Immune-related Adverse Events and Survival in Solid Tumors Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

Petrelli, Fausto; Grizzi, Giulia; Ghidini, Michele; Ghidini, Antonio; Ratti, Margherita; Panni, Stefano; Cabiddu, Mary; Ghilardi, Mara; Borgonovo, Karen; Parati, Maria Chiara; Tomasello, Gianluca; Barni, Sandro; Berruti, Alfredo; Brighenti, Matteo

doi:10.1097/cji.0000000000000300

Cited by 86 publications

(75 citation statements)

References 60 publications

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“…26 As stated, several studies have described a significant association between irAEs and improved clinical outcomes with checkpoint inhibitors, even in patients with NSCLC. 1,2 However, to date, only 1 real world study, with a relatively small sample size, investigated this association in the setting of patients with NSCLC with PD-L1 expression ! 50% receiving first-line pembrolizumab, finding a significant association with improved PFS.…”

Section: Discussionmentioning

confidence: 99%

“…The role of immune-related adverse events (irAEs) as a surrogate predictor of the efficacy of immune-checkpoint inhibitors has previously been described in a variety of malignancies. 1,2 Studies reported an association between the incidence of irAEs and improved outcomes, including among patients with nonesmall-cell lung-cancer (NSCLC) receiving programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors in different treatment lines. [3][4][5][6] Patients with metastatic NSCLC with a PD-L1 expression !…”

Section: Introductionmentioning

confidence: 99%

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Immune-related Adverse Events of Pembrolizumab in a Large Real-world Cohort of Patients With NSCLC With a PD-L1 Expression ≥ 50% and Their Relationship With Clinical Outcomes

Cortellini

Friedlaender

Banna

et al. 2020

Clinical Lung Cancer

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The role of immune-related adverse event (irAE) occurrence, as a surrogate predictor of the clinical efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic nonesmall-cell lung-cancer with a programmed death-ligand 1 expression of ‡ 50%. A total of 1010 patients were evaluated, and after a 6-week landmark selection, 877 patients were included. We confirmed the irAE profile of first-line, single-agent pembrolizumab, in a large, real-life cohort of patients with nonesmall-cell lung-cancer with programmed death-ligand 1 expression of ‡ 50%. The occurrence of irAEs might be considered a surrogate of clinical activity and improved outcomes also in this setting. Background: The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic nonesmall-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ! 50%. Patients and Methods: We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ! 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes. Results: A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P < .0001), grade 3/4 irAEs (P ¼ .0025), leading to discontinuation irAEs (P ¼ .0144), multiple-site and single-site irAEs (P < .0001), cutaneous irAEs (P ¼ .0001), endocrine irAEs (P ¼ .0227), pulmonary irAEs (P ¼ .0479), and rheumatologic irAEs (P ¼ .0018) were significantly related to a higher objective response rate. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P ¼ .0005), cutaneous irAEs (P ¼ .0042), endocrine irAEs (P < .0001), gastrointestinal irAEs (P ¼ .0391), and rheumatologic irAEs (P ¼ .0086) were significantly related to progression-free survival. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P ¼ .0003), cutaneous irAEs (P ¼ .0002), endocrine irAEs (P ¼ .0001), and rheumatologic irAEs (P ¼ .0214) were significantly related to overall survival. Conclusions: This study confirms the feasibility and the safety of first-line, singleagent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ! 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immune-related Adverse Events of Pembrolizumab in a Large Real-world Cohort of Patients With NSCLC With a PD-L1 Expression ≥ 50% and Their Relationship With Clinical Outcomes

Cortellini

Friedlaender

Banna

et al. 2020

Clinical Lung Cancer

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“…This process is defined as epitope spreading, which plays a crucial role in the initial stage of irAE development ( 62 ). Multiple studies demonstrated that the incidence of irAEs is significantly associated with the efficacy of ICIs ( 63 ), which can be partly explained by epitope spreading. Epitope spreading can also explain why different tumors treated with ICIs are associated with specific irAEs.…”

Section: Strategies To Prevent and Manage Iraes In Aid Patientsmentioning

confidence: 99%

The Efficacy and Safety of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease

2021

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Immune checkpoint inhibitor (ICI) is a revolutionary breakthrough in the field of cancer treatment. Because of dysregulated activation of the immune system, patients with autoimmune disease (AID) are usually excluded from ICI clinical trials. Due to a large number of cancer patients with preexisting AID, the safety and efficacy of ICIs in these patients deserve more attention. This review summarizes and analyzes the data regarding ICI therapy in cancer patients with preexisting AID from 17 published studies. Available data suggests that the efficacy of ICIs in AID patients is comparable to that in the general population, and the incidence of immune-related adverse events (irAEs) is higher but still manageable. It is recommended to administer ICIs with close monitoring of irAEs in patients with a possibly high benefit-risk ratio after a multidisciplinary discussion based on the patient’s AID category and severity, the patient’s tumor type and prognosis, alternative treatment options, and the patient’s intention. Besides, the prevention and management of irAEs in AID patients have been discussed.

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“…This finding is compatible with suggestions of sustained responses of anti-PD-1 or anti-PD-L1 despite their suspension due to immune-related adverse effects. A meta-analysis shows an association between patient prognosis and the occurrence of immune-related adverse effects ( 19 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Successful Treatment of Steroid-Refractory Immune Checkpoint Inhibitor-Related Pure Red Cell Aplasia With Cyclosporin

et al. 2020

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Anemia associated with Immune checkpoint inhibitor (ICI) is usually hemolytic and regenerative. Cases of non-regenerative pure red cell aplasia are rare, and typically improve upon drug discontinuation and after corticotherapy. We herein report a case of nivolumab-related erythroblastopenia refractory to steroids in a melanoma patient that improved only after treatment with cyclosporin. Nivolumab had been well tolerated for 2 months after being introduced as an adjuvant treatment. Hemoglobin level then progressively decreased from 12.7 g/dl as baseline value to a nadir of 4.3 g/dL despite transfusion with a total of 29 packed red blood cells in 3 months. Extensive workup including repeated bone marrow examinations led to the diagnosis of pure red cell aplasia. Anemia persisted despite nivolumab discontinuation and over a month of corticotherapy, but improved dramatically 3 days after cyclosporin initiation and did not recur upon cyclosporin tapering. The patient remains cancer-free 9 months after nivolumab withdrawal. This case highlights the under-recognized risk of erythroblastopenia in patients treated with ICI and proves cyclosporin is a valid alternative for the treatment of steroid-refractory cases.

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Immune-related Adverse Events and Survival in Solid Tumors Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

Cited by 86 publications

References 60 publications

Immune-related Adverse Events of Pembrolizumab in a Large Real-world Cohort of Patients With NSCLC With a PD-L1 Expression ≥ 50% and Their Relationship With Clinical Outcomes

Immune-related Adverse Events of Pembrolizumab in a Large Real-world Cohort of Patients With NSCLC With a PD-L1 Expression ≥ 50% and Their Relationship With Clinical Outcomes

The Efficacy and Safety of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease

Case Report: Successful Treatment of Steroid-Refractory Immune Checkpoint Inhibitor-Related Pure Red Cell Aplasia With Cyclosporin

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