Nivolumab for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia: A multicenter, open-label single-arm phase II trial

Fujimoto, Daichi; Yomota, Makiko; Sekine, Akimasa; Morita, Mitsunori; Morimoto, Takeshi; Hosomi, Yukio; Ogura, Takashi; Tomioka, Haruaki; Tomii, Keisuke

doi:10.1016/j.lungcan.2019.06.001

Cited by 71 publications

(71 citation statements)

References 30 publications

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“…Historically, patients with ECOG PS > 1 treated with chemotherapy had poor outcomes, with median OS of 1.8e3.6 months [28e30], one-year survival rates of <20% [31], tumour response rates of 16e22% [32], and a high incidence of grade 3e5 TRAEs (44%) [33]. The results presented herein and the findings from previous studies of nivolumab and other antiePD-1 agents [7,24,34,35] suggest that patients with ECOG PS 2 may derive benefit from immunotherapy, with median survival of 4.0e6.8 months [7,24], one-year survival rates of 27% (current study), objective response rates of 11e30% [34e36], and lower incidences of grade 3e4 TRAEs (7% in the current study and 8e12% in previous studies) [24,35]. However, there are concerns over immunotherapy due to the lack of clinical data supporting a favourable benefiterisk profile in this heterogenous population with multiple factors that may contribute to poor performance [37]; randomised studies are warranted to assess clinical benefit in these patients.…”

Section: Discussionmentioning

confidence: 64%

CheckMate 171: A phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS 2 and elderly populations

Felip

Ardizzoni

Ciuleanu

et al. 2020

European Journal of Cancer

130

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Background: CheckMate 171 (NCT02409368) is an open-label, multicentre, phase 2 trial of nivolumab in previously treated advanced squamous non-small cell lung cancer (NSCLC), conducted as part of a post-approval commitment to the European Medicines Agency (EMA). We report outcomes from this trial. Methods: Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0e2 and disease progression during/after !1 systemic treatment (!1 being platinum-based chemotherapy) for advanced or metastatic disease were treated with nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary end-point was incidence of grade 3e4 treatment-related select adverse events (AEs). Other end-points included overall survival (OS) and safety. Results: Of 811 patients treated, 103 had ECOG PS 2; 278 were aged !70 years and 125 were !75 years of age. Minimum follow-up was~18 months. Safety was similar across populations; the most frequent grade 3e4 treatment-related select AEs in all treated patients were diarrhoea (1%), increased alanine aminotransferase (ALT, 1%), pneumonitis (0.7%), colitis (0.6%) and increased aspartate aminotransferase (AST, 0.5%). Median OS was similar in all treated patients and those aged !70 and !75: 10.0 months, 10.0 months and 11.2 months, respectively. Median OS was 5.2 months in patients with ECOG PS 2. Conclusion: These results suggest that nivolumab is well tolerated and active in patients with advanced, relapsed squamous NSCLC, including the elderly, with OS outcomes consistent with phase 3 data. In patients with ECOG PS 2, nivolumab had similar tolerability, but outcomes were worse, as expected in this difficult-to-treat, poor prognosis population. Clinical trial registration: NCT02409368.

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Section: Discussionmentioning

confidence: 64%

CheckMate 171: A phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS 2 and elderly populations

Felip

Ardizzoni

Ciuleanu

et al. 2020

European Journal of Cancer

130

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“…Previously reported nivolumab trials excluded patients with a honeycomb lung, 4,5 but in this study, 41.1% of the patients (7 of 17) had honeycomb lungs. In terms of pneumonitis or acute exacerbation of preexisting IP induced by cytotoxic chemotherapy, a honeycomb lung is one of the most common risk factors.…”

Section: Discussionmentioning

confidence: 65%

A Phase 2 Study of Atezolizumab for Pretreated NSCLC With Idiopathic Interstitial Pneumonitis

Ikeda

Kato

Kenmotsu

et al. 2020

Journal of Thoracic Oncology

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Introduction: Interstitial pneumonia (IP) is one of the most common and poor prognostic comorbidities in patients with NSCLC and a known risk factor for pneumonitis. Atezolizumab monotherapy is an established treatment for recurrent NSCLC and reported to have a lower risk of pneumonitis than programmed cell death protein 1 inhibitors. This study aimed to assess the safety and efficacy of atezolizumab monotherapy in patients with pretreated advanced or recurrent NSCLC with idiopathic IP. Methods: Patients with advanced or recurrent NSCLC with comorbid idiopathic, chronic fibrotic IP with % forced vital capacity of greater than 70% and no history of immune checkpoint inhibitors were enrolled. The patients received atezolizumab (1200 mg) every 3 weeks until the discontinuation criteria were met. The primary end point of this study was the 1-year survival rate. A sample size of 38 patients was set. Results: This study was terminated early owing to high incidence of pneumonitis. A total of 17 patients were enrolled, with a median age of 70 years. The median % forced vital capacity and % diffusing capacity for carbon monoxide at baseline were 85.4% and 54.4%, respectively. The incidence of pneumonitis was 29.4% (5 of 17) for all grades, 23.5% (4 of 17) for grade greater than or equal to 3, and 5.9% (1 of 17) for grade 5. A total of 57.1% patients (4 of 7) with honeycomb lung developed pneumonitis with a grade greater than or equal to 3, whereas only one patient (10%) without honeycomb lung (n ¼ 10) with grade 1 pneumonitis was found. Conclusions: Patients with NSCLC with comorbid IP as defined by the selection criteria for this study might have an increased risk of immune checkpoint inhibitor-induced pneumonitis.

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“…Moreover, some studies have reported that preexisting ILD in patients with lung cancer, whether induced by cytotoxic anticancer agents or ICI, is a risk factor for developing ILD [16][17][18][19][20] . In contrast, under pre-existing mild ILD, there was no increase in ICI-ILD frequency after treatment with nivolumab, an anti-PD-1 antibody 21 . Therefore, in the real-world setting, ICI treatment is limited to patients with no pre-existing or mild ILD to avoid the development of ICI-ILD.…”

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confidence: 77%

Risk factors of immune checkpoint inhibitor-related interstitial lung disease in patients with lung cancer: a single-institution retrospective study

Okada

Matsuoka

Sakurada

et al. 2020

Sci Rep

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Immune checkpoint inhibitors (ICIs) elicit antitumour effects by activating the host immunity and cause immune-related adverse events (irAes). ici-related interstitial lung disease (ici-iLD) is a fatal irAE that is difficult to treat; moreover, its incidence is relatively higher in patients with lung cancer. therefore, early ici-iLD detection and intervention are important for patient safety. However, a risk assessment method for ici-iLD has not been established and the prediction of ici-iLD occurrence is difficult. The aim of our study was to identify the risk factors associated with ICI-ILD. To this end, we retrospectively analysed 102 patients with lung cancer who first received ICI and completed the treatment between April 2016 and December 2019 at Tokushima University Hospital. Nineteen patients had all grades of ICI-ILD and 10 had grade ≥ 3 ICI-ILD. The 30-day mortality rate of patients with grade ≥ 3 ICI-ILD was the highest among all patients (P < 0.01). The multivariate logistic analysis indicated that the performance status ≥ 2 alone and both performance status ≥ 2 and ≥ 50 pack-year were independent risk factors of ICI-ILD of grade ≥ 3 and all grades, respectively. Overall, our study provides insights to predict ici-iLD occurrence. Immune checkpoint inhibitors (ICIs) are antibodies that inhibit programmed death-1 (PD-1), PD ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), which are called immune checkpoint molecules. These molecules negatively regulate the host immunity; thus, the inhibition of these molecules activates the host immunity and exerts cross-organ antitumour effects 1. In the treatment of lung cancer, some clinical trials have revealed that the administration of ICI alone and in combination with cytotoxic anticancer agents resulted in better clinical outcomes than previous standard treatments; thus, the use of ICI significantly improved lung cancer treatment 2-4. However, the activation of the host immunity by ICI leads to characteristic adverse events, known as immune-related adverse events (irAEs), which exhibit profiles different from those caused by cytotoxic anticancer agents 5,6. Therefore, the management of irAEs is essential for an effective ICI treatment. These irAEs affect various organs, such as the skin, endocrine glands, gastrointestinal tract, and liver, but only a few events are fatal because the majority of them can be controlled by adequate treatment 5,7. Specifically, ICI-related interstitial lung disease (ICI-ILD) has a low incidence (1-5%) and a high severity or mortality rate, according to clinical trials (50-60%) 8,9. Patients with lung cancer are known to have relatively higher ICI-ILD rates than those with other cancers 10. A prospective study of patients with lung cancer reported that the incidence of ICI-ILD was 14.5%, which is higher than that in clinical trials 11. ICI-ILD has also been reported to affect the prognosis of patients with lung cancer 11,12 .

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Nivolumab for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia: A multicenter, open-label single-arm phase II trial

Cited by 71 publications

References 30 publications

CheckMate 171: A phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS 2 and elderly populations

CheckMate 171: A phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS 2 and elderly populations

A Phase 2 Study of Atezolizumab for Pretreated NSCLC With Idiopathic Interstitial Pneumonitis

Risk factors of immune checkpoint inhibitor-related interstitial lung disease in patients with lung cancer: a single-institution retrospective study

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