TARGET-EU: Clinical benefit of bevacizumab in metastatic colorectal cancer

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Effectiveness study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Study drug International non-proprietary name (INN) or common name:
  BEVACIZUMAB
• Anatomical Therapeutic Chemical (ATC) code:
  (L01FG01) bevacizumab

  bevacizumab
• Medical condition to be studied:
  Colorectal cancer metastatic

Population studied

• Short description of the study population:
  The study population will consist of adults with metastatic colorectal cancer who initiate treatment with a regimen consisting of capecitabine and oxaliplatin (CapOx), either with or without bevacizumab, during the study period. Cohort entry (index date) will be defined as the date of treatment initiation (CapOx or CapOx-B).; ; To be eligible, individuals must:; * have histologically confirmed metastatic colorectal cancer (mCRC) ; * be aged 18 years or older at cohort entry. ; * have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of ≤ 1; * not have had prior systemic therapy for mCRC or previous treatment with bevacizumab and/ or oxaliplatin, ; * not have had radiotherapy or surgery for mCRC within 4 weeks prior to time 0.; ; No exclusion criteria will be applied. ;
• Age groups:
  • Adult and elderly population (≥18 years)

    • Adults (18 to < 65 years)

      • Adults (18 to < 46 years)
      • Adults (46 to < 65 years)
    • Elderly (≥ 65 years)

      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)

Study design details

• Study design:
  This study will emulate a hypothetical target trial using a retrospective, active-comparator, new-user cohort design based on routinely collected health records.
• Main study objective:
  The overall aim is to assess progression-free survival (PFS) in patients with mCRC when treated with CapOx-B compared with CapOx alone.
• Setting:
  This study is conducted using routinely collected electronic health records from 2021 to 2024, reflecting the period of bevacizumab use in routine clinical practice. The study is set in secondary care, drawing on longitudinal cancer registry data from the NCR. Data are sourced from the Netherlands, ; providing nation-wide, population-based and representative coverage of real-world clinical care.
• Comparators:
  The comparator group consists of patients who initiate the a regimen consisting of capecitabine and oxaliplatin (CapOx regimen).; ; The acceptance of bevacizumab in mCRC treatment landscape varies largely throughout the Netherlands, presumably due to differences in policy and attitude. ; ; The use of an active comparator is the most appropriate approach because it aligns with real-world clinical practice and helps to address confounding by indication. It allows for the effectiveness of bevacizumab addition (to the CapOx regimen) to be benchmarked against the CapOx regimen alone.
• Outcomes:
  The primary endpoint will be time to first occurrence of disease progression or death. In the NCR, disease progression is marked by the end of a so-called "episode". An “episode” is defined as the clinical trajectory of a patient up until disease progression.
• Data analysis plan:
  The analyses are conducted within a target trila emulation framework to estimate the effect of the CapOx-B regimen compared with the CapOx regimen on progression-free survival (PFS).; For Estimand 1, the main estimand supporting decision making, the primary causal effect summary measure is the hazard ratio for time to first disease progression or death, estimated using a (1:1 matched or inverse probability of treatment weighted (IPTW)) Cox proportional hazards model.; ; Sensitivity analyses will assess robustness of the primary findings to key assumptions, including inverse probability of censoring weighting (IPCW), tipping point analysis, and probabilistic bias analysis for non-differential outcome misclassification.; ; Two supplemental estimands are also defined: Estimand 2, applying a hypothetical and composite strategy for intercurrent events, and Estimand 3, estimating treatment effects using restricted mean survival time (RMST) derived from an IPTW-weighted Weibull accelerated failure time (AFT) model. In addition, supplemental analyses (e.g., crude and IPTW-adjusted Kaplan-Meier curves, crude Cox models, event counts and incidence rates, propensity score and weight distributions, covariate balance before and after weighting, censoring and intercurrent event patterns, proportional hazards diagnostics, positivity checks, and multiple-imputation diagnostics) will be conducted to support interpretation of the main analysis.
• Summary results:
  Not yet available