Byeon, Jeong‐Sik

ObjectivesThere have been significant advances in the management of large (≥20 mm) laterally spreading tumors (LSTs) or nonpedunculated colorectal polyps; however, there is a lack of clear consensus on the management of these lesions with significant geographic variability especially between Eastern and Western paradigms. We aimed to provide an international consensus to better guide management and attempt to homogenize practices.MethodsTwo experts in interventional endoscopy spearheaded an evidence‐based Delphi study on behalf of the World Endoscopy Organization Colorectal Cancer Screening Committee. A steering committee comprising six members devised 51 statements, and 43 experts from 18 countries on six continents participated in a three‐round voting process. The Grading of Recommendations, Assessment, Development and Evaluations tool was used to assess evidence quality and recommendation strength. Consensus was defined as ≥80% agreement (strongly agree or agree) on a 5‐point Likert scale.ResultsForty‐two statements reached consensus after three rounds of voting. Recommendations included: three statements on training and competency; 10 statements on preresection evaluation, including optical diagnosis, classification, and staging of LSTs; 14 statements on endoscopic resection indications and technique, including statements on en bloc and piecemeal resection decision‐making; seven statements on postresection evaluation; and eight statements on postresection care.ConclusionsAn international expert consensus based on the current available evidence has been developed to guide the evaluation, resection, and follow‐up of LSTs. This may provide guiding principles for the global management of these lesions and standardize current practices.

10514 Background: FAP is the most common hereditary adenomatous polyposis syndrome and, if left untreated, will lead to colorectal cancer development in nearly all patients. Chronic inflammation, driven in part by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, may promote polyp formation. Enteric-selective inhibition of the JAK/STAT pathway may provide a treatment for FAP. Lorpucitinib is an oral, small molecule, potent pan-JAK inhibitor with favorable enteric-selective properties. Here, we report the efficacy, safety, and pharmacokinetic (PK) results from a phase 1b study of lorpucitinib in patients with FAP (NCT05014360). Methods: Patients aged ≥18 years with ≥6 polyps ≥2 mm in diameter in the rectum or colon with FAP ( APC germline mutation or obligate carrier) received lorpucitinib 75 mg twice daily for 24 weeks. The primary objective was to evaluate the effect of lorpucitinib on colorectal polyp burden at Week 24, assessed by endoscopy at baseline and Week 24. Secondary objectives were safety, PK, and biomarker assessments of lorpucitinib activity. Results: Overall, 42 (23 pre-colectomy; 19 post-colectomy) patients with FAP were enrolled, with a median age of 33 (range, 19-61) years. No clear effect on polyp burden was observed at Week 24. Gut mucosal and polyp concentrations of lorpucitinib were much higher than plasma concentrations, indicating an enteric-selective distribution. Mean sigmoid colon, rectum, and polyp concentrations of lorpucitinib at Week 8 were 112-, 473-, and 108-fold higher, respectively, than the observed maximum plasma concentration at Week 8 (1 hour). At Week 8, lorpucitinib achieved JAK tyrosine kinase inhibition in mucosal biopsies as evidenced by a median 37% reduction in normalized pSTAT-3 levels. Lorpucitinib reduced serum-based inflammatory biomarkers such as C-reactive protein and serum amyloid A by Week 16 of therapy. Some patients reported an improvement of clinical symptoms such as less frequent bowel movements and less blood in the stool. The most common adverse events (AEs) were abdominal pain (16%), bilirubin increased (13%), headache (13%), lipase increased (13%), and diarrhea (13%). There were no treatment-related serious AEs, grade 3 treatment-emergent AEs, serious infections, or venous thromboembolisms. Conclusions: These results show that lorpucitinib had no clear effect on polyp burden. The study found that lorpucitinib is safe and exhibits an enteric-selective distribution in FAP patients. Inhibition of JAK tyrosine kinase signaling was associated with reduced STAT-3 phosphorylation in mucosal biopsies from FAP patients. While reductions observed in polyp burden were not clinically significant, lorpucitinib treatment lowered levels of several serum inflammatory biomarkers. Treatment with lorpucitinib was safe and well tolerated, and may improve clinical symptoms associated with FAP. Clinical trial information: NCT05014360 .