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.
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.
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
Background:Description and initial management of rheumatic immune-related adverse-events (irAEs) from cancer immunotherapies have been reported by several groups but to date, few studies have evaluated the long-term outcomes and management of rheumatic irAEs (1).Objectives:To describe the long-term management and assess the one-year outcomes of patients who experienced rheumatic immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICI).Methods:This was a single-centre prospective observational study including patients referred for musculoskeletal symptoms while treated with ICI. After baseline rheumatological evaluation defining the clinical entity presented, follow-up visits were organised according to the type and severity of irAE. At one year, persistence of irAE, ongoing treatment, as well as cancer outcomes were assessed.Results:63 patients were included between September 2015 and June 2018. 24 patients (38%) presented with non-inflammatory musculoskeletal conditions managed with short-term symptomatic treatment and did not require specific follow-up. 39 patients (62%) experienced inflammatory manifestations, mimicking either rheumatoid arthritis (RA, n=19), polymyalgia rheumatica (PMR, n=16), psoriatic arthritis (PsA, n=3) and one flare of a preexisting axial spondyloarthritis. Overall, 32 patients (82%) received systemic glucocorticoids, with a median rheumatic dosage of 15mg/day (range: 5-60mg/day). None of the patients had to permanently discontinue ICI therapy for rheumatic irAE. 20 patients (67%) were still receiving glucocorticoids at one year, with a median dosage of 5mg/day (range: 2-20mg/day). Glucocorticoids were more frequently discontinued for patients with RA-like condition (44%) than PMR-like condition (23%), but no other predictive factor of glucocorticoids withdrawal could be identified. At one year, overall survival and progression-free survival were comparable between patients who were still receiving glucocorticoids for rheumatic irAE and patients who have discontinued. Eight patients required csDMARDs.Conclusion:At one year, a majority of patients required long-term low-dose glucocorticoids for chronic rheumatic irAE, which seems not altering oncological control.References:[1]Braaten TJ, Brahmer JR, Forde PM, et al. Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann Rheum Dis. 2019 Sep 20.Disclosure of Interests:None declared
BackgroundHepatic arterial infusion (HAI) of chemotherapy is an option for the treatment of patients with liver metastases from colorectal cancer (LMCRC). Though HAI with oxaliplatin (HAI-Ox) is generally used, intravenous (IV) 5-fluoro-uracil (5FU)-oxaliplatin-irinotecan HAI (HAI-Folfirinox) is feasible and leads to curative-intent surgery in 30% of pretreated patients. We compared the efficacy and safety of HAI-Ox and HAI-Folfirinox.MethodsPatients who underwent HAI chemotherapy for LMCRC were retrospectively included from 2008 to 2019 from six French expert centers.ResultsData were collected from 273 previously treated patients with LMCRC. Patients received HAI-Folfirinox (n = 52) or HAI-Ox (n = 221) combined with IV chemotherapy. The objective response rate (ORR) was 43.2% in patients with HAI-Folfirinox and 45.9% (ns) in patients with HAI-Ox. Median overall survival (OS) was 17 months (95% CI: 15–32.3) with HAI-Folfirinox and 26.2 months (95% CI: 19.4–34.4; p = 0.1) with HAI-Ox. Median progression-free survival (PFS) was 7.9 months (95% CI: 4.9–10.3) with HAI-Folfirinox and 6.4 months (95% CI: 6.0–7.7; p = 0.6) with HAI-Ox. The secondary liver resection rate was 35.6% with HAI-Folfirinox and 16.7% with HAI-Ox (p = 0.007). Grade 2 and above toxicities were significantly more frequent with HAI-Folfirinox. In the global population, only 2 factors were prognostic for OS in multivariable analyses: liver-only disease [hazard ratio (HR): 0.4; 95% CI 0.20–0.83; p = 0.013] and local complications of the catheter (HR: 3.8; 95% CI 1.6–9.0; p = 0.002).ConclusionHepatic arterial infusion results in high response rates, secondary resections, and long survival in pretreated patients with LMCRC.
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