this study was to characterize the clinical and radiological features, cancer-related and CIP-related factors of lung cancer patients experiencing CIP-R, in order to identify potential risk factors to CIP-R either related or not to ICIs rechallenge. We present the following article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-168/rc).