The diagnosis and treatment of gastrointestinal (GI) bleeding secondary to malignancy can be challenging. Endoscopy is the gold standard to diagnose and treat gastrointestinal bleeding but clinical characteristics and outcomes of patients with malignancy‐related bleeding are not well understood. This study aims to look at clinical characteristics, endoscopic findings, safety and clinical outcomes of endoscopic interventions for GI malignancy‐related bleeding.

The broad activity of agents blocking the programmed cell death protein 1 and its ligand (the PD-(L)1 axis) revolutionized oncology, offering long-term benefit to patients and even curative responses for tumors that were once associated with dismal prognosis. However, only a minority of patients experience durable clinical benefit with immune checkpoint inhibitor monotherapy in most disease settings. Spurred by preclinical and correlative studies to understand mechanisms of non-response to the PD-(L)1 antagonists and by combination studies in animal tumor models, many drug development programs were designed to combine anti-PD-(L)1 with a variety of approved and investigational chemotherapies, tumor-targeted therapies, antiangiogenic therapies, and other immunotherapies. Several immunotherapy combinations improved survival outcomes in a variety of indications including melanoma, lung, kidney, and liver cancer, among others. This immunotherapy renaissance, however, has led to many combinations being advanced to late-stage development without definitive predictive biomarkers, limited phase I and phase II data, or clinical trial designs that are not optimized for demonstrating the unique attributes of immune-related antitumor activity—for example, landmark progression-free survival and overall survival. The decision to activate a study at an individual site is investigator-driven, and generalized frameworks to evaluate the potential for phase III trials in immuno-oncology to yield positive data, particularly to increase the number of curative responses or otherwise advance the field have thus far been lacking. To assist in evaluating the potential value to patients and the immunotherapy field of phase III trials, the Society for Immunotherapy of Cancer (SITC) has developed a checklist for investigators, described in this manuscript. Although the checklist focuses on anti-PD-(L)1-based combinations, it may be applied to any regimen in which immune modulation is an important component of the antitumor effect.

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]

Background and Objective: Immune-mediated diarrhea and colitis (IMDC) is a common adverse event in cancer patients receiving immune checkpoint inhibitors (ICIs). Gastrointestinal (GI) infections can co-occur with IMDC, and its impact on the course and outcome of IMDC remains unclear. Patients and Methods: We retrospectively reviewed cancer patients who received ICIs and developed IMDC between January 2015 and September 2019. GI multiplex panel is used to assess GI infection. The study group included patients with positive infection except those who are only positive for Clostridioides difficile or cytomegalovirus. The control group is IMDC patients with negative infection using frequency matching. Patients' disease course and outcome were compared between groups. Results: A total of 72 patients with IMDC were included: 22 in the study group and 50 as control. Escherichia coli of different pathotypes was observed in 17 patients. Five patients had viral infections, for example, adenovirus, norovirus, and sapovirus. Patients with GI infections more frequently had grade 3 or 4 colitis (43% vs. 18%, P=0.041). Overall, GI infections were not associated with different risks of IMDC recurrence or overall survival. Antibiotics treatment did not affect the requirement for infliximab or vedolizumab but relate to a higher risk of IMDC recurrence (50.0% vs. 0.0%, P=0.015). Conclusions: In our study, concomitant GI infections are associated with more severe symptoms in IMDC patients. Antimicrobial treatment did not circumvent the need for immunosuppressive therapy for IMDC or improve the clinical outcome. Concomitant GI infection was not associated with a higher risk of IMDC recurrence or poor overall survival.

The gut microbiome is increasingly being described as one of the underlying mechanisms for development of immune checkpoint inhibitor (ICI)-induced colitis. Similarities in gut microbiome profiles have been found among various diseases associated with intestinal inflammation, including inflammatory bowel disease. Certain bacterial species have been reported to be preventive for colitis, as well as beneficial for cancer outcome, in patients receiving ICI therapy. Alternatively, other bacterial classes have been shown to be associated with immunologic alterations causing intestinal inflammation with subsequent increase in the risk of ICI-related colitis. Gut microbiome manipulation by fecal transplantation has been proposed as one of the modalities to ameliorate inflammation in patients with ICI-related colitis refractory to immunosuppressive therapy. Additional investigations are needed to clarify the role of gut microbiome in the pathogenesis of ICI-related colitis.

SummaryBackgroundImmune checkpoint inhibitors have revolutionised cancer treatment, but at the cost of off‐target immune‐mediated organ damage. This includes checkpoint inhibitor‐induced enterocolitis which frequently requires hospitalisation and may be life‐threatening. Empiric treatment typically includes corticosteroids and infliximab, although no large‐scale studies have confirmed their effectiveness.AimTo investigate the effectiveness of anti‐inflammatory therapy in checkpoint inhibitor‐induced enterocolitisMethodsWe performed a systematic review and meta‐analysis of studies reporting clinical outcomes of checkpoint inhibitor‐induced enterocolitis in adult cancer patients treated with anti‐inflammatory agents. We searched Medline, EMBASE, and the Cochrane library through April and extracted the proportion of patients responding to anti‐inflammatory therapy. Variation in effect size was studied using a random‐effects meta‐regression analysis, with checkpoint inhibitor agent and tumour type as the variables.ResultsData were pooled from 1210 treated patients across 39 studies. Corticosteroids were effective in 59% (95% CI 54‐ 65) of patients, with response significantly more favourable in patients treated with anti‐PD‐1/L1 monotherapy, compared with anti‐CTLA‐4 containing regimens (78%, 95% CI 69‐85 vs 56 %, 95% CI 49‐63, P = 0.003), and more favourable in lung cancer patients compared with melanoma patients (88%, 95% CI 62‐97 vs 55%, 95% CI 47‐63, P = 0.04). Infliximab was effective in 81% (95% CI 73‐87) of patients, and vedolizumab in 85% (95% CI 60‐96).ConclusionCorticosteroids, infliximab and vedolizumab, are effective in the treatment of checkpoint inhibitor‐induced enterocolitis. Checkpoint inhibitor regimen and cancer type were significant moderators in response to corticosteroid therapy.

Immune checkpoint inhibitors (ICIs) are increasingly used for multiple cancer types. Hepatotoxicity is a reported adverse event of ICI treatment. It can present as asymptomatic elevation of aspartate transaminase and alanine transaminase or symptomatic hepatitis with fever, malaise, and even death in rare cases. The diagnosis of ICI-induced hepatitis is made after exclusion of other etiologies based on medical history, laboratory evaluation, and imaging and histological findings. Treatment of ICI-induced hepatitis consists of ICI discontinuation and immunosuppression in severe cases. Pancreatic injury as asymptomatic lipase elevation or acute pancreatitis-like disease with abdominal pain and evidence on imaging has been documented as a toxicity of ICI therapy. Appropriate treatment of pancreatitis still needs further investigation. Few cases, reports, and series documented cholecystitis and cholangitis as possible adverse events related to ICI therapy as well.

BACKGROUND:Data on gastrointestinal toxicities related antiangiogenesis cancer therapy is very limited. We aim to describe the clinical, endoscopic, and histologic features and outcomes of antiangiogenesis-associated colitis and diarrhea (ACD) at a tertiary-care cancer center.PATIENTS AND METHODS:We performed a retrospective study of cancer patients who received antiangiogenesis therapy (AAT) and underwent endoscopy for ACD symptoms during 2000-2018.RESULTS:A total of 12,045 patients received AAT during the study period. Of these, 552 patients underwent lower gastrointestinal tract endoscopic evaluation after AAT. Among them, we identified 41 patients who developed ACD. The median time from AAT initiation to ACD onset was 20 weeks. Most patients received bevacizumab (83%). The median duration of ACD symptoms was 6 days. On endoscopy, 7 patients (17%) had mucosal ulceration, and 16 (39%) had nonulcerative inflammation. Active histologic inflammation was evident in 8 patients (20%). Thirteen patients (32%) received treatment for ACD: antibiotics in 5 (12%) and antimotility agents in 11 (27%). Sixteen patients (39%) were hospitalized for ACD, and 2 were admitted to the intensive care unit. One colonic perforation (2%) related to underlying malignancy was reported after colonoscopy. Patients with enterocolitis symptoms had more frequent abnormal endoscopic findings (P = .024) and less frequently received antimotility agents (P = .011) compared to those with diarrhea only. Abnormal endoscopic findings were associated with more hospitalizations (P = .063) compared to normal group.CONCLUSION:ACD is a rare adverse event of AAT and is usually mild. Despite its rarity, complications of ACD can be serious, requiring intensive care unit and surgery. Colonic perforation occurred after routine endoscopy after AAT in 2% of our cohort.

e15166 Background: ICI therapies have revolutionized the landscape of cancer treatment. However, their increased use has also contributed to adverse events, e.g. IMDC. Clinically it is difficult to distinguish between infectious etiology or IMDC. It is unclear whether antimicrobial treatment substantially impacts the disease course. Here, we evaluated the characteristics and outcome of IMDC in cancer patients with superimposed diarrheagenic GI infections. Methods: We retrospectively evaluated cancer patients who received ICI with clinical symptoms of IMDC and confirmed stool microbiology of E. coli or non-CMV viral infections either at the time of IMDC, or within 60 days after IMDC diagnosis at MD Anderson Cancer Center 01/2011-08/2019. We described the disease course and outcome of IMDC based on their status of GI infection and antimicrobial treatment. Results: Total 72 patients were included, among them, 50 control patients with IMDC and no GI infection, 22 had diarrheagenic infections, composed of 17 E coli pathogens: Enteropathogenic, Enterotoxigenic, Enteroaggregative, and E coli 0157:H7 serotype; and 5 viral etiologies: Adenovirus, Norovirus, and Sapovirus. Patients in the infection group had higher grade of colitis (42.9% vs 18.4%, P = 0.041), and more frequent hospitalization (86.4% vs 62%, P = 0.052). 68.2% patients in the infection group received infliximab/vedolizumab add-on treatment compared to 40% in the no infection group (P = 0.078). Patients with GI infection and antimicrobial treatment had much higher IMDC recurrence rate than no antimicrobial treatment (50% vs 0, P = 0.015). GI infection was not associated with higher IMDC recurrence or worse overall survival of these patients. Conclusions: IMDC can occasionally be complicated by infection from common GI pathogens. Antimicrobial treatment was mostly used in severe IMDC cases and did not circumvent the need for immunosuppressant or improve the clinical outcomes. GI infection was not associated with higher IMDC recurrence or worse overall survival of these patients. [Table: see text]

s 17.33±6.4 vs. 0.38±0.18 hours, means + SD, p<0.01, n=6). Conclusions The ability of EGFr TKIs to reverse the inhibitory effect of EGF on calcium-dependent chloride secretion, and to potentiate the secretory response to CCh, could contribute to the diarrheal side-effects of these agents.Their ability to disrupt epithelial barrier dysfunction is likely also pathophysiologically significant.CCh activated Erk1/2 phosphorylation in a manner that was insensitive to EGFr TKIs and also delayed the deleterious effects of the drugs on barrier function.These findings may be related, and also of relevance in designing strategies to overcome the diarrheal effects of EGFr TKIs, which sometimes are severe enough to require treatment cessation.

s 17.33±6.4 vs. 0.38±0.18 hours, means + SD, p<0.01, n=6). Conclusions The ability of EGFr TKIs to reverse the inhibitory effect of EGF on calcium-dependent chloride secretion, and to potentiate the secretory response to CCh, could contribute to the diarrheal side-effects of these agents.Their ability to disrupt epithelial barrier dysfunction is likely also pathophysiologically significant.CCh activated Erk1/2 phosphorylation in a manner that was insensitive to EGFr TKIs and also delayed the deleterious effects of the drugs on barrier function.These findings may be related, and also of relevance in designing strategies to overcome the diarrheal effects of EGFr TKIs, which sometimes are severe enough to require treatment cessation.

Endoscopic ultrasound-guided tissue acquisition (EUS-TA) by either fine needle aspiration (FNA) or fine needle biopsy (FNB) has become a useful tool in the diagnosis and staging of gastrointestinal malignancies. Besides the utility of EUS as an alternative for locoregional staging in gastric cancer, EUS-TA can be a helpful modality to achieve a histologic diagnosis when mucosal biopsies are indeterminate for malignancy. The aim of this study is to evaluate the diagnostic yield of EUS-TA in patients with suspected gastric malignancy.

PCD that was managed expectantly.Compared with patients that received other PBT, patients that received carboplatin had higher incidence of diarrhea (P=0.002) and restarted PBT more frequently (P=0.037) with more PCD recurrence (P=0.046)(Table 1).Colonic perforation occurred more frequently with oxaliplatin and cisplatin compared to carboplatin (P=0.050).The duration of PCD symptoms was numerically higher in patients receiving carboplatin and cisplatin as opposed to oxaliplatin (median, 30 days and 25 days vs. 7 days, respectively; P=0.182).Conclusion: PCD is rare, but in a small subset of patients, can lead to dreadful complications requiring surgical intervention.Resumption of PBT after PCD results in mild PCD recurrence in 25% of patients.

2616 Background: A deep understanding of the immunobiology of checkpoint inhibitor (CPI) induced immune related toxicities, such as immune related enterocolitis (irEC), and how these compare to the immune signatures in tumors could lead to the development of strategies that de-couple autoimmunity from anti-tumor immunity. Methods: Total RNA from patient-matched irEC and normal colon FFPE tissue from patients [n = 12] receiving CPIs were profiled with the 770 gene NanoString nCounter PanCancer Immune Profiling Panel (NanoPCIP). The mean fold change in gene expression from normal vs. irEC inflamed colonic tissue and baseline vs. on-treatment tumor samples from patients responding or non-responding to ipilimumab based therapy were analyzed. C57BL/6 mice with B16.BL6 melanoma tumors were treated with systemic anti-IL-6 + anti-CTLA-4 vs. anti-CTLA4 alone vs. placebo and tumor size was measured. Results: In patients with irEC, the highest significantly upregulated differentially expressed gene (DEG) in inflamed colon tissue encoded for IL-6 (Fold change +24.1). None of the significant and highest upregulated DEGs in the colitis, including IL-6, were significantly upregulated in responding tumors. Interestingly, IL-6 was also the highest upregulated DEG in non-responding tumors numerically. When comparing mean fold changes across these analyses, the gene with the largest difference in upregulatation between colitis and responding tumors was IL-6; the other highest upregulated genes in colitis encoded for neutrophil and monocyte chemotactic molecules. In our mouse models, the addition of IL-6 blockade to anti-CTLA-4 therapy significantly improved tumor shrinkage compared to anti-CTLA-4 alone. Conclusions: Our data demonstrates that IL-6-mediated inflammation may be more prevalent in irEC and tumors not responding to CPIs than in tumors responding, and blocking IL-6 enhances CPI anti-melanoma activity. Targeting IL-6 may ameliorate irEC without hindering anti-tumor immunity.

Fecal microbiota transplantation (FMT) represents a promising management modality for Clostridium difficile infection (CDI). In immunocompromised patients, FMT is utilized for CDI as well as emerging non-CDI indications such as inflammatory bowel disease and graft versus host disease. This review aims to shed light on the safety and efficacy of FMT in immunocompromised patients, including patients suffering for human immunodeficiency virus infection, solid organ and hematopoietic stem cell transplant recipients, cancer patients, and patients on immunosuppressive therapies. Though the body of evidence concerning the use of FMT in immunocompromised is growing, no clinical trials exist to date. Present literature weighs in favor of FMT in immunocompromised patients, with an acceptable adverse effect profile and minimal risk of infectious adverse events. Further large scale studies and randomized controlled trials to validate the utility of FMT in immunocompromised individuals will be a welcomed endeavor.