As gut microbiota composition is an important determinant of response to immune checkpoint inhibitors (ICIs), we examined the effect of various co-medications known for their interaction with microbiota, when given at ICI initiation. Patients and methods: We identified patients with advanced cancer treated with ICI between May 2015 and September 2017 in our institution. Co-medications given within 1 month before or 1 month after the first administration of ICI were reviewed from medical records. Survival data were analysed with univariable Cox regression, and the combined effect of multiple factors was assessed with factor analysis of mixed data (FAMD). The impact of co-medications on immune-related adverse events (irAEs) occurrence was also assessed.

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Immune checkpoint inhibitors (ICIs) have radically changed the clinical outcome of several cancers with durable responses. CTLA-4 (cytotoxic T lymphocyte antigen-4), PD-1 (programmed cell death protein 1) or PDL-1 (programmed cell death ligand protein 1) represent ICIs that can be used as monotherapy or in combination with other agents. The toxicity p\rofiles of ICIs differ from the side effects of cytotoxic agents and come with new toxicities like immune-related adverse events. Typically, these toxicities occur in all organs. However, the main organs affected are the skin, digestive, hepatic, lungs, rheumatologic, and endocrine. Most of the immune toxicity that occurs is low grade but some more severe toxicities can occur that require a rapid diagnosis and appropriate treatment. The recognition of symptoms by physicians and patient is necessary to resolve them rapidly and adapt treatment to allow the toxicity to resolve.

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BackgroundImmune checkpoint inhibitors (ICIs) are revolutionizing the treatment of some advanced cancers. Gut microbiota has emerged as an important component of anti-tumoral response and can also be related to the occurrence of immune-related adverse events (irAEs). It has recently been shown that antibiotic treatment given at the initiation of ICI therapy had a dramatic impact on microbiota that compromised the anti-tumoral effect of ICIs (1).ObjectivesTo evaluate whether co-medications known to have a potential impact on gut microbiota may alter ICI efficacy and/or irAE occurrence when given at ICI onset.MethodsThis was a retrospective cohort study including all cancer patients who received ICIs at our institution from May 2015 to September 2017. Co-medications given to the patients within one month before or one month after the first administration of ICI were extracted from medical records on the basis of a predefined list of medications known to impact gut microbiota. The tumour response, occurrence of irAEs and patient outcomes were assessed on a regular basis. Overall survival (OS) has been considered from the start of ICI therapy.Results635 patients (70% male, mean age 64.5 years) were included, of whom 293 had melanoma, 150 had advanced non-small cell lung cancer and 83 had renal carcinoma. A previous autoimmune disorder was present in 8% of patients, mainly rheumatic and endocrine diseases. Psychotropic drugs (41.1%), proton pump inhibitors (PPIs) (37.3%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARBs) (32%), glucocorticoids (GC) (24.2%), antibiotics (21.4%), statins (20.8%) and morphine (20.6%) were the most co-prescribed medications. Baseline GC use, when ≥ 10mg of prednisone equivalent, was associated with a significant decrease in OS (median 4.5 months versus 24.3 months; p<0.0001) and a less frequent tumour response (55% versus 73%; p=0.0001). When given after ICI onset for the management of irAEs, GC did not influence ICI efficacy (Figure A). Baseline PPIs use also altered both OS (median 10.9 versus 24.3 months; p<0.0001) and tumour response (62% versus 71%; p=0.02) (Figure B). We confirmed the detrimental impact of antibiotics when given at ICI onset, and also found worse outcomes for patients receiving baseline psychotropic drugs (median OS 9.3 versus 19.4 months; p=0.0001). No significant difference was observed with baseline use of NSAIDs, aspirin, statins and ARBs/ACE. Furthermore, co-medication with antibiotics, GC, PPIs, morphine, NSAIDs, aspirin and psychotropic drugs was associated with decreased occurrence of irAEs.ConclusionAs many of these treatments are used by rheumatologists, one should be aware of their potential detrimental effect when used at ICI initiation, that sometimes could have been avoided.Reference[1] Routy B et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018 Jan 5;359(6371):91-97.Disclosure of InterestsNone declared