Treatment-related adverse events of PD-1 and PD-L1 inhibitor-based combination therapies in clinical trials: a systematic review and meta-analysis

Zhou, Xiaoxiang; Yao, Zhuoran; Bai, Hua; Duan, Jianchun; Wang, Zhijie; Wang, Xin; Zhang, Xue; Xu, Jiachen; Fei, Kailun; Zhang, Zhen; Tan, Fengwei; Xue, Qi; Gao, Shugeng; Gao, Yibo; Wang, Jie; He, Jie

doi:10.1016/s1470-2045(21)00333-8

Cited by 146 publications

(110 citation statements)

References 28 publications

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“…In addition, thyroid-related adverse events (hyperthyroidism and hypothyroidism) were the most common endocrine dysfunctions in the two groups. Concerning neoadjuvant ICIs plus chemotherapy, hematology-related adverse events (neutropenia and anemia) had the highest incidence, consistent with ICIs plus chemotherapy in advanced cancers (38), and the phenomenon is mainly due to the cytological toxicity of chemotherapy.…”

Section: Discussionsupporting

confidence: 61%

“…To compare the incidence of trAEs in immunotherapy between the neoadjuvant group and the advanced group, the incidence of trAEs in advanced cancer immunotherapy was obtained in two meta-analyses ( 38 , 39 ), and the incidence of trAEs was recalculated using our method. As shown in Table S4 , the recalculated incidence for all-grade trAEs was 71% (95% CI, 68%-74%) in neoadjuvant ICIs, and 98% (95% CI, 97%-99%) in neoadjuvant ICIs plus chemotherapy.…”

Section: Resultsmentioning

confidence: 99%

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Safety of Neoadjuvant Immunotherapy in Resectable Cancers: A Meta-Analysis

et al. 2022

Front. Immunol.

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BackgroundNeoadjuvant immunotherapy has preliminarily been effective in multiple resectable cancers. However, its safety is still largely unknown.MethodsA systematic literature search was conducted in PubMed, Embase, Web of Science, and Cochrane Library up to February 28th, 2021. Pooled incidence and risk ratio (RR) of adverse events were calculated using the R software.ResultsTwenty-eight studies involving 2863 patients were included. First, the incidence for all-grade treatment-related adverse events (trAEs) was 94% (95% CI, 81%-98%), with 43% (95% CI, 24%-64%) for high-grade trAEs. For different treatment groups, neoadjuvant immune checkpoint inhibitors (ICIs) plus chemotherapy was associated with a higher incidence of all-grade [99% (95% CI, 98%-99%) vs. 76% (95% CI 47%-92%); P < 0.001] and high-grade [80% (58%-92%) vs. 15% (9%-24%); P < 0.001] trAEs compared with neoadjuvant ICIs alone. The most common high-grade trAEs were lipase increased (5%; 95% CI, 2%-10%), colitis (3%; 95% CI, 0-7%) and transaminitis (3%; 95% CI, 0-7%) for neoadjuvant ICIs, and neutropenia (53%; 95% CI, 31%-74%), anemia (8%; 95% CI, 3%-15%) and AST increased (4%; 95% CI, 2%-7%) for neoadjuvant ICIs plus chemotherapy. Furthermore, the incidence rates of progressive disease while on treatment, treatment-related surgical delays and deaths were 6% (95% CI, 4%-10%), 3.2% (12 of 377 patients) and 0.47% (5 of 1075 patients), respectively.ConclusionCompared with neoadjuvant ICIs alone, neoadjuvant ICIs plus chemotherapy had a higher incidence of trAEs. In addition, neoadjuvant immunotherapy had a low rate of progressive diseases, surgical delays and deaths.

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Section: Discussionsupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Safety of Neoadjuvant Immunotherapy in Resectable Cancers: A Meta-Analysis

et al. 2022

Front. Immunol.

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“…Undoubtedly, treatment-related adverse events of the checkpoint inhibitors are abundant, especially if administered in combinations [ 98 , 99 ]. The most commonly reported adverse events were anaemia (45.4%), fatigue (34.3%) and dysphagia (30%), although among grade 3 or higher adverse events, the most common were neutropenia (19.6%), hypertension (9.3%) and lymphopenia (10.3%), but also pyrexia, diarrhoea, skin toxicity, haematological events, thyroid dysfunction, endocrinological aberrations and pneumonitis, to name just a few [ 100 ]. Treatment related death is rather rare, although not impossible, and in most cases, it is caused by the severe toxicity of the combination treatment or the aggressive reaction from the immune system, including cytokine storm.…”

Section: Immunotherapy-related Adverse Eventsmentioning

confidence: 99%

“…Treatment related death is rather rare, although not impossible, and in most cases, it is caused by the severe toxicity of the combination treatment or the aggressive reaction from the immune system, including cytokine storm. Especially among patients receiving both chemotherapy and anti-PD-1 or anti-PD-L1 inhibitors, grade 3 or higher adverse events were very frequent and often severe and prolonged [ 98 , 100 ]. Thus, balancing the efficacy and safety of the regimens should be accurately considered with regard to the individual cases.…”

Section: Immunotherapy-related Adverse Eventsmentioning

confidence: 99%

Challenges of the Immunotherapy: Perspectives and Limitations of the Immune Checkpoint Inhibitor Treatment

Dobosz

Stępień

Golke

et al. 2022

IJMS

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Immunotherapy is a quickly developing type of treatment and the future of therapy in oncology. This paper is a review of recent findings in the field of immunotherapy with an emphasis on immune checkpoint inhibitors. The challenges that immunotherapy might face in near future, such as primary and acquired resistance and the irAEs, are described in this article, as well as the perspectives such as identification of environmental modifiers of immunity and development of anti-cancer vaccines and combined therapies. There are multiple factors that may be responsible for immunoresistance, such as genomic factors, factors related to the immune system cells or to the cancer microenvironment, factors emerging from the host cells, as well as other factors such as advanced age, biological sex, diet, many hormones, existing comorbidities, and the gut microbiome.

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“…The ongoing phase 3 clinical trials on radiotherapy with PD-1 or PD-L1 inhibitors for NSCLC are summarized in Table 1 . Of importance, a meta-analysis showed that the incidence of severe treatment-related adverse events after a concurrent combination of anti-PD-1/PD-L1 therapies with radiotherapy was 12.4%, while those with chemotherapy and targeted therapy were 68.3% and 35.9%, respectively [ 90 ]. Thus, radiotherapy might be safer compared to systemic therapies in combination with ICIs.…”

Section: Combination Of Radiotherapy and Icis For Nsclcmentioning

confidence: 99%

A Promising Treatment Strategy for Lung Cancer: A Combination of Radiotherapy and Immunotherapy

Miyasaka

Sato

Okano

et al. 2021

Cancers

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Lung cancer is a leading cause of cancer-related deaths worldwide despite advances in treatment. In the past few decades, radiotherapy has achieved outstanding technical advances and is being widely used as a definitive, prophylactic, or palliative treatment of patients with lung cancer. The anti-tumor effects of radiotherapy are considered to result in DNA damage in cancer cells. Moreover, recent evidence has demonstrated another advantage of radiotherapy: the induction of anti-tumor immune responses, which play an essential role in cancer control. In contrast, radiotherapy induces an immunosuppressive response. These conflicting reactions after radiotherapy suggest that maximizing immune response to radiotherapy by combining immunotherapy has potential to achieve more effective anti-tumor response than using each alone. Immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated protein 4, programmed cell death-1/programmed death-ligand 1, and their inhibitors, have attracted significant attention for overcoming the immunosuppressive conditions in patients with cancer. Therefore, the combination of immune checkpoint inhibitors and radiotherapy is promising. Emerging preclinical and clinical studies have demonstrated the rationale for these combination strategies. In this review, we outlined evidence suggesting that combination of radiotherapy, including particle therapy using protons and carbon ions, with immunotherapy in lung cancer treatment could be a promising treatment strategy.

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Treatment-related adverse events of PD-1 and PD-L1 inhibitor-based combination therapies in clinical trials: a systematic review and meta-analysis

Cited by 146 publications

References 28 publications

Safety of Neoadjuvant Immunotherapy in Resectable Cancers: A Meta-Analysis

Safety of Neoadjuvant Immunotherapy in Resectable Cancers: A Meta-Analysis

Challenges of the Immunotherapy: Perspectives and Limitations of the Immune Checkpoint Inhibitor Treatment

A Promising Treatment Strategy for Lung Cancer: A Combination of Radiotherapy and Immunotherapy

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