Balaguer, Francesc

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 .

BACKGROUND: Colectomy and proctocolectomy are the initial standard of care for patients with familial adenomatous polyposis. Pharmacotherapy to prevent the progression of polyposis and surgeries in the lower GI tract would be beneficial to patients with this disease. OBJECTIVE: This analysis aimed to evaluate the impact of eflornithine-sulindac combination versus monotherapy in delaying time to disease progression in the lower GI tract of patients with familial adenomatous polyposis. DESIGN: This is a post hoc analysis of a randomized phase 3 trial. SETTING: This study was conducted in 21 hospitals in 7 countries treating patients with familial adenomatous polyposis. PATIENTS: Adults with familial adenomatous polyposis were randomly assigned 1:1:1 into 3 arms. INTERVENTIONS: Patients received either eflornithine (750 mg), sulindac (150 mg), or both once daily for up to 48 months. MAIN OUTCOME MEASURES: Efficacy was evaluated as the time from randomization to predefined primary disease progression end points. RESULTS: A total of 158 patients were included in the study. Disease progression was observed in 2 of 54 (3.7%), 9 of 53 (17.0%), and 10 of 51 (19.6%) patients with at least partial lower GI tract in the combination, sulindac, and eflornithine arms, corresponding to risk reductions of 80% (p = 0.02) and 83% (p = 0.01) between combination and sulindac or eflornithine. When endoscopic excision of adenomas ≥10 mm in size was censored, the need for major surgery was observed in 0 of 54, 7 of 53 (13.2%), and 8 of 51 (15.7%) patients in the combination, sulindac, and eflornithine arms, corresponding to risk reductions approaching 100% between combination and sulindac (p = 0.005) or combination and eflornithine (p = 0.003). LIMITATIONS: This was a post hoc analysis, the sample size was small, and there were fewer than expected events. CONCLUSIONS: Eflornithine-sulindac combination therapy was superior to either drug alone in delaying or preventing the need for lower GI tract surgery in patients with familial adenomatous polyposis. See Video Abstract at http://links.lww.com/DCR/B658. REGISTRATION: ClinicalTrials.gov, NCT01483144; EU Clinical Trials Register, EudraCT 2012-000427-41 LA COMBINACIÓN DE SULINDAC Y EFLORNITINA RETRASA LA NECESIDAD DE CIRUGÍA DEL TUBO DIGESTIVO BAJO EN PACIENTES CON PAF: ANÁLISIS POST-HOC DE UN ENSAYO CLÍNICO ALEATORIZADO ANTECEDENTES: La colectomía y la proctocolectomía son el estándar inicial de atención para los pacientes con poliposis adenomatosa familiar. La farmacoterapia para prevenir la progresión de la poliposis y las cirugías en el tracto gastrointestinal inferior sería beneficiosa para los pacientes con esta enfermedad. OBJETIVO: Este análisis tuvo como objetivo evaluar el impacto de la combinación de eflornitina-sulindac versus la monoterapia en el retraso del tiempo hasta la progresión de la enfermedad en el tracto gastrointestinal inferior de pacientes con poliposis adenomatosa familiar. DISEÑO: Este es un análisis posthoc de un ensayo de fase 3 aleatorizado. ENTORNO CLINICO: Veintiún hospitales en 7 países que tratan a pacientes con poliposis adenomatosa familiar. PACIENTES: Adultos con poliposis adenomatosa familiar fueron aleatorizados 1: 1: 1 en 3 brazos. INTERVENCIONES: Los pacientes recibieron eflornitina (750 mg), sulindac (150 mg) o ambos una vez al día durante un máximo de 48 meses. PRINCIPALES MEDIDAS DE VALORACION: La eficacia se evaluó como el tiempo desde la aleatorización hasta los criterios de valoración primarios predefinidos de progresión de la enfermedad. RESULTADOS: Los resultados se informan para la población de estudio excluyendo a los pacientes que se habían sometido a ileostomías permanentes (n = 158). Se observó progresión de la enfermedad en 2/54 (3,7%), 9/53 (17,0%) y 10/51 (19,6%) pacientes con al menos tracto gastrointestinal inferior parcial en los brazos de combinación, sulindac y eflornitina, respectivamente, correspondientes al riesgo de reducciones del 80% (p = 0,02) y del 83% (p = 0,01) entre la combinación y el sulindaco o la eflornitina, respectivamente. Cuando se censuró la escisión endoscópica de adenomas ≥10 mm de tamaño, se observó la necesidad de cirugía mayor en 0/54, 7/53 (13,2%) y 8/51 (15,7%) pacientes en la combinación, sulindac y eflornitina, respectivamente, correspondientes a reducciones de riesgo cercanas al 100% entre combinación y sulindac (p = 0,005) o combinación y eflornitina (p = 0,003). LIMITACIONES: Este fue un análisis posthoc, el tamaño de la muestra fue pequeño y hubo menos eventos de los esperados. CONCLUSIONES: La terapia de combinación de eflornitina-sulindac fue superior a cualquier fármaco solo para retrasar o prevenir la necesidad de cirugía del tracto gastrointestinal inferior en pacientes con poliposis adenomatosa familiar. Consulte Video Resumen en http://links.lww.com/DCR/B658.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.