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; Marino, Pietro Di; 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:10.1016/j.ejca.2020.04.025

Cited by 51 publications

(41 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Immune-checkpoint inhibitors have complex immune-related side effects, which range from being mild to potentially life threatening or life-changing. Onset most likely occurs early however late-onset toxicity (beyond 12 months) has previously been reported in 30% of patients completing a minimum treatment duration of 12 months [ 15 ]. The incidence of toxicity varies with regimen, with treatment related grade 3–4 adverse events (AE) occurring in 23% of nivolumab-treated, 28% of ipilimumab–treated and 59% of ipilimumab-nivolumab-treated patients [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma

et al. 2021

View full text Add to dashboard Cite

Background Immunotherapy is revolutionising the treatment of patients diagnosed with melanoma and other cancers. The first immune checkpoint inhibitor, ipilimumab (targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)), showed a survival advantage over standard chemotherapy. Subsequently the anti-programmed cell death protein 1 (PD-1) antibodies, nivolumab and pembrolizumab were shown to be more effective than ipilimumab. Ipilimumab combined with nivolumab gives an incremental gain in overall survival compared with nivolumab alone but increases the risk of severe, potentially life-threatening toxicities. In contrast to ipilimumab monotherapy, anti-PD-1 antibodies are licensed to be continued until disease progression. Follow-up of patients recruited to the first trials evaluating 2 years of pembrolizumab showed that three-quarters of responding patients continue responding after stopping treatment. Suggestive of early response, we hypothesised that continuing anti-PD-1 treatment beyond 1 year in progression-free patients may be unnecessary and so designed the DANTE trial. Methods DANTE is a multicentre, randomised, phase III, non-inferiority trial to evaluate the duration of anti-PD-1 therapy in patients with metastatic (unresectable stage III and stage IV) melanoma. It uses a two-stage recruitment strategy, registering patients before they complete 1 year of first-line anti-PD-1 +/− CTLA-4 therapy and randomising eligible patients who have received 12 months of treatment and are progression-free at 1 year. At randomisation, 1208 patients are assigned (1:1) to either 1) continue anti-PD-1 treatment until disease progression/ unacceptable toxicity/ for at least 2 years in the absence of disease progression/ unacceptable toxicity or 2) to stop treatment. Randomisation stratifies for baseline prognostic factors. The primary outcome is progression-free survival at 3, 6, 9 and 12 months and then, 6-monthly for up to 4-years. Secondary outcomes collected at all timepoints include overall survival, response-rate and duration and safety, with quality of life and cost-effectiveness outcomes collected 3-monthly for up to 18-months. Sub-studies include a qualitative analysis of patient acceptance of randomisation and sample collection to inform future translational studies into response/ toxicity biomarkers. Discussion DANTE is a unique prospective trial investigating the optimal duration of anti-PD-1 therapy in metastatic melanoma patients. Outcomes will inform future use of these high burden drugs. Trial registration ISRCTN15837212, 31 July 2018.

show abstract

Section: Introductionmentioning

confidence: 99%

The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma

et al. 2021

View full text Add to dashboard Cite

show abstract

“…While late irAE occur less frequently than early toxicities, they are relatively common in long-term responders such as the patient described here. 2 Our analysis of systemic immune parameters revealed a broad but modest increase shortly after ICI initiation. A more profound change occurred 9 months after treatment initiation, an event that may explain the delayedonset irAE.…”

Section: Discussionmentioning

confidence: 77%

“…While late irAE occur less frequently than early toxicities, they are relatively common in long-term responders such as the patient described here. 2 …”

Section: Discussionmentioning

confidence: 99%

Humoral and cellular correlates of a novel immune-related adverse event and its treatment

Gonugunta

Itzstein

Mu-Mosley

et al. 2021

J Immunother Cancer

View full text Add to dashboard Cite

Immune-related adverse events (irAE) may affect almost any organ system and occur at any point during treatment with immune checkpoint inhibitors (ICI). We present a patient with advanced lung cancer receiving antiprogrammed death 1 checkpoint inhibitor who developed a delayed-onset visual irAE treated with corticosteroids. Through assessment of longitudinal biospecimens, we analyzed serial autoantibodies, cytokines, and cellular populations. Months after ICI initiation and preceding clinical toxicity, the patient developed broad increases in cytokines (most notably interleukin-6 (IL-6), interferon-γ (IFNγ), C-X-C motif chemokine ligand 2 (CXCL2), and C–C motif chemokine ligand 17 (CCL17)), autoantibodies (including anti-angiotensin receptor, α-actin, and amyloid), CD8 T cells, and plasmablasts. Such changes were not observed in healthy controls and ICI-treated patients without irAE. Administration of corticosteroids resulted in immediate and profound decreases in cytokines, autoantibodies, and inflammatory cells. This case highlights the potential for late-onset changes in humoral and cellular immunity in patients receiving ICI. It also demonstrates the biologic effects of corticosteroids on these parameters. Application of humoral and cellular immune biomarkers across ICI populations may inform toxicity monitoring and management.

show abstract

“… 12 , 13 Late-emerging irAEs have been noticed in long-term responders to PD-1/PD-L1 checkpoint inhibitors. 41 A systematic review also reported that early and late ICI-related encephalitis were possible. 42 In addition, not all irAEs will disappear when antitumor treatment is stopped; some late-irAEs could occur a year after first application.…”

Section: Incidence Of Naesmentioning

confidence: 99%

“…In this condition, any suspicious symptoms occurring during medication should be noticed even after a long time of drug withdraw. 41 , 43 Wide ranges of time in neurological toxicity initiation possibly augment clinicians’ difficulties in detecting and diagnosing ICI-related NAEs.…”

Section: Incidence Of Naesmentioning

confidence: 99%

Neurological Adverse Events Induced by Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer: Current Perspectives and New Development

Cheng

Wang

Zhou

et al. 2021

Clin Med Insights Oncol

View full text Add to dashboard Cite

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of multiple malignancies, especially in non-small cell lung cancer (NSCLC). With the extensive application of ICIs in clinical practice, clinicians have to manage their toxicities, which are often termed immune-related adverse events (irAEs). Several ICIs, such as nivolumab, pembrolizumab, atezolizumab, and durvalumab, have been approved by the US Food and Drug Administration (FDA) to treat advanced NSCLC, accompanied by a broad spectrum of toxicity reactions. However, ICIs-associated neurological toxicities, regarding polyneuropathy, Bell palsy, encephalopathy, and myasthenia gravis, as uncommon emerging toxicities have not been well recognized, present a challenge for clinicians to improve awareness of supervision, recognition, and management before death from them. Herein, we have summarized the incidence, diagnosis, clinical manifestations, potential mechanisms, treatments, and outcomes of ICIs-related neurotoxicity and optimized the management approach for NSCLC patients. Prompt recognition and proper management are indispensable to reduce the morbidity of these patients with immune-related neurological toxicities.

show abstract

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

Abstract: doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Cited by 51 publications

References 39 publications

The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma

The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma

Humoral and cellular correlates of a novel immune-related adverse event and its treatment

Neurological Adverse Events Induced by Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer: Current Perspectives and New Development

Contact Info

Product

Resources

About