Colon chaos: when drugs turn against your gut.

Immune checkpoint inhibitors (ICIs) have emerged as an integral component of the management of various cancers and have contributed to significant improvements in overall survival. Most available ICIs target anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4), and anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD1/PDL1). Gastrointestinal immune-related adverse events remain a common complication of ICIs. The predominant manifestations include diarrhea and colitis, which often manifest concurrently as immune-mediated diarrhea and colitis (IMDC). Risk factors for developing these side effects include baseline gut microbiota, preexisting autoimmune disorders, such as inflammatory bowel disease, and type of neoplasm. The hallmark symptom of colitis is diarrhea which may be accompanied by mucus or blood in stools. Patients may also experience abdominal pain, fever, vomiting, and nausea. If not treated rapidly, ICI-induced colitis can lead to serious life-threatening complications. Current management is based on corticosteroids as first-line, and immunosuppressants like infliximab or vedolizumab for refractory cases. Microbiota transplantation and specific cytokines and lymphocyte replication inhibitors are being investigated. Optimal patient care requires maintaining a balance between treatment toxicity and efficacy, hence the aim of this review is to enhance readers’ comprehension of the gastrointestinal adverse events associated with ICIs, particularly IMDC. In addition to identifying the risk factors, we discuss the incidence, clinical presentation, workup, and management options of IMDC.

e14683 Background: Immune checkpoint inhibitors (ICIs) have altered the landscape of cancer treatment. ICIs are associated with immune mediated diarrhea and colitis (IMDC) which can be challenging to diagnose and differentiate from other etiologies of diarrhea. Clostridium difficile infection (CDI) is a common cause of diarrhea in patients with cancer and can have similar symptoms. In a similar study, CDI was found to be relatively common in ICI-treated cancer patients and especially those with IMDC requiring immunosuppressants. Our study evaluates the incidence of CDI and IMDC in patients with ICI exposure and compares clinical characteristics between the two to determine risk factors that may predispose patients to CDI or IMDC. Methods: This is a retrospective, single-center study of cancer patients on an ICI from 1/1/2011 to 4/7/2022 who were tested for Clostridium difficile with stool nucleic acid amplification tests during or after treatment with an ICI. Patients were determined to have CDI if clinically suspected and had to have a positive stool GDH Ag along with positive C. difficile toxins A & B or a positive stool C. difficile toxin B gene. Patients with positive GDH Ag in the stool but with negative toxins A&B were determined to be colonized. The diagnosis of IMDC was based on the clinical presentation and had to be made by the treating oncologist. Results: 375 patients met our study criteria and got CDI testing at any point during or after ICI exposure. 27 patients tested positive for CDI, whereas 24 were colonized. 105 patients were determined to have IMDC and 97/105 received treatment with steroids or immunosuppressants. Among patients determined to have IMDC, 6 were colonized for clostridium difficile. There were no patients with IMDC who were also positive for clostridium difficile. 71 patients were on a dual ICI regimen whereas 304 patients were on a single ICI. In patients on the dual ICI regimen, 67.6% were diagnosed with IMDC when compared to patients on a single ICI regimen where 18.8% of patients were diagnosed with IMDC (p<0.0001). The absolute lymphocyte count on the day of CDI testing was 1.185 ± 0.066 in the IMDC group when compared to 0.948 ± 0.044 in the non-IMDC group (p=0.003). The mean duration of diarrhea was longer in the IMDC group at 16.905 ± 1.211 days when compared to the CDI group at 9.852 ± 2.387 days (p= 0.0094). Smoking status, sex, history of autoimmunity, and history of prior immune related adverse events did not impact incidence of IMDC or CDI. Conclusions: IMDC was a common cause of diarrhea in patients with ICI exposure who were tested for CDI. We did not find IMDC to be a risk factor for CDI. IMDC has a longer duration of diarrhea and colitis symptoms when compared to CDI. The absolute lymphocyte count on symptom onset is higher in patients with IMDC when compared to patients with CDI and may be useful in identifying patients with IMDC earlier.

e24083 Background: Immune-mediated diarrhea and colitis (IMDC) is a common toxicity to immune checkpoint inhibition (ICI) that is becoming increasingly common. Studies exploring the clinical course and outcomes of IMDC have been limited to relative small sample sizes ( < 200). We therefore aimed to provide a comprehensive account of the clinical, endoscopic, and histologic features of IMDC as well as the efficacy of IMDC treatment in a representative sample. Methods: This was a single-center retrospective study of all patients who received ICIs between January 2010 to February 2024 and developed IMDC. Detailed information was collected from the electronic health record regarding patient demographics, and IMDC stool biomarkers, endoscopic and histologic reports, clinical symptoms and treatment, and outcomes such as clinical symptom resolution, hospitalization, and mortality. SPSS 26.0 was used for data analysis. Results: A total of 1,151 patients were included. Patients commonly presented with diarrhea (98.3%) or abdominal pain (38.6%). Selective immunosuppressive therapy was needed in around 40% of patients, and 85% of patients were able to achieve symptom resolution. Around 40% had non-ulcerative inflammation and 23% had ulcerative inflammation, with 37% having normal macroscopic findings. Around 60% of patients had acute histological inflammation, 28% with chronic inflammation, and 11.7% with microscopic inflammation. Infliximab was associated with shorter time to clinical response and in fewer doses than vedolizumab with equal efficacy between the two medications. Conclusions: Our study is the largest to date exploring the various manifestations of IMDC as well as its treatment and outcomes. We found that its features overlap with different inflammatory colitides. Infliximab and vedolizumab are equally effective at achieving symptom remission, although infliximab has a shorter time to response. As more patients develop IMDC, larger scale studies can be carried out to validate these results.

Incidence and Predictors of CKD and Estimated GFR Decline in Patients Receiving Immune Checkpoint Inhibitors

2577 Background: Immune checkpoint inhibitor (ICI) therapy is often suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the recurrence rate and risk factors for IMDC after ICI resumption. Methods: This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between 1/2010 and 11/2018. Univariate and multivariate logistic regression analyses assessed the association of clinical covariates and IMDC recurrence. Results: Of the 167 patients in our analysis, 32 resumed an anti-CTLA-4 agent and 135 an anti-PD-1/L1 agent. The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136). IMDC recurred in 57 (34%) patients overall (44% of those resuming an anti–CTLA-4 and 32% resuming an anti–PD-1/L1 agent); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC (Table). The median duration from ICI resumption to IMDC recurrence was 53 days (IQR 22-138). On multivariate logistic regression, patients who received anti-PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45, 95%CI, 1.59-7.69; P<0.01). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95%CI, 1.08-9.62; P=0.02) or had longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95%CI, 1.00-1.03; P=0.03). Risk of IMDC recurrence was lower for those who resumed anti–PD-1/L1 therapy than for those who resumed anti–CTLA-4 therapy (OR, 0.30; 95%CI, 0.11-0.81; P=0.02). Conclusions: One-third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. IMDC recurrence was less frequent after resumption of anti–PD-1/L1 than after anti–CTLA-4. Characteristics of recurrent IMDC based on resumed ICI therapy. [Table: see text]

Introduction: Immune checkpoint inhibitors (ICI) have revolutionized management of advanced malignancies, but predispose to toxicities such as immune-mediated diarrhea and colitis (IMDC). Systematic management strategy including early evaluation, diagnosis, treatment and close follow up of IMDC ensures high efficacy of clinical remission and reduces the delay and interruption of cancer treatment. We evaluate the quality outcomes of cancer patients in regards to IMDC and cancer after implementation of an institutional practice change following a standardized algorithm by a dedicated toxicity GI service among inpatients in a tertiary cancer hospital. Methods: This is a retrospective quality improvement study comparing outcomes of inpatients admitted with IMDC among years 2017 and 2019. IMDC practice algorithm was implemented in 10/2017. Results: Our sample includes 59 and 67 patients admitted for IMDC in 2017 and 2019 respectively. Genitourinary cancer is the most frequent cancer type (36%) followed by melanoma (23%). Baseline IMDC characteristics are shown in Table-1. We found no significant differences in duration, number of ICI treatments or time from ICI exposure to IMDC as well as clinical severity of IMDC in both groups. Patients admitted in 2019 had significantly higher rates of GI consultation (82% vs 53%, p< 0.001), endoscopic evaluation (70% vs 49%, P=0.01) and acceptance of GI medical management recommendations (55% vs 34%, P=0.015). Same group of patients more frequently received SIT as opposed to 2017 during their index hospital admission (41% vs 21%, P=0.039) which notably translated into significantly lower days to clinical remission (4 vs 10, P=0.046), hospital re-admissions (25% vs 51%, P=0.002) and recurrence of IMDC (24% vs 49%, P=0.002). Patients in 2019 had higher portion of close post discharge GI follow up compared to 2017 (50% vs 32%, P=0.038), and the dedicated IMDC GI specialist follow up contributed to better overall survival (P=0.003, Figure-1). Conclusion: Early evaluation, aggressive treatment and close post hospital follow up by a dedicated toxicity GI service is associated with earlier clinical remission, lower re-admissions, lower recurrence and better overall survival among inpateints with IMDC through a systematic management algorithm. We speculate the substantial improvement in quality of care and outcome of these complex cancer patients with the early involvement of an expert service specialized in this field.Figure 1:: GI follow up vs not Hazard ratio: 0.473 (0.285 - 0.783) P = 0.003Table 1:: IMDC related characteristics in patients treated for colitis in 2017 and 2019 (N=126). ICI: immune checkpoint inhibitor, IMDC: immune mediated diarrhea and colitis; IQR: interquartile range; IV: intravenous

INTRODUCTION: Immune checkpoints are immunosuppressive proteins expressed by activated T-lymphocytes which evade the attack of the endogenous immune system on tumor cells. The role of immune checkpoint inhibitors (ICIs) in modern cancer treatment has gained more widespread attention in the last ten years with their favorable outcomes on survival rates. Immune mediated gastrointestinal side effects, including diarrhea and colitis, were reported in approximately 30% of patients receiving therapy with ICIs. Current practice guidelines recommend corticosteroid therapy as first-line management of immune-mediated colitis (IMC), and immunosuppressive therapy, such as with Infliximab or Vedolizumab, for steroid-refractory IMC. Yet, there is very little awareness in the literature on tailoring the management of pre-existing inflammatory bowel disease (IBD) in patients who experience IMC due to ICI therapy. CASE DESCRIPTION: A 63-year-old woman with left-sided ulcerative colitis (UC) diagnosed at the age of 23 was in clinical and endoscopic remission on 250 mg azathioprine (AZA) and sulfasalazine 4 g daily. AZA was discontinued after her diagnosis of metastatic melanoma, and she was started on immunotherapy with Ipilimumab and Nivolumab. After 4 cycles of treatment she presented with symptoms of diffuse abdominal cramping, bleeding per rectum and increased bowel frequency. Initial work up revealed CRP 2.5 mg/dL (normal: 0.5 mg/dL), and stool studies that were negative for any bacterial infection, including Clostridium difficile, or parasitic infection. Colonoscopy demonstrated moderate inflammation, Mayo Clinic Score 2 (MCS), extending continuously from the rectum proximally to 35 cm from the anal verge, with gradual transition to normal healthy mucosa in the proximal colon. Pathology showed cryptitis and crypt abscesses with focal ulceration in the recto-sigmoid colon. Initial trial of oral prednisone failed to achieve induction. Her immunotherapy was held and she was started on Vedolizumab therapy. She was successfully tapered off of steroids and achieved clinical and endoscopic remission after 7 months of maintenance therapy with Vedolizumab. Follow-up colonoscopy demonstrated mildly active pan-ulcerative colitis (MCS 1). Subsequently, she was able to resume treatment with Nivolumab monotherapy without any issues. The patient continues on Vedolizumab every 4 weeks as her maintenance therapy for UC. DISCUSSION: There have been a few reports documenting clinical outcomes of Vedolizumab therapy in patients with IMC. To our knowledge, there is no published data on the specific management of pre-existing IBD in patients starting immunotherapy. Our case is unique in that the patient had achieved clinical remission of her UC while on AZA, but required discontinuation of therapy after diagnosis of cancer. It is important to raise awareness among clinicians on the aftermath of discontinuing IBD therapy for patients who are anticipating immunotherapy. This special population requires a multidisciplinary approach and an integrated management plan in order to avoid potentially life-threatening immune-related adverse events and a flare from underlying IBD. Switching to therapies with a better safety profile and no systemic immunosuppression, like anti-integrins, might be a possible option both prior to and during immunotherapy. Whether this will decrease the incidence of future IMC in this population is yet to be supported with future research.

e24084 Background: Immune checkpoint inhibitors (ICI) enhance immune function and may cause gastrointestinal adverse events (GIAEs), such as immune-mediated diarrhea and colitis (IMDC). Patients with pre-existing inflammatory bowel disease (IBD) are usually excluded from ICI trials. This study aims to compare GIAE in patients with and without a history of IBD, elaborating the difference in disease behavior and outcome among these two groups. Methods: This single-center, retrospective study at a tertiary care cancer center included patients who received ICI between 2015 and 2023, comprising those with and without a history of IBD who developed IMDC and those with pre-existing IBD, regardless IMDC occurrence. Results: A total of 1302 patients were included, 151 (11.6%) with IBD history, of whom 59 (39%) developed GIAE. IBD patients were more likely to receive PD-1/L1 inhibitors (86.7% vs 48.9%, p &lt; 0.0001), and experienced more GIAE when also on tyrosine kinase inhibitors (12.1% vs 4.3%, p = 0.077). IBD patients who developed AE were more likely to be on IBD-specific therapy within 3 months of the event, including budesonide (7.9% vs 1.8%, p = 0.076), TNF-α inhibitors (7.9% vs 1.8%, p = 0.076), α4β7 integrin inhibitor (15.8% vs 4.6%, p = 0.024), and IL-12/IL-23 blocker (7.9% vs 1.8%, p = 0.076). Mortality was higher in non-AE group (32.6% vs 7.9%, p = 0.055). Comparison of GIAE between IBD (IBDG) and non-IBD (NIBDG) groups revealed a shorter median time to onset following ICI therapy in NIBDG ( 3.3 vs 4 months). Grade 2 or higher diarrhea was more common in NIBDG (80.1% vs 64%, p = 0.006), while no difference in colitis grade was observed. At GIAE onset, normal endoscopy was more common in NIBDG (38.5% vs 4%, p &lt; 0.0001), as was positive lactoferrin (78.4% vs 53.3%, p = 0.020). Initiation of steroid (46.6% vs 90.5%, p &lt; 0.0001) and selective immunosuppressive therapy (SIT) (17.2% vs 44.7%, p &lt; 0.0001), or their escalation from baseline treatment, was less frequent in IBDG, but colectomy rates were higher (3.4% vs 0.8%, p = 0.039). Clinical remission occurred more often in NIBDG (93.1% vs 25.9%, p &lt; 0.0001), but symptom duration was longer (30 vs 12 days, p &lt; 0.0001). Hospitalization rates (27% vs 60.1%, p = 0.067) and length of stay (5 vs 6 days, p = 0.034) were lower in IBDG. No differences were observed in all-cause mortality, or rate of ICI discontinuation and resumption. Conclusions: This study is the first to compare GIAE in IBD and non-IBD patients after ICI therapy. We found a 39% incidence of GIAE in IBD patients, primary treated with PD-1/L1 inhibitors, who often received immunosuppressant as baseline IBD treatment before ICI but had lower colitis remission rate of 25.9% compared to non-IBD patients. Despite this, IBD with GIAE after ICI did not increase overall mortality compared to those without IBD.

2642 Background: Immune-mediated colitis (IMC) may limit immune checkpoint inhibitors (ICI) treatment. Current guidelines recommend consideration of resuming ICI when IMC symptoms subside to ≤ grade 1. We aimed to investigate the effect of maintenance immunosuppressive therapy (IST) on the outcome of IMC in patients who resume ICI therapy. Methods: We retrospectively studied patients who resumed ICI therapy after adequate treatment of IMC from March 2015 to June 2020 at MD Anderson Cancer Center. Relevant demographic, oncologic, and ICI data were collected and analyzed. Univariate logistic regression analysis was conducted to assess risk factors of IMC recurrence. Results: We included 102 patients with a median age of 61 years. 66% were males and 97% were Caucasians. 48 patients (47%) received IST maintenance in conjunction with ICI resumption and 54 patients did not. Symptoms of IMC recurred in 28 patients, 8 (17%) in the concurrent IST group and 20 (37%) in the other group. Compared to no concurrent IST group, patients on concurrent IST were more likely to have received combined ICI regimen (60% vs 41%, p = 0.003) and more initial ICI doses (9 vs 5 doses, p = 0.030). Concurrent IST group had significantly longer ICI treatment duration on resumption (72 vs 62 days, p = 0.023), more ICI resumed doses (5 vs 4 doses, p = 0.038), and lower IMC recurrence (17% vs 37%, p = 0.027). Patient who received more IST doses, both therapeutic and prophylactic, had lower rate of IMC recurrence (OR 0.72, p = 0.012; table). IST maintenance treatment (OR 0.34, p = 0.024) was associated with lower IMC recurrence rate after ICI resumption. Vedolizumab was the predominant IST used. Overall survival was comparable among the two groups (p = 0.934). Conclusions: Concurrent IST treatment with ICI resumption after IMC was associated with significantly lower IMC recurrence and more extended ICI treatment while reserving similar overall survival to patients without IST maintenance therapy. Future prospective randomized trial of concurrent IST is still merited for further clarification.[Table: see text]

Obesity defined by high body mass index (BMI) has traditionally been associated with gastrointestinal inflammatory processes but has recently been correlated with better survival in patients receiving immune checkpoint inhibitors (ICI). We sought to investigate the association between BMI and immune-mediated diarrhea and colitis (IMDC) outcomes and whether BMI reflects body fat content on abdominal imaging. This retrospective, single-center study included cancer patients with ICI exposure who developed IMDC and had BMI and abdominal computed tomography (CT) obtained within 30 days before initiating ICI from April 2011 to December 2019. BMI was categorized as <25, ≥25 but <30, and ≥30. Visceral fat area (VFA), subcutaneous fat area (SFA), total fat area (TFA: VFA+SFA), and visceral to subcutaneous fat (V/S) ratio were obtained from CT at the umbilical level. Our sample comprised 202 patients; 127 patients (62.9%) received CTLA-4 monotherapy or a combination, and 75 (37.1%) received PD-1/PD-L1 monotherapy. Higher BMIs ≥ 30 were associated with a higher incidence of IMDC than BMIs ≤ 25 (11.4% vs. 7.9%, respectively; p = 0.029). Higher grades of colitis (grade 3-4) correlated with lower BMI (p = 0.03). BMI level was not associated with other IMDC characteristics or did not influence overall survival (p = 0.83). BMI is strongly correlated with VFA, SFA, and TFA (p < 0.0001). Higher BMI at ICI initiation was linked to a higher incidence of IMDC but did not appear to affect outcomes. BMI strongly correlated with body fat parameters measured by abdominal imaging, suggesting its reliability as an obesity index.

Introduction:Aging is the biggest cancer risk, and immune checkpoint (IC) inhibition (ICI) is a revolutionary cancer immunotherapy approach. Nonetheless, there are limited preclinical/clinical data regarding aging effects on ICI outcomes or age effects on IC expression in different organs or tumors.Methods:Flow cytometry assessed IC on immune and non-immune cells in various organs in young and aged BL6 mice. Comparisons: aged versus young naïve WT versus interferon-γKO mice and WT challenged with B16F10 melanoma and treated with αPD-1 or αPD-L1 ICI. We co-cultured young and aged T cells and myeloid cells in vitro and used OMIQ analyses to test cell–cell interactions.Results:αPD-1 ICI treated melanoma in young and aged hosts, whereas αPD-L1 ICI was only effective in young. We found considerable, previously undescribed age effects on expression of various IC molecules participating in the ICI treatment, including PD-1, PD-L1, PD-L2, and CD80, in distinct organs and in the tumor. These data help explain differential ICI efficacy in young and aged hosts. Host interferon-γ influenced age effects on IC expression in both directions depending on specific IC molecule and tissue. IC expression was further affected by tumor challenge on immune, non-immune, and tumor cells in tumor and other organs. In in vitro co-culture, αPD-1 versus αPD-L1 distinctly influenced polyclonal T cells in young versus aged, suggesting mechanisms for distinct age-related ICI outcomes.Conclusion:Age affects IC expression on specific immune cells in an organ- and tissue-specific manner. ICs were generally higher on aged immune cells. High immune-cell PD-1 could help explain αPD-1 efficacy in aged. High co-expression of CD80 with PD-L1 on dendritic cells could help explain lack of αPD-L1 efficacy in aged hosts. Factors other than myeloid cells and interferon-γ also affect age-related IC expression and T cell function, meriting additional studies.

PURPOSEImmune checkpoint inhibitor (ICI) therapy often is suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the rate of and risk factors for IMDC recurrence after ICI resumption.METHODSThis retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between January 2010 and November 2018. Univariable and multivariable logistic regression analyses assessed the association of clinical covariates and IMDC recurrence.RESULTSOf the 167 patients in our analysis, 32 resumed an anti–cytotoxic T-cell lymphocyte-4 (CTLA-4) agent, and 135 an anti–programmed cell death 1 or ligand 1 (PD-1/L1) agent. The median age was 60 years (interquartile range [IQR], 50-69 years). The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136 days). IMDC recurred in 57 patients (34%) overall (44% of those receiving an anti–CTLA-4 and 32% of those receiving an anti–PD-1/L1); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC, and all required permanent discontinuation of ICI therapy. The median duration from ICI resumption to IMDC recurrence was 53 days (IQR, 22-138 days). On multivariable logistic regression, patients who received anti–PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45; 95% CI, 1.59 to 7.69; P = .002). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95% CI, 1.08 to 9.62; P = .019) or had a longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95% CI, 1.00 to 1.03; P = .031). Risk of IMDC recurrence was lower after resumption of anti–PD-1/L1 therapy than after resumption of anti–CTLA-4 therapy (OR, 0.30; 95% CI, 0.11 to 0.81; P = .019).CONCLUSIONOne third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. Recurrence of IMDC was less frequent after resumption of anti–PD-1/L1 than after resumption of anti–CTLA-4.

<b>Introduction:</b> ICIs are a cornerstone in advanced NSCLC. ICIs are interrupted after two years in most trials in case of long lasting oncologic response. However, concerns about the proper schedule for&nbsp;discontinuing ICIs have been raised by many clinicians. <b>Objectives:</b> we aim to describe the long-term clinical outcomes in metastatic NSCLC patients treated by ICIs for a minimal duration of 2 years. <b>Methods:</b> This is a retrospective chart review in the three units of thoracic oncology of Lyon University Hospital. We selected all patients with NSCLC who completed at least 2 years of treatment by pembrolizumab or nivolumab. ICIs should have been started from January 2015 to April 2019 and&nbsp;the minimal follow-up duration was set at&nbsp;30 months after the initiation of ICIs. <b>Results:</b> 61 patients were enrolled. 72% were male, with a median age of 64 years. ICIs were discontinued for 54% of patients after a median duration of 27.8 months (+/−SD) for pembrolizumab and 29.2 months (+/−SD) for nivolumab, because of a controlled disease according to RECIST criteria. 82% of these patients remained under control until data cutoff and 18% experienced disease progression after a median duration of 10 months after ICIs discontinuation. 3 patients were successfully rechallenged with ICIs after disease progression and all experimented an objective response. Among those who did not stop ICIs, 78% remained with a controlled disease. <b>Conclusion:</b> Our study suggests the discontinuation of ICIs is feasible for responders while still obtaining good results. Progressive disease&nbsp;could be rechallenged.

Gastrointestinal (GI) infections, which often result in or stem from intestinal dysbiosis, can affect the efficacy of immune checkpoint inhibitors (ICIs) and increase the risk of adverse effects, such as colitis. In this study, we explored the impact of GI infections before initiation of ICI therapy on the incidence and severity of immune-mediated colitis(IMC) and survival. A single-center, retrospective review including all patients who received ICIs from January 2010 to February 2024 and subsequently developed IMC. Patients were screened for IMC and prior GI infections based on symptoms and stool tests. Patients' demographic, IMC, and GI infection-related clinical data were collected. Thirty-four of the 1132 patients (3.0%) included in the analysis had GI infections before ICI therapy. GI infections were most commonly caused by Clostridioides difficile and most often treated with oral antibiotics (interquartile range [IQR], 7-14 days). The incidence of IMC was higher in patients with prior GI infections compared to patients without prior infections (8.7% vs. 5.1%, p = 0.002). IMC symptoms, severity, and outcomes were similar in both groups (p > 0.05). In multivariate Cox proportional survival analysis, prior GI infection was independently associated with an increased risk of mortality (odds ratio, 1.6 [95% CI, 1.4-1.8]; p < 0.001) for patients who received ICIs. Our study is the first to explore the impact of GI infection before ICI therapy on IMC risk and survival. We found that prior GI infection was associated with an increased incidence of IMC and an increased risk of mortality in patients receiving ICIs.

INTRODUCTION: Background Immune-mediated diarrhea and colitis (IMDC) is the second most common immune-related adverse effect related to immune checkpoint inhibitor (ICI) therapy. In this study, we aimed to identify risk factors for chronic IMDC and the prognostic value of chronic IMDC in terms of cancer outcome. METHODS: We retrospectively reviewed the charts of all patients with an established diagnosis of IMDC over a study period from January, 2018, through October, 2019, and grouped them, based on duration of disease, into acute (≤3 months) and chronic ( >3 months) IMDC categories. Patient demographics, clinical variables, and overall survival (OS) data were collected. A logistic regression model was used to assess the factors associated with chronic IMDC. The Kaplan-Meier and log-rank tests were used to estimate and compare OS differences between the two groups. RESULTS: Our sample was comprised of 88 patients, with 43 in the chronic IMDC, and 45 in the acute IMDC group. Median age was 65.5 years at the time of IMDC. Genitourinary cancer and melanoma accounted for 70% of malignancies in our cohort. PD-1/L1 monotherapy (52%) was more frequently used than CTLA-4 monotherapy (17%) or combination therapy (31%). Our analysis demonstrated that chronic IMDC was associated with PPI use (OR = 3.96, P = 0.026), long duration of IMDC symptoms (OR = 1.05, P < 0.001) and hospitalization (OR = 1.065, P = 0.043), histological feature of chronic active colitis (OR = 4.8, P = 0.025) or microscopic colitis (OR = 5.0, P = 0.045) and delayed introduction of SIT for IMDC (OR = 1.06, P = 0.047). Our results also demonstrated that chronic IMDC reflected a better cancer response to ICIs (30% vs. 51%, P = 0.002) and is accompanied by improved OS (P = 0.035). Similarly, we observed that high doses of SIT were associated with better OS (P = 0.018). CONCLUSION: Chronic IMDC can develop among patients with more aggressive IMDC disease course and chronic features on colon histology. It likely reflects a prolonged ICI effect, therefore is associated with a better cancer outcome and overall survival. Optimization of IMDC treatment target should be considered to improve treatment outcome in the future.Figure 1Figure 2.: Kaplan-Meier OS curve, stratified by patient. (A) OS duration between the chronic IMDC (>3 months) and acute IMDC groups (≤3 months). (B) OS duration in cases with 1–2 doses of SIT (infliximab or vedolizumab) vs. ≥3 doses of SIT.Table 1