Abstract
BackgroundImmune checkpoint inhibitors (CPIs) are effective against a variety of malignancies but can be limited by inflammatory toxicities such as enterocolitis. Enterocolitis is typically treated with systemically active glucocorticoids. Endoscopy can stratify patients by the severity of mucosal inflammation, including identifying patients with colitis in the absence of visible mucosal changes: microscopic colitis. Whether patients with CPI microscopic colitis could be managed differently from colitis with more severe mucosal involvement is unclear. The objective of this study was to describe outcomes in CPI microscopic colitis focusing on the response to first line treatment with budesonide.MethodsWe evaluated data from a retrospective cohort from a single-center large academic hospital. The participants were all adult patients evaluated by endoscopy for suspected CPI enterocolitis between 3/2017 and 3/2019. The exposures were: Mayo Endoscopic Score (range 0–3). The subset was: oral budesonide, maximum dose 12 mg daily, administered minimum of 5 weeks. The main outcomes and measures were: Primary: time from first CPI exposure to first glucocorticoid use; use of systemic glucocorticoids; time from symptom onset to resolution; continuation of CPI therapy; number of additional CPI infusions received. Secondary: admissions for symptom control; novel irAE development; need for second-line immunosuppression; oncologic outcomes.ResultsWe identified 38 patients with biopsy confirmed CPI enterocolitis, 13 in the microscopic colitis cohort, and 25 in the non-microscopic colitis cohort. Budesonide use was higher in the microscopic colitis cohort (12/13 vs 3/25, p < 0.001), and systemic glucocorticoid use was higher in non-microscopic colitis (22/25 vs. 3/13, p < 0.001). Time from symptom onset to resolution did not differ. Microscopic colitis patients more frequently remained on CPI after developing (entero)colitis (76.9% vs 16.0%, p < 0.001). Microscopic colitis patients tolerating further CPI received, on average, 4.2 CPI infusions more than non-microscopic colitis patients tolerating CPI (5.8 vs 1.6, p = 0.03). Microscopic colitis was associated with increased time-to-treatment-failure (HR 0.30, 95% CI 0.14–0.66) and progression-free survival (HR 0.22, 95% CI 0.07–0.70).ConclusionsGastrointestinal mucosal inflammation without visible mucosal injury is a distinct, prevalent CPI enterocolitis subset that can be diagnosed by endoscopy. First-line budesonide appears effective in controlling “microscopic colitis” symptoms and prolonging immunotherapy duration. These findings present a compelling rationale for routine endoscopic evaluation of suspected CPI enterocolitis and suggest an alternative glucocorticoid-sparing treatment strategy for a subset of such patients.
Highlights
Immune checkpoint inhibitors (CPIs) are highly effective against a range of advanced malignancies, but are associated with treatment-limiting inflammatory toxicities termed “immune-related adverse events” [1,2,3,4,5]
The spectrum and severity of immune-related adverse events” (irAEs) are related to the specific checkpoint pathway inhibited, with cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors generally associated with more frequent and more severe irAEs compared to inhibitors of programmed cell death1 (PD-1) or its ligand (PD-L1); combination immunotherapies are associated with the highest rates of toxicity, and are likely to see increased clinical use in the future [1, 2, 6]
(Entero)colitis is among the most common and severe irAEs associated with current CPIs, and is an important reason for CPI discontinuation, in patients treated with combination immunotherapy blocking both PD-1 and CTLA-4 [1, 6, 10,11,12]
Summary
Immune checkpoint inhibitors (CPIs) are highly effective against a range of advanced malignancies, but are associated with treatment-limiting inflammatory toxicities termed “immune-related adverse events” (irAEs) [1,2,3,4,5]. (Entero)colitis is among the most common and severe irAEs associated with current CPIs, and is an important reason for CPI discontinuation, in patients treated with combination immunotherapy blocking both PD-1 and CTLA-4 [1, 6, 10,11,12]. Developing treatment strategies that can reduce or replace systemic glucocorticoids while allowing patients to remain on immunotherapy is of substantial clinical importance [1, 6, 16]. The objective of this study was to describe outcomes in CPI microscopic colitis focusing on the response to first line treatment with budesonide
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