A Clinical Decision Support Tool May Help to Optimise Vedolizumab Therapy in Crohn's Disease

Parambir S. Dulai; Aurelien Amiot; Laurent Peyrin-Biroulet; Vipul Jairath; Melanie Serrero; Jerome Filippi; Siddharth Singh; Benjamin Pariente; Edward V. Loftus Jr; Xavier Roblin; Sunanda Kane; Anthony Buisson; Corey A. Siegel; Yoram Bouhnik; William J. Sandborn; Karen Lasch; Maria Rosario; Brian G. Feagan; Daniela Bojic; Caroline Trang-Poisson; Bo Shen; Romain Altwegg; Bruce E. Sands; Jean-Frederic Colombel; Franck Carbonnel

Disclosures

Aliment Pharmacol Ther. 2020;51(5):553-564. 

In This Article

Abstract and Introduction

Abstract

Background: A clinical decision support tool (CDST) has been validated for predicting treatment effectiveness of vedolizumab (VDZ) in Crohn's disease.

Aim: To assess the utility of this CDST for predicting exposure-efficacy and disease outcomes.

Methods: Using data from three independent datasets (GEMINI, GETAID and VICTORY), we assessed clinical remission rates and measured VDZ exposure, rapidity of onset of action, response to dose optimisation and progression to surgery by CDST-defined response groups (low, intermediate and high).

Results: A linear relationship existed between CDST-defined groups, measured VDZ exposure, rapidity of onset of action and efficacy in GEMINI through week 52 (P < 0.001 at all time points across three CDST-defined groups). In GETAID, CDST predicted differences in clinical remission at week 14 (AUC = 0.68) and rapidity of onset of action (P = 0.04) between probability groups. The high-probability patients did not benefit from shortening of infusion intervals, and differences in onset of action between the high-intermediate and low-probability groups within GETAID were no longer significant when including low-probability patients who received a week 10 infusion. CDST predicted a twofold increase in surgery risk over 12 months of VDZ therapy among low- to intermediate-probability vs high-probability patients (adjusted HR 2.06, 95% CI 1.33–3.21).

Conclusions: We further extended the clinical utility of a previously validated VDZ CDST, which accurately predicts at baseline exposure-efficacy relationships and rapidity of onset of action and could be used to help identify patients who would most benefit from interval shortening and those most likely to require surgery while on active therapy.

Introduction

In the GEMINI 2 pivotal phase 3 clinical trial of vedolizumab (VDZ) for Crohn's disease (CD), approximately one-third of patients with active CD achieved corticosteroid-free remission at week 52.[1] Similar results were recently reported in a meta-analysis of observational studies with an estimated 1 year corticosteroid-free remission rate of 31% (95% confidence interval [CI] 20–45%).[2,3] These data underscore that while a substantial proportion of treatment-resistant patients respond to VDZ therapy, the majority do not. Although this circumstance is likely multifactorial, variability in VDZ pharmacokinetics (PK) is a potential explanation in some patients. Specifically, high drug clearance resulting in inadequate drug exposure may be responsible for suboptimal results in some.

Multiple studies in patients with active CD have shown a correlation between VDZ exposure and response, and higher clinical and endoscopic remission rates when stratified by drug exposure.[4–10] These findings hold out the possibility that dose intensification in patients with low VDZ trough concentrations during induction may result in higher remission rates. In support of this notion, observational data suggest that empiric administration of an additional drug dose in patients with suboptimal response to induction may improve outcomes.[11] It is also relevant to note that a perception exists that VDZ induction therapy has a slower onset of action and is generally less effective in CD than in ulcerative colitis (UC). Notwithstanding that prior exposure to a TNF antagonist has been consistently associated with low response and remission rates,[12] no single clinical factor accurately predicts which patients will respond quickly to VDZ therapy or will benefit from therapeutic drug monitoring and/or dose intensification. Accurate identification of these patients could allow a personalised medicine approach to induction therapy and greater treatment efficiency.

The VICTORY consortium investigators previously developed and validated a clinical decision support tool (CDST) that classifies CD patients according to low, intermediate and high probability of response to VDZ.[13] In the current analysis, we used the GEMINI 2 clinical trial data (NCT00783692) to assess whether these differences were related to differences in measured VDZ concentrations (exposure-efficacy) and whether the CDST predicts differences in rapidity of onset of action. We subsequently performed a second external validation of the CDST based on data from a prospective cohort study (GETAID) and then, using data from both the GETAID and VICTORY cohorts, assessed whether the CDST accurately identified patients who might benefit from dose intensification. Finally, we evaluated whether the CDST estimated the likelihood of surgery for CD while on VDZ, which is of importance when determining the incremental value of aggressive treatment-monitoring approaches.

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