Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies

Naidoo, Jarushka; Page, David B.; Li, Bob T.; Connell, Louise C.; Schindler, Katja; Lacouture, Mario E.; Postow, Michael A.; Wolchok, Jedd D.

doi:10.1093/annonc/mdv383

Cited by 1,231 publications

(1,079 citation statements)

References 112 publications

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“…The observed increased incidence of pneumonitis in NSCLC patients from previous studies might be attributed to the poor lung function induced by prior thoracic radiotherapy or NSCLC itself rather than the anti‐PD‐1 therapy. Pneumonitis incidence might increase if anti‐PD‐1 mAb was combined with other agents, such as anti‐CTLA‐4 mAb,9 also known to carry a risk of pneumonitis 2. In this study, we confirmed these observations and further clarified that anti‐PD‐1 treatment combined with chemotherapy, targeted therapy or CTLA‐4 blockade was also associated with pneumonitis risk, indicating the additive effects of multiple agents on lung‐toxic effects.…”

Section: Discussionsupporting

confidence: 78%

“…Checkpoint blockade disrupts normal immune homeostasis and results in immune‐related adverse events (irAEs), including dermatologic, hepatic, endocrine, gastrointestinal, and pulmonary complications as well as other less common side effects 2, 3. Among these irAEs, pneumonitis, which is defined as focal or diffuse inflammation of the lung parenchyma,4 is rare but potentially life threatening.…”

Section: Introductionmentioning

confidence: 99%

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Risk factors for pneumonitis in patients treated with anti‐programmed death‐1 therapy: A case‐control study

Cui

Liu

Wang³

et al. 2018

Cancer Medicine

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Immune checkpoint blockade‐related pneumonitis is a rare but potentially life‐threatening adverse effect, but its risk factors are not completely understood. This case‐control study was conducted to identify pneumonitis risk factors in patients treated with anti‐PD1 monoclonal antibodies (mAbs), including all the patients who developed pneumonitis after anti‐PD‐1 mAbs treatment in the Cancer Center of the Chinese People's Liberation Army from September 2015 to September 2017. Two controls per case were matched according to a propensity‐score matching algorithm to account for confounding effects caused by individual baseline variables. Demographic and clinical information was obtained from medical records. In total, 55 cases and 110 controls were included in the study. No association was observed between smoking status or primary lung cancer and risk of pneumonitis. Significant risk factors for pneumonitis related to anti‐PD‐1 mAbs were prior thoracic radiotherapy, prior lung disease and combination therapy with odds ratios of 3.34 (1.51‐7.39), 2.86 (1.45‐5.64) and 2.73 (1.40‐5.31), respectively. The associations remained significant in the multivariable logistic regression model. The risk of pneumonitis induced by anti‐PD‐1 mAbs is associated with prior thoracic radiotherapy, prior lung disease, and combination therapy. Clinicians should monitor these features in patients receiving anti‐PD‐1 therapy to optimize clinical safety and efficacy.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Risk factors for pneumonitis in patients treated with anti‐programmed death‐1 therapy: A case‐control study

Cui

Liu

Wang³

et al. 2018

Cancer Medicine

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“…The rates of the remaining symptoms were similar to those reported previously (fever, 15% in our study vs. 12%; chest pain, 8 vs. 7%) [1]. …”

Section: Discussion/conclusionsupporting

confidence: 91%

Risk of Pneumonitis with the Use of Different Immune Checkpoint Inhibitors in a Mexican Population

et al. 2019

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Purpose: The incidence of pneumonitis reported in previous trials in patients with advanced cancer and use of programmed cell death protein 1 (PD-1) immunotherapy inhibitors was 2.7–3.6%. However, none of these trials included Mexican populations. Methods: This was a retrospective analysis involving 87 patients with advanced cancer who received PD-1 inhibitors as part of their therapy. The primary outcome was the incidence of pneumonitis after using PD-1 inhibitors. The secondary outcomes were major risk factors and radiological patterns of pneumonitis. Results: We found 13 cases of pneumonitis, giving an overall incidence of 15%; three of the cases were high-grade (grade 3). A ground-glass pattern was the major form found by chest computed tomography scans. We did not find any significant risk factor for pneumonitis. Conclusion: The incidence of pneumonitis secondary to treatment with PD-1 inhibitors in our Mexican population was 15%, which is 5 times higher than that found in other studies. No risk factor was identified for this increased incidence of drug-induced pneumonitis following the use of PD-1 inhibitors.

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“…Patient and disease characteristics also affect the spectrum and frequency of AEs. The safety profile of ICIs varies by tumor type and disease histology, with pneumonitis occurring more often in patients with lung cancer and vitiligo and colitis more commonly noted in patients with melanoma 2, 20. The phase 1 multicohort monotherapy data for this class of antibodies support the growing body of evidence attributing a manageable safety outcome for patients treated with anti–PD‐L1/PD‐1 antibodies.…”

Section: Discussionmentioning

confidence: 94%

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

Kelly

Infante

Taylor

et al. 2018

Cancer

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BACKGROUNDAntibodies targeting the programmed death‐ligand 1 (PD‐L1)/programmed cell death protein 1 (PD‐1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy.METHODSPatients with advanced solid tumors who were enrolled in the phase 1 JAVELIN Solid Tumor (1650 patients) and phase 2 JAVELIN Merkel 200 (88 patients) trials received avelumab, a human anti–PD‐L1 IgG1 antibody at a dose of 10 mg/kg every 2 weeks. Treatment‐related AEs (TRAEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). In post hoc analyses, immune‐related AEs (irAEs) were identified via an expanded AE list and medical review, and infusion‐related reactions (IRRs) occurring ≤2 days after infusion and symptoms occurring ≤1 day after infusion and resolving ≤2 days after onset were identified based on prespecified Medical Dictionary for Regulatory Activities (MedDRA) terms.RESULTSOf the 1738 patients analyzed, grade ≥3 TRAEs occurred in 177 (10.2%); the most common were fatigue (17 patients; 1.0%) and IRR (10 patients; 0.6%). TRAEs led to discontinuation in 107 patients (6.2%) and death in 4 patients (0.2%). Grade ≥3 irAEs occurred in 39 patients (2.2%) and led to discontinuation in 34 patients (2.0%). IRRs or related symptoms occurred in 439 patients (25.3%; grade 3 in 0.5% [9 patients] and grade 4 in 0.2% [3 patients]). An IRR occurred at the time of first infusion in 79.5% of 439 patients who had an IRR, within the first 4 doses in 98.6% of 439 patients who had an IRR, and led to discontinuation in 35 patients (2.0%).CONCLUSIONSAvelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and discontinuation was uncommon. IRRs occurred mainly at the time of first infusion, and repeated events were infrequent. Cancer 2018;124:2010‐7. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies

Cited by 1,231 publications

References 112 publications

Risk factors for pneumonitis in patients treated with anti‐programmed death‐1 therapy: A case‐control study

Risk factors for pneumonitis in patients treated with anti‐programmed death‐1 therapy: A case‐control study

Risk of Pneumonitis with the Use of Different Immune Checkpoint Inhibitors in a Mexican Population

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

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