Late immune-related adverse events in long-term responders to PD-1/PD-L1 checkpoint inhibitors: a multicentre study

Nigro, Olga; Pinotti, Graziella; Galitiis, Federica De; Pietro, Francesca Di; Giusti, Raffaele; Filetti, Marco; Bersanelli, Melissa; Lazzarin, Alessandro; Bordi, Paola; Catino, Annamaria; Pizzutilo, Pamela; Galetta, Domenico; Marchetti, Paolo; Botticelli, Andrea; Scagnoli, Simone; Russano, Marco; Santini, Daniele; Torniai, Mariangela; Berardi, Rossana; Ricciuti, Biagio; Giglio, Andrea De; Chiari, Rita; Russo, Alessandro; Adamo, Vincenzo; Tudini, Marianna; Silva, Rosa Rita; Bolzacchini, Elena; Giordano, Monica; Tursi, Michele De; Rijavec, Erika; Ghidini, Michele; Vallini, I.; Stucci, Luigia Stefania; Tucci, Marco; Pala, Laura; Conforti, Fabio; Queirolo, Paola; Tanda, Enrica T.; Spagnolo, Francesco; Cecchi, Federica; Bracarda, Sergio; Macrini, Serena; Santoni, Matteo; Battelli, Nicola; Fargnoli, Maria Concetta; Porzio, Giampiero; Tuzi, Alessandro; Suter, Matteo B.; Ficorella, Corrado; Cortellini, Alessio

doi:10.1101/2020.04.09.20054031

Cited by 4 publications

(5 citation statements)

References 36 publications

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“…Moreover, the spectrum of irAEs is in line with what has been described in both clinical trials and real life studies with PD-1/PD-L1 inhibitors across different malignancies. 6,[22][23][24] Therefore, we confirm the feasibility and safety of first-line, single-agent pembrolizumab in a large real-world cohort of patients with NSCLC with PD-L1 expression ! 50%, including frail patients with poor performance status, who are usually not enrolled in clinical trials.…”

Section: Discussionsupporting

confidence: 64%

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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: Discussionsupporting

confidence: 64%

“…As previously described, 6,24 single-site irAEs were more frequent than multiple-site irAEs. IrAEs result from an aberrant immune selfresponse, and it is reasonable to assume that, as in autoimmune disorders, 25 the pathologic mechanisms of irAEs are based on tissuespecific T-cell and B-cell mediated cross-reactions.…”

Section: Discussionsupporting

confidence: 54%

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 time from treatment to rst thoracentesis was as long as 25 months (case no.8). It is not surprising that the occurrence of irAEs was delayed, since Nigro et al reported earlier that late-irAEs (after 12 months) are common (incidence 30.3%) in long responders to ICIs 15 . The cytology of pleural effusion was never documented positive before or after ICI use so this type was not categorized as pseudoprogression.…”

Section: Discussionmentioning

confidence: 99%

CD4/CD8 Ratio of Pleural Effusion Is A Prognostic Predictor for Non-Small Cell Lung Cancer Patients Under Immune Checkpoint Inhibitor Treatments

Lee

Yang

Chen

et al. 2021

Preprint

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Pleural effusion is a rare immune-related adverse event for lung cancer patients receiving immune checkpoint inhibitors (ICIs). We enrolled 281 lung cancer patients treated with ICIs and 17 were analyzed. We categorized the formation of pleural effusion into 3 patterns: type 1, rapid and massive; type 2, slow and indolent and type 3, with disease progression. CD4/CD8 ratio of 1.93 was selected as the cutoff threshold to predict survival. Most patients of types 1 and 2 effusions possessed pleural effusion with CD4/CD8 ratios > = 1.93. The median OS time in type 1, 2, and 3 patients were not reached, 24.8, and 2.6 months. The median PFS time in type 1, 2, and 3 patients were 35.5, 30.2, and 1.4 months. The median OS for the group with pleural effusion CD4/CD8 > = 1.93 and < 1.93 were not reached and 2.6 months. The median PFS of those with pleural effusion CD4/CD8 > = 1.93 and < 1.93 were 18.4 and 1.2 months. In conclusion, patients with type 1 and 2 effusion patterns had better survival than those with type 3. Type 1 might be interpreted as pseudoprogression of malignant pleural effusion. CD4/CD8 ratio > = 1.93 in pleural effusion is a good predicting factor for PFS.

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“…Last, focus should also be on minimizing long-term toxicity of systemic therapies and LRT, as aim is to improve long-term survival in these patients. Importantly, approximately 30% of patients with metastatic NSCLC treated with PD-(L)1 inhibition experience late (>12 months after start of ICI) immune related toxicity (46). Furthermore, attention should be paid to the organ receiving LRT, as for example patients with brain metastases treated with ICI and SRT could develop symptomatic radiation necrosis as a late toxicity (47).…”

Section: Local Radical Therapymentioning

confidence: 99%

How to optimize the incorporation of immunotherapy in trials for oligometastatic non-small cell lung cancer: a narrative review

Remón¹,

Menis²,

Lévy³

et al. 2021

Transl Lung Cancer Res

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Patients with oligometastatic disease (OMD) non-small cell lung cancer (NSCLC) are considered as a subgroup of metastatic NSCLC that can obtain long-term survival or even cure. Oligometastatic refers to a state of a limited number of metastases in a limited number of organs. In clinical guidelines it is stated that patients with oligometastatic NSCLC can benefit from the addition of local radical therapy (LRT) to systemic therapy. With the introduction of minimally invasive surgery, advances in interventional radiology and stereotactic radiotherapy (SRT), LRT is becoming feasible for more and more patients. Furthermore, the introduction of immune checkpoint inhibitors (ICI) in the treatment landscape of advanced NSCLC has improved the survival of these patients. Importantly, the use of ICI in combination with LRT is also of interest in the subgroup of NSCLC patients with OMD. For example, it has been suggested that SRT may synergize with ICI as several preclinical studies reported an increased tumor antigen release, improved antigen presentation, and T-cell infiltration in irradiated tumors. In this narrative review, we describe the current evidence of immunotherapy treatment in OMD NSCLC, with a focus on future trial design and problems that need to be addressed.

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Late immune-related adverse events in long-term responders to PD-1/PD-L1 checkpoint inhibitors: a multicentre study

Cited by 4 publications

References 36 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

CD4/CD8 Ratio of Pleural Effusion Is A Prognostic Predictor for Non-Small Cell Lung Cancer Patients Under Immune Checkpoint Inhibitor Treatments

How to optimize the incorporation of immunotherapy in trials for oligometastatic non-small cell lung cancer: a narrative review

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