Vedolizumab, Adalimumab, and Methotrexate Combination Therapy in Crohn’s Disease (EXPLORER)

BACKGROUND & AIMS Although biologics have revolutionized treatment of Crohn's disease (CD), an efficacy ceiling has been reached. Combining biologic therapies may improve remission rates. METHODS EXPLORER, a phase 4, single-arm, open-label study, evaluated triple combination therapy with vedolizumab (300 mg on day 1, weeks 2 and 6, then every 8 weeks), adalimumab (160 mg on day 2, 80 mg at week 2, then 40 mg every 2 weeks), and methotrexate (15 mg weekly) in biologic-naïve patients with newly diagnosed, moderate- to high-risk CD. Endoscopic remission at week 26 (primary end point; Simple Endoscopic Score for Crohn's Disease [SES-CD] ≤2), clinical remission at weeks 10 and 26 (secondary end point; Crohn's Disease Activity Index [CDAI] <150), and incidences of adverse events and serious adverse events (SAEs) were evaluated. RESULTS Among 55 enrolled patients, mean CD duration was 0.4 years, mean baseline SES-CD was 12.6, and mean baseline CDAI was 265.5. At week 26, 19 patients (34.5%) were in endoscopic remission. At weeks 10 and 26, 34 (61.8%) and 30 patients (54.5%), respectively, were in clinical remission. Post hoc Bayesian analysis demonstrated that the probabilities that triple combination therapy produced a higher endoscopic remission rate (33.5%; 95% credible interval, 22.4–45.7) than placebo (14%), vedolizumab monotherapy (27%), or adalimumab monotherapy (30%) were ≥99.9%, 86.3%, and 71.4%, respectively. Six patients had SAEs. CONCLUSIONS Combination therapy resulted in endoscopic and clinical remission at week 26 in 34.5% and 54.5% of patients, respectively, with no safety signal related to the treatment regimen. This supports further evaluation of combination therapy in CD. ClinicalTrials.gov number: NCT02764762.