The association between tumor burden and severe immune-related adverse events in non-small cell lung cancer patients responding to immune-checkpoint inhibitor treatment

Sakata, Yoshihiko; Kawamura, Kodai; Shingu, Naoki; Yasuda, Yuko; Eguchi, Yoshitomo; Anan, Keisuke; Hisanaga, Junpei; Nitawaki, Tatsuya; Iio, Miwa; Sekido, Yuko; Nakano, Aiko; Sakagami, Takuro

doi:10.1016/j.lungcan.2019.02.011

Cited by 31 publications

(25 citation statements)

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“…49,59 Among patients who respond to ICI therapy, high tumour burden may correlate to the development of more severe irAE. 60 Preexisting ILD or pulmonary fibrosis is a significant risk factor for the development of ICI pneumonitis. 48,61,62 Interestingly, smoking history has not been found to be a significant risk factor for the development of ICI pneumonitis.…”

Section: Risk Factorsmentioning

confidence: 99%

Pulmonary toxicity of systemic lung cancer therapy

Long

Suresh

2020

Respirology

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Lung cancer is the leading cause of cancer-related deaths worldwide. As new therapies are developed, it is important to understand the pulmonary toxicities associated with systemic lung cancer therapies. Cytotoxic chemotherapy regimens for NSCLC often include taxanes. Pulmonary toxicity from taxanes presents as an ILD-type reaction characterized by increasing dyspnoea, dry cough, fever and bilateral pulmonary interstitial infiltrates. The incidence of taxane-induced pneumonitis is rare, and many patients respond to steroid therapy; however, fatal cases have been reported. Patients with NSCLC are routinely tested for the presence of tumour oncogenes to determine their candidacy for targeted therapies, such as TKI. EGFR-TKI can cause pneumonitis characterized by progressive dyspnoea and hypoxia. EGFR-TKIassociated ILD rarely presents as an AIP with rapidly progressive respiratory failure and high mortality rates. The most recent development in lung cancer therapy has been the discovery of immune checkpoint inhibitor (ICI). ICI pneumonitis has been increasingly recognized as a common complication of ICI therapy, with reported incidence as high as 19% in some clinical settings. Early-grade ICI pneumonitis may be asymptomatic; however, high-grade ICI pneumonitis can result in progressive dyspnoea, hypoxia and respiratory failure. ICI pneumonitis is unique in that only half of the patients will improve with steroid treatment, and mortality rates are high. As treatment of NSCLC evolves, providers must be able to recognize and respond to the development of drug-induced pulmonary toxicities.

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Section: Risk Factorsmentioning

confidence: 99%

Pulmonary toxicity of systemic lung cancer therapy

Long

Suresh

2020

Respirology

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“…7 Studies so far investigating determinants of anti-PD(L)1 toxicity were of limited sample size with a median of 78 patients at risk (IQR 50-128). [8][9][10][11][12][13][14][15][16][17][18][19][20][21] Here we analysed whether demographic and disease-specific patient characteristics present at start of treatment were associated with an increased risk of severe irAEs using a large dataset from our nationwide melanoma treatment registry.…”

Section: Introductionmentioning

confidence: 99%

Lower risk of severe checkpoint inhibitor toxicity in more advanced disease

et al. 2020

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BackgroundImmune checkpoint inhibitor (ICI) can cause severe and sometimes fatal immune-related adverse events (irAEs). Since these irAEs mimick immunological disease, a female predominance has been speculated on. Nevertheless, no demographic or tumour-related factors associated with an increased risk of irAEs have been identified until now.MethodsRisk ratios of severe (grade ≥3) irAEs for age, sex, WHO performance status, number of comorbidities, stage of disease, number of metastases and serum lactate dehydrogenases (LDH) were estimated using data from anti-PD1-treated patients with advanced melanoma in the prospective nationwide Dutch Melanoma Treatment Registry.Results111 (11%) out of 819 anti-programmed cell death 1 treated patients experienced severe irAEs. Patients with non-lung visceral metastases (stage IV M1c or higher) less often experienced severe irAEs (11%) compared with patients with only lung and/or lymph node/soft tissue involvement (stage IV M1b or lower; 19%; adjusted risk ratio (RRadj) 0.63; 95% CI 0.41 to 0.94). Patients with LDH of more than two times upper limit of normal had a non-significantly lower risk of developing severe irAEs than those with normal LDH (RRadj 0.65; 95% CI 0.20 to 2.13). None of the other variables were associated with severe irAEs.ConclusionIn patients with melanoma, more advanced disease is associated with a lower rate of severe irAEs. No association with sex was found.

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“…Alternatively, the different tumor burden existed in nonsquamous NSCLC and UC. The prior study suggested that a high tumor burden was related to serious irAEs in patients with NSCLC (Sakata et al, 2019), which forcefully implied that tumor burden was likely to be an underlying predictor for fatal adverse events associated with PD-L1 inhibitors. There is abundant room for further progress in determining the correlation between them.…”

Section: Discussionmentioning

confidence: 99%

Fatal Adverse Events Associated With Programmed Cell Death Ligand 1 Inhibitors: A Systematic Review and Meta-Analysis

Wang

Chen

et al. 2020

Front. Pharmacol.

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Purpose: We performed this systematic review and meta-analysis to assess the incidence of fatal adverse events that were associated with the use of programmed cell death ligand 1 (PD-L1) inhibitors, to describe them and to statistically depict factors that were associated with these events.Method: PubMed, Embase, and Cochrane Library were completely searched based on the following terms or relevant Medical Subject Heading ones: "atezolizumab", "durvalumab", "avelumab", and "cemiplimab".Results: A total of 26 eligible studies were identified, incorporating 6,896 unique participants. The overall incidence was 1.24% (95% CI: 0.93-1.65%). The incidence and odds were higher in patients with non-squamous non-small cell lung cancer (NSCLC) than those with urothelial carcinoma [(2.25 vs. 0.85, p = 0.04), (odds ratio [OR]: 2.69; 95% CI: 1.04-6.97, p = 0.04)], higher in the middle-aged group than the young group [(1.74 vs. 0.89, p = 0.01), (OR: 2.13; 95% CI: 1.26-3.61, p = 0.01)], and higher in the trial phase I than the trial phase II [(1.76 vs. 0.60, p = 0.01), (OR: 0.31; 95% CI: 0.13-0.75, p = 0.01)]. Notably, the trial phase I had a higher incidence than trial phase II or III following regulating for cancer types and average age (OR: 0.28; 95% CI: 0.11-0.71, p = 0.01, OR: 0.48; 95% CI: 0.24-0.95, p = 0.04, respectively). In terms of organ-specific fatal adverse events, interstitial lung disease (ILD) was frequently documented. A variety of respiratory systemrelated fatal adverse events were recorded, including but not limited to pneumonia and respiratory failure. As for organ-unspecific fatal adverse events, substantial cases of sepsis and neutropenia were recorded. Conclusion:This study firstly provided a comprehensive incidence and the spectrum of fatal adverse events associated with PD-L1 inhibitors, and identified three potential susceptible factors of that, yielding a capability for clinicians to distinguish high-risk Frontiers in Pharmacology | www.frontiersin.org

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The association between tumor burden and severe immune-related adverse events in non-small cell lung cancer patients responding to immune-checkpoint inhibitor treatment

Cited by 31 publications

References 10 publications

Pulmonary toxicity of systemic lung cancer therapy

Pulmonary toxicity of systemic lung cancer therapy

Lower risk of severe checkpoint inhibitor toxicity in more advanced disease

Fatal Adverse Events Associated With Programmed Cell Death Ligand 1 Inhibitors: A Systematic Review and Meta-Analysis

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