Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer

Cho, Jun Yeun; Kim, Jung-Hoon; Lee, Jong Seok; Kim, Yu Jung; Kim, Se Hyun; Lee, Yeon Joo; Cho, Young Jae; Yoon, Ho Il; Lee, Jae Ho; Lee, Choon Taek; Park, Jong Sun

doi:10.1016/j.lungcan.2018.09.015

Cited by 160 publications

(193 citation statements)

References 21 publications

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“…Similarly, the reported severe grade CIP incidence rates were 1%–3% and 3.4%–4.2% in large scale clinical trials and real‐world clinical studies, respectively. Furthermore, although mortality related to CIP was not observed in large scale clinical trials, the CIP‐related mortality rate ranged from 12.8% to 18.2% in real‐world clinical studies . Patients who are elderly, in poor clinical condition, or with pre‐existing ILDs are usually excluded from large scale clinical trials.…”

Section: Discussionmentioning

confidence: 85%

“…Importantly, the CIP‐related mortality rate was 22.7% in the current study. The CIP morbidity rates were 1%–5% and 13.2%–19.0% in large scale clinical trials and studies in real‐world settings, respectively. Similarly, the reported severe grade CIP incidence rates were 1%–3% and 3.4%–4.2% in large scale clinical trials and real‐world clinical studies, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…The CIP morbidity rates were 1%–5% and 13.2%–19.0% in large scale clinical trials and studies in real‐world settings, respectively. Similarly, the reported severe grade CIP incidence rates were 1%–3% and 3.4%–4.2% in large scale clinical trials and real‐world clinical studies, respectively. Furthermore, although mortality related to CIP was not observed in large scale clinical trials, the CIP‐related mortality rate ranged from 12.8% to 18.2% in real‐world clinical studies .…”

Section: Discussionmentioning

confidence: 99%

“…Checkpoint inhibitor pneumonitis (CIP) is one irAE that can lead to death, particularly in patients with NSCLC . Large scale clinical trials reported 1%–5% as the morbidity rate of CIP in patients with NSCLC, whereas high morbidity rates ranging from 13.2% to 19.0% have been reported in studies in real‐world settings . This is because the real‐world clinical studies included patients who were older, in poor general condition, or with pre‐existing interstitial lung diseases (ILDs).…”

Section: Introductionmentioning

confidence: 99%

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High mortality and poor treatment efficacy of immune checkpoint inhibitors in patients with severe grade checkpoint inhibitor pneumonitis in non‐small cell lung cancer

et al. 2019

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Background The treatment efficacy of immune checkpoint inhibitor (ICI) and clinical outcomes in patients with non‐small cell lung cancer (NSCLC) who develop severe grade checkpoint inhibitor pneumonitis (CIP) are unclear. Here, we report on the treatment efficacy of ICI and prognosis in NSCLC patients with severe grade CIP. Methods In this retrospective cohort study, CIP severity, CIP‐related mortality, and ICI efficacy in 71 patients with advanced NSCLC treated with ICIs were evaluated. Data was obtained from the patients’ medical charts. Results All grade and severe grade CIP were observed in 22 and 11 patients, respectively. The CIP‐related mortality rate was 22.7% (N = 5). An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of ≥2 and pre‐existing interstitial lung disease (ILD) were significantly associated with the development of severe grade CIP (P = 0.001 and P = 0.035, respectively). The median progression‐free survival (PFS) and overall survival (OS) were significantly shorter in patients with severe grade CIP than in those without severe grade CIP (PFS 1.0 month, 95% confidence interval [CI] 0.5–2.0 vs. 3.5 months, 95% CI 2.0–5.0 months, P = 0.003; OS 3.0 months, 95% CI 0.5–13 vs. 12.7 months, 95% CI 8.0–21.0 months, P = 0.011). Conclusion CIP is a serious complication with a poor prognosis associated with high mortality. The efficacy of ICI is significantly worse in patients with severe grade CIP than in those without severe grade CIP. Whether ICIs should be administered to patients with CIP risk factors, such as an ECOG PS score of ≥2 or pre‐existing ILD, should be carefully assessed.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High mortality and poor treatment efficacy of immune checkpoint inhibitors in patients with severe grade checkpoint inhibitor pneumonitis in non‐small cell lung cancer

et al. 2019

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“…Although CIP can result in high morbidity, it was previously thought to be an uncommon complication of ICI therapy, with an incidence of around 3% to 5% (7,8) based on clinical trial data. Recent evidence from our group and others suggests, however, that the occurrence of CIP may be higher in real-world settings (9,10). For instance, using a multidisciplinary, standardized approach (11), we recently observed an incidence of 19% in a cohort of 205 patients with NSCLC treated with ICI (12).…”

Section: Introductionmentioning

confidence: 82%

The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis

Suresh

Naidoo

Zhong

et al. 2019

Journal of Clinical Investigation

108

104

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BACKGROUND. Checkpoint inhibitor pneumonitis (CIP) is a highly morbid complication of immune checkpoint immunotherapy (ICI), one which precludes the continuation of ICI. Yet, the mechanistic underpinnings of CIP are unknown. METHODS. To better understand the mechanism of lung injury in CIP, we prospectively collected bronchoalveolar lavage (BAL) samples in ICI-treated patients with (n = 12) and without CIP (n = 6), prior to initiating first-line therapy for CIP (high-dose corticosteroids). We analyzed BAL immune cell populations using a combination of traditional multicolor flow cytometry gating, unsupervised clustering analysis, and BAL supernatant cytokine measurements. RESULTS. We found increased BAL lymphocytosis, predominantly CD4 + T cells, in patients with CIP. Specifically, we observed increased numbers of BAL central memory T cells, evidence of type I polarization, and decreased expression of cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 in BAL Tregs, suggesting both activation of proinflammatory subsets and an attenuated suppressive phenotype. CIP BAL myeloid immune populations displayed enhanced expression of IL-1β and decreased expression of counterregulatory interleukin-1 receptor antagonist. We observed increased levels of T-cell chemoattractants in the BAL supernatant, consistent with our proinflammatory, lymphocytic cellular landscape. CONCLUSION. We observe several immune cell subpopulations that are dysregulated in CIP, which may represent possible targets that could lead to therapeutics for this morbid immune-related adverse event.

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Variation in the Assessment of Immune-Related Adverse Event Occurrence, Grade, and Timing in Patients Receiving Immune Checkpoint Inhibitors

et al. 2019

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IMPORTANCE Toxic effects of conventional chemotherapy and molecularly targeted cancer therapies are generally well defined and occur at predictable points. By contrast, owing to their heterogeneous manifestations, unpredictable timing, and clinical overlap with other conditions, immune-related adverse events (irAE) may be more difficult to diagnose and characterize. OBJECTIVE To determine concordance of algorithm-driven medical record review by medical oncologists for the characterization of 8 irAE in patients treated with immune checkpoint inhibitors. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of patients treated with immune checkpoint inhibitors at a National Cancer Institute-designated comprehensive cancer center from November 30, 2015, to March 7, 2018. A sample size of 52 patients provided 80% power to distinguish substantial agreement (κ = 0.85) from poor agreement (κ = 0.5) based on the Cohen κ. MAIN OUTCOMES AND MEASURES Interrater agreement of 2 observers in the occurrence and grade of irAE. RESULTS Of 52 patients (32 [61.5%] male; mean [SD] age, 69 [9] years) analyzed, 42 (80.8%) had non-small cell lung cancer and all received anti-programmed cell death 1 or anti-programmed cell death ligand 1 antibodies, with 3 patients (5.8%) receiving combinations with anti-cytotoxic T-lymphocyte antigen 4 antibodies. A median (interquartile range) of 82 (47-180) documents were reviewed per case. There was limited or poor interrater agreement on irAE occurrence (Cohen κ, 0.37-0.64), with the exception of hypothyroidism (κ = 0.8). Weighted κ similarly showed limited or poor agreement for irAE grade (κ = 0.31-0.75). Differences in assessed time of onset ranged from 5 to 188 days. As a control for data availability and access, observers had a high degree of agreement for the exact start date (98%) and end date (96%) of immunotherapy administration, suggesting that information interpretation rather than identification largely accounted for assessment differences. In multivariable analysis, therapy duration (adjusted odds ratio, 4.80; 95% CI, 1.34-17.17; P = .02) and Charlson Comorbidity Index (adjusted odds ratio, 4.09; 95% CI, 1.10-15.18; P = .03) were significantly associated with discordant irAE assessment. CONCLUSIONS AND RELEVANCE These findings underscore critical challenges in assessing the occurrence, type, timing, and severity of irAE. Apart from hypothyroidism (a condition that has a discrete diagnostic laboratory test and few other likely etiologies during immunotherapy treatment), interobserver agreement was poor. Given the importance of accurate and timely assessment of toxic effects for clinical trials and real-world disease management, efforts to improve irAE diagnosis and characterization are needed.

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Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer

Cited by 160 publications

References 21 publications

High mortality and poor treatment efficacy of immune checkpoint inhibitors in patients with severe grade checkpoint inhibitor pneumonitis in non‐small cell lung cancer

High mortality and poor treatment efficacy of immune checkpoint inhibitors in patients with severe grade checkpoint inhibitor pneumonitis in non‐small cell lung cancer

The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis

Variation in the Assessment of Immune-Related Adverse Event Occurrence, Grade, and Timing in Patients Receiving Immune Checkpoint Inhibitors

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