Late-occurring toxicity induced by an immune checkpoint blockade in adjuvant treatment of a stage III melanoma patient

Mandalà, Mario; Merelli, Barbara; Indriolo, A.; Tondini, Carlo

doi:10.1016/j.ejca.2018.02.019

Cited by 24 publications

(23 citation statements)

References 7 publications

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“…2a). We identified 21 cases of DIRE using a definition of autoimmune sequelae newly diagnosed ≥90 days following discontinuation of immunotherapy [2–19]. Only one case could be confirmed from an I-O trial, reflecting the lack of granularity inherent to conventional SAE reporting (eg.…”

Section: Resultsmentioning

confidence: 99%

Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance

Couey¹,

Bell²,

Patel³

et al. 2019

j. immunotherapy cancer

150

124

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Background The risk of delayed autoimmunity occurring months or years after discontinuation of immunotherapy is frequently asserted in the literature. However, specific cases were rarely described until 2018, when a wave of reports surfaced. With expanding I-O indications in the adjuvant/neoadjuvant curative setting, growing numbers of patients will receive limited courses of immunotherapy before entering routine surveillance. In this context, under-recognition of DIRE could pose a growing clinical hazard. Methods The aim of this study was to characterize DIRE through identification of existing reports of delayed post-treatment irAE in cancer patients treated with immunotherapy. We performed a PubMed literature review from 2008 through 2018 to determine the median data safety reporting window from existing I-O clinical trials, which we then applied to define the DIRE cutoff, and collated all qualifying reports over the same time span. DIRE was defined as new immune-related adverse events (irAE) manifesting ≥90 days after discontinuation of immunotherapy. Results Median duration of I-O clinical trials data safety reporting was 90 days (82% ≤ 90 days). DIRE cutoff was thus set as ≥90 days post-immunotherapy. We identified 23 qualifying cases; 21 by literature review and 2 from our institution. Median off-treatment interval to DIRE was 6 months (range: 3 to 28). Median cumulative immunotherapy exposure was 4 doses (range: 3 to 42). Involvement included endocrine, neurologic, GI, pulmonary, cardiac, rheumatologic and dermatologic irAE. Conclusions As immunotherapy indications expand into the curative setting, often with brief exposure and potentially sequenced with multimodality treatments, it will be necessary to recognize an emerging diagnostic complex, which we have termed delayed immune-related events (DIRE). Clinical vigilance has the potential to reduce morbidity from diagnostic delay, as irAE are generally manageable with prompt initiation of treatment – or from misdiagnosis - as misattribution can lead to unnecessary or harmful interventions as we describe. DIRE should therefore figure prominently in the differential diagnosis of patients presenting with illnesses of unclear etiology, irrespective of intervening treatments or interval post-immunotherapy, both of which can confound diagnosis. Increased recognition will rest on delineation of DIRE as a clinical diagnostic entity. Electronic supplementary material The online version of this article (10.1186/s40425-019-0645-6) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance

Couey¹,

Bell²,

Patel³

et al. 2019

j. immunotherapy cancer

150

124

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“…20 The safety profile of BRAFi and MEKi agents has been well characterized both in clinical trials and from routine clinical practice. 37,38 The intracranial and extracranial ORR as well as the DCR were significantly higher with combination TT than with MI, whereas the intracranial ORR was similar between CTT and CMI. 37 The majority of adverse events are transient and easily manageable with temporary treatment Cancer November 1, 2019 withdrawal, without requiring dose adjustments.…”

Section: Discussionmentioning

confidence: 98%

“…Unlike "immunotoxicities," which can occur late as well as after treatment discontinuation, BRAFi-related and MEKi-related adverse events usually resolve with therapy withdrawal and late toxicities are uncommon after drug discontinuation. 37,38 The intracranial and extracranial ORR as well as the DCR were significantly higher with combination TT than with MI, whereas the intracranial ORR was similar between CTT and CMI. Furthermore, CTT demonstrated a statistically significantly higher extracranial response rate than CMI and therefore, in symptomatic patients with BRAFV600-mutant MBMs, CTT could be considered the treatment of choice, particularly in those who deserve a quick response.…”

Section: Discussionmentioning

confidence: 98%

The impact of targeted therapies and immunotherapy in melanoma brain metastases: A systematic review and meta‐analysis

Rulli

Legramandi

Salvati

et al. 2019

Cancer

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BACKGROUND: Targeted therapies (TT), combination immunotherapy (CMI), and monoimmunotherapy (MI) in combination with radiotherapy (CRI) or not are commonly used in patients with melanoma brain metastases, but studies that directly compare these strategies are lacking. The current meta-analysis aimed to better elucidate their activity and efficacy. METHODS: A systematic search of MEDLINE, Embase, and conference proceedings up to January 2019 was performed to identify trials investigating combination TT, monotargeted TT (mono TT), MI, CMI, and CRI in melanoma brain metastases. The outcomes considered were progression-free survival (PFS), overall survival (OS), and the objective response rate (ORR) as evaluated at both intracranial and extracranial sites. Random effects models were used to compare the different therapeutic strategies. RESULTS: A total of 15 trials were included that provided 1132 patients for analyses. CMI demonstrated a statistically significant better OS compared with MI (P = .03, P = .05, and P = .03, respectively, at 6 months, 18 months, and 24 months) and combination TT (P = .04 and P = .03, respectively, at 18 months and 24 months). CMI demonstrated a statistically significant better PFS compared with combination TT (P < .001 at 12 months and 18 months), MI (P = .02, P < .02, and P = .05, respectively, at 6 months, 12 months, and 18 months), and mono TT (P < .001 at 6 months, 12 months, and 18 months). The intracranial objective response rate was higher with CMI compared with mono TT (P < .001) and MI (P < .001), whereas there was no difference between CMI and combination TT. CONCLUSIONS: The results of the current metaanalysis suggested that CMI increases long-term PFS and OS compared with MI and combination TT. Combination TT and CMI are associated with a similar intracranial response rate. The role of systemic therapy in combination with radiotherapy remains to be better elucidated. Cancer 2019;125:3776-3789.

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“…For adjuvant setting besides longterm endocrine dysfunction that is possible, also the lateoccurring pneumonia was reported. Toxicities may develop as long as a year after last dose of treatment, probably as a result of CD8+ effector memory T-cells activity [99,100]. In young patients treated with nivolumab in adjuvant setting safety and irAE need to be considered in the oncofertility context.…”

Section: General Safety Of Nivolumab Treatment In Melanoma Patientsmentioning

confidence: 99%

An update on the safety of nivolumab for the treatment of advanced melanoma

Czarnecka

Rutkowski

2020

Expert Opinion on Drug Safety

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Introduction: Due to its unique mechanism of action as an immune checkpoint inhibitor, nivolumab has high antitumor activity, but at the same time this mechanism is responsible for immune-related adverse events that may limit patients' safety and therapy continuation. Areas covered: Long-term safety of nivolumab including 5-year follow-up, safety of nivolumab treatment after ipilimumab therapy, safety of nivolumab in challenging subgroups (elderly, patients with brain metastases, patients with autoimmune disorders), safety of nivolumab in with rare melanoma subtypes (including mucosal melanoma), as well as specificity of AEs reported for nivolumab treatment in melanoma patients in comparison to other cancer types and other immunotherapy molecules, and impact of AEs on response rates and PFS on nivolumab treatment are discussed. Expert opinion: Search for biomarkers that would help us to identify patient populations that may suffer from severe nivolumab toxicity could help in selecting patients that should not be treated with this type of therapy. Novel combinations and immunotherapy drugs including use of NKTR-214 (IL-2 pathway), lymphocyte-activation gene 3 (LAG-3), local injections of talimogene laherparepvec (T-VEC), or systemic use of T-cell receptors agonists such as OX40, CD137, ICOS-1, could provide regimens with limited toxicity and higher activity.

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Late-occurring toxicity induced by an immune checkpoint blockade in adjuvant treatment of a stage III melanoma patient

Cited by 24 publications

References 7 publications

Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance

Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance

The impact of targeted therapies and immunotherapy in melanoma brain metastases: A systematic review and meta‐analysis

An update on the safety of nivolumab for the treatment of advanced melanoma

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