Immune Checkpoint Inhibitors (ICI) have revolutionized cancer therapy, providing unprecedented responses in a wide range of malignancies. However, they induced various immune-related adverse events (iRAE) that can be life-threatening. About 20% of patients treated with an ICI monotherapy, and up to 60% of patients treated with a combination of ICIs, experienced a severe iRAE. Most side effects are reversible if managed early, but can affect survival and quality of life, leading to treatment interruptions or hospitalization. Some of these irAEs, particularly those affecting hormonal functions, may be irreversible and persist even after treatment discontinuation.
The development of predictive biomarkers of such toxicities is an unmet medical need. The variety of mechanisms involved in iRAE, and the lack of effective animal models, could probably explain why the topic remains largely unexplored. To date, some biomarkers predictive of the occurrence of iRAE, irrespective of the type of organ affected, have been identified by state-of-the-art techniques on small cohorts prior to treatment initiation, but none is individually robust enough to be used in daily practice.
We hypothesize that a signature derived from the integrative analysis of various biological parameters (immunomonitoring, auto-immunity features, viral monitoring, microbiota monitoring, fragmentome analysis, pharmacokinetics, radiomics and genetics), available in routine hospital practice, could answer this question, and thus enable the development of specific prevention strategies
The objectives are :
Primary objective:
Identify a baseline predictive signature for severe iRAE, irrespective of the type of organ affected.
Secondary objectives:
* Identify a predictive signature for severe iRAE including baseline and T1 data, irrespective of the type of organ affected. * Identify a baseline predictive signature for organ-specific severe iRAE. * Identify a predictive signature for organ-specific severe iRAE including baseline and T1 data. * Identify a baseline predictive signature for severe iRAE, irrespective of the type of organ affected, for patient receiving an anti-PD(L)1 in monotherapy. * Identify a baseline predictive signature for severe iRAE, irrespective of the type of organ affected, for patient receiving an anti-PD(L)1 in combination. * Identify a baseline predictive signature for severe iRAE, irrespective of the type of organ affected, for each specific immunotherapy received. * Compare the predictive signatures between responders and non-responders according to RECIST 1.1 in order not to overlook the influence of clinical response on the variability observed. * Describe the results obtained for each biological parameter between severe irAEs and non-severe irAEs patients. * Describe patient-reported outcomes and quality of life parameters.
Adult patient (≥18 years old)
Patient presenting an histologically or cytologically confirmed solid tumour malignancy
Patient scheduled to receive his/her first infusion of immunotherapy with anti-PD1, anti-PDL1, anti-CTLA4, anti-LAG3, alone or in combination, as part of standard care, in all validated solid oncology indications.
Patient must have at least one measurable lesion according to RECIST 1.1 criteria
Patient previously treated with ICIs
Patient whose treatment plan includes targeted therapy, chemotherapy or any other systemic treatment in combination with ICI
Patient included in a trial with an experimental molecule
Patient has an active autoimmune disease or any other pathology requiring systemic corticosteroid therapy at more than 10 mg prednisone equivalent per day or any other immunosuppressive drug
Single group
Bloodsampling
Other interventionBlood will be sampled At Visit 1, 2, 3 and 4. For patients presenting immuno-induced adverse events (iRAEs), an additionnal visit V tox will be planned will a blood sampling.
Pharyngeal swab sampling
Other interventionPharyngeal swab will be sampled at visit 4 for patients without immuno-induced adverse events (iRAEs) Pharyngeal swab will be sampled at visit Tox for patients presenting immuno-induced adverse events (iRAEs)
Cuteanous swab sampling
Other interventionCuteanous swab will be sampled at visit 1, 2, 3 and 4 for patients without immuno-induced adverse events (iRAEs). Cuteanous swab will be sampled at visit 1, 2, 3 and tox for patients presenting immuno-induced adverse events (iRAEs).
Stools sample collection
Other interventionStools sample will be collected at visit 1, 2, 3 and 4 for patients without immuno-induced adverse events (iRAEs). Stools sample will be collected at visit 1, 2, 3 and tox for patients presenting immuno-induced adverse events (iRAEs).
Identification of a predictive baseline signature who maximize the rate of prediction of severe iRAE
The primary endpoint is the identification of a predictive baseline signature who maximize the rate of prediction of severe iRAE among patients who had a severe iRAE (iRAE + patients) and minimize the rate of prediction of severe iRAE among patients who had not a severe iRAE (iRAE- patients), we choose a minimum of 70% of prediction in iRAE + population and a maximum of 15% of prediction in iRAE- population.
Assesment of safety according to NCI-CTCAE v5.0 criteria
Identification of signatures for severe iRAEs
Predictive performance of baseline + T1 signatures for severe iRAEs
Identification of signatures for organ-specific severe iRAEs
Predictive performance of baseline signatures for organ-specific severe iRAEs using the same performance thresholds.
Identification of signatures for organ-specific severe iRAEs at baseline and T1
Predictive performance of baseline + T1 signatures for organ-specific severe iRAEs.
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