Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: An overlooked aspect in immunotherapy

Ghisoni, Eleonora; Wicky, Alexandre; Bouchaab, Hasna; Imbimbo, Martina; Delyon, Julie; Moura, Bianca Gautron; Gérard, Camille L.; Latifyan, Sofiya; Özdemir, Berna C.; Caikovski, Marian; Pradervand, Sylvain; Tavazzi, Erica; Gatta, Roberto; Marandino, Laura; Valabrega, Giorgio; Aglietta, Massimo; Obéid, Michel; Homicsko, Krisztian; Alfonso, Nuria Neisy Mederos; Zimmermann, Stefan; Coukos, George; Peters, Solange; Cuendet, Michel A.; Maïo, Massimo Di; Michielin, Olivier

doi:10.1016/j.ejca.2021.03.010

Cited by 114 publications

(95 citation statements)

References 32 publications

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“…Real-world evidence shows that around half of the patients treated with ICI experience at least one grade ≥ 2 toxicity, of which 35-40% are long-lasting [8]. Endocrinopathies are among the most common immune-mediated side effects and are usually irreversible and accordingly require lifelong substitution therapy [34].…”

Section: Discussionmentioning

confidence: 99%

“…The grade 3-4 toxicity rate of adjuvant dabrafenib-trametinib (41%) [5] is higher than that of nivolumab (14.4%) [3] and pembrolizumab (14.7%) [4]. While dabrafenib and trametinib toxicity is, in general, reversible and comprises pyrexia, unspecific symptoms, such as fatigue, headache and nausea, and, rarely, cardiac toxicity, immune-related adverse events (irAEs) can affect any organ, might require systemic corticosteroids or other immunosuppressive drugs, and can be long-lasting and irreversible [8]. In particular, myocarditis is a rare but potentially fatal complication of ICI [9].…”

Section: Introductionmentioning

confidence: 99%

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Prescription Patterns, Recurrence, and Toxicity Rates of Adjuvant Treatment for Stage III/IV Melanoma—A Real World Single-Center Analysis

Hoffmann

Hayoz

Özdemir

2022

Biology

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Approved adjuvant treatment options for stage III melanoma are the immune checkpoint inhibitors (ICI) pembrolizumab and nivolumab, and in presence of a BRAF V600E/K mutation additionally dabrafenib in combination with trametinib (BRAFi/MEKi). This study aims to describe prescription patterns and recurrence and toxicity rates of adjuvant-treated melanoma patients from the Cancer Center of the University Hospital Bern, Switzerland. One hundred and nine patients with an indication for adjuvant treatment were identified. Five (4.6%) had contraindications and, as such, were not proposed any adjuvant treatment, while 10 patients (9.2%) declined treatment. BRAF status was known for 91 (83.5%) patients. Of 40 (36.7%) patients with BRAF V600E/K melanoma, pembrolizumab was prescribed to 18 (45.0%), nivolumab to 16 (40.0%), and dabrafenib/trametinib to three (7.5%) patients. Grade 3–4 toxicity was reported in 18.9% and 16.7% of all the patients treated with pembrolizumab and nivolumab, respectively. No toxicities were observed for dabrafenib/trametinib. Thirty-eight percent of the patients treated with pembrolizumab and 40.0% of those treated with nivolumab relapsed. No relapses were reported for dabrafenib/trametinib. Prescription patterns indicate a clear preference for adjuvant ICI treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prescription Patterns, Recurrence, and Toxicity Rates of Adjuvant Treatment for Stage III/IV Melanoma—A Real World Single-Center Analysis

Hoffmann

Hayoz

Özdemir

2022

Biology

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“…The time to onset of irAEs described in other publications varies between 2 and 16 weeks [ 18 , 19 , 34 , 37 ]. In our cohort, the median time to onset of irAEs was 12 weeks (95% CI 12–20), which is longer than previously reported, probably because we did not consider the irAEs that have an earlier onset, such as cutaneous and gastro-intestinal irAEs, and included those with later onset as endocrine and renal irAEs [ 19 , 38 ]. The time of onset of irAEs, however, does not seem to be associated with response, as publications involving different tumor entities, including in melanoma, show conflicting results [ 21 ].…”

Section: Discussionmentioning

confidence: 98%

Association between Immune-Related Adverse Events and Survival in 319 Stage IV Melanoma Patients Treated with PD-1-Based Immunotherapy: An Approach Based on Clinical Chemistry

Higuita

Amaral

Forschner

et al. 2021

Cancers

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(1) Background: Immune checkpoint inhibitors have improved the prognosis of patients with advanced melanoma. Published data suggested that the objective response rates appear to be superior in patients who developed immune-related adverse events (irAEs). (2) The primary aim of this cohort study was to evaluate the association between irAEs and disease control rate in patients with stage IV melanoma treated with first-line PD-1-based immunotherapy. (3) Among 319 patients, 53% experienced at least one irAE. A higher percentage of patients with irAEs had disease control compared to those without irAEs (69.8% vs. 49.3%). In multivariate analysis, development of grade 3 and 4 irAEs was significantly associated with a protective effect for the outcome primary resistance (OR: 0.40 95% CI 0.23–0.70, p = 0.001). The presence of any grade irAEs was significantly associated with longer OS (irAEs grade 1–2 HRadj: 0.61 95% CI: 0.4–0.93, p = 0.02, irAEs grade 3–4 HRadj: 0.55 95% CI 0.31–0.99, p = 0.04), but not with PFS (irAEs grade 1–2 HRadj: 1.21 95% CI: 0.91–1.79, p = 0.16, irAEs grade 3–4 HRadj: 1.14 95% CI 0.83–2.02, p = 0.24). (4) The presence of irAEs with laboratorial expression is positively associated with response and OS, suggesting that irAEs might be a predictive factor in this setting.

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“…The optimal timing of 18 F-FDG PET during ICI treatment for early detection of irAEs is currently unknown. The timing of irAE development varies widely, and an irAE can even occur after discontinuation or completion of ICI therapy [ 32 ]. Perhaps a quantitative analysis of an early timepoint 18 F-FDG PET/CT (e.g., at 1 month after ICI treatment initiation) could identify patients who are at greater risk for irAE, as 18 F-FDG PET/CT after 1 month has been shown to be predictive of patient response to ICI [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Quantitative imaging biomarkers of immune-related adverse events in immune-checkpoint blockade-treated metastatic melanoma patients: a pilot study

Hribernik

Huff

Studen

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose To develop quantitative molecular imaging biomarkers of immune-related adverse event (irAE) development in malignant melanoma (MM) patients receiving immune-checkpoint inhibitors (ICI) imaged with 18F-FDG PET/CT. Methods 18F-FDG PET/CT images of 58 MM patients treated with anti-PD-1 or anti-CTLA-4 ICI were retrospectively analyzed for indication of irAE. Three target organs, most commonly affected by irAE, were considered: bowel, lung, and thyroid. Patient charts were reviewed to identify which patients experienced irAE, irAE grade, and time to irAE diagnosis. Target organs were segmented using a convolutional neural network (CNN), and novel quantitative imaging biomarkers — SUV percentiles (SUVX%) of 18F-FDG uptake within the target organs — were correlated with the clinical irAE status. Area under the receiver-operating characteristic curve (AUROC) was used to quantify irAE detection performance. Patients who did not experience irAE were used to establish normal ranges for target organ 18F-FDG uptake. Results A total of 31% (18/58) patients experienced irAE in the three target organs: bowel (n=6), lung (n=5), and thyroid (n=9). Optimal percentiles for identifying irAE were bowel (SUV95%, AUROC=0.79), lung (SUV95%, AUROC=0.98), and thyroid (SUV75%, AUROC=0.88). Optimal cut-offs for irAE detection were bowel (SUV95%>2.7 g/mL), lung (SUV95%>1.7 g/mL), and thyroid (SUV75%>2.1 g/mL). Normal ranges (95% confidence interval) for the SUV percentiles in patients without irAE were bowel [1.74, 2.86 g/mL], lung [0.73, 1.46 g/mL], and thyroid [0.86, 1.99 g/mL]. Conclusions Increased 18F-FDG uptake within irAE-affected organs provides predictive information about the development of irAE in MM patients receiving ICI and represents a potential quantitative imaging biomarker for irAE. Some irAE can be detected on 18F-FDG PET/CT well before clinical symptoms appear.

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Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: An overlooked aspect in immunotherapy

Cited by 114 publications

References 32 publications

Prescription Patterns, Recurrence, and Toxicity Rates of Adjuvant Treatment for Stage III/IV Melanoma—A Real World Single-Center Analysis

Prescription Patterns, Recurrence, and Toxicity Rates of Adjuvant Treatment for Stage III/IV Melanoma—A Real World Single-Center Analysis

Association between Immune-Related Adverse Events and Survival in 319 Stage IV Melanoma Patients Treated with PD-1-Based Immunotherapy: An Approach Based on Clinical Chemistry

Quantitative imaging biomarkers of immune-related adverse events in immune-checkpoint blockade-treated metastatic melanoma patients: a pilot study

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