title: A VELOUR post hoc subset analysis: prognostic groups and treatment outcomes in patients with metastatic colorectal cancer treated with aflibercept and FOLFIRI.
abstract: BACKGROUND
  The VELOUR study demonstrated a survival benefit for FOLFIRI + aflibercept versus FOLFIRI + placebo in metastatic colorectal cancer (mCRC) patients who progressed on oxaliplatin-based chemotherapy. Continued divergence of overall survival (OS) curves in the intension to treat (ITT) population, with the survival advantage persisting beyond median survival time, suggested subpopulations might have different magnitudes of survival gain. Additionally, 10% of patients within VELOUR had recurrence during or within 6 months of completing oxaliplatin-based adjuvant therapy (adjuvant fast relapsers)--previously identified as having poorer survival outcomes.
  
  
  METHODS
  To determine which patients received the greatest benefit from FOLFIRI-aflibercept, a post hoc multivariate analysis of the VELOUR ITT population was conducted. Prognostic factors identified were applied to the ITT population, excluding adjuvant fast relapsers, to derive OS prognostic profiles.
  
  
  RESULTS
  The better efficacy subgroup was identified as patients within VELOUR exclusive of adjuvant fast relapsers and had performance status (PS) 0 with any number of metastatic site or PS 1 with <2 metastatic site. A significant improvement in efficacy outcome was observed with aflibercept in the better efficacy subgroup. Median OS for FOLFIRI-aflibercept and FOLFIRI-placebo:16.2 and 13.1 months (adjusted Hazard Ratio [HR] = 0.73; 95% confidence interval [CI]: 0.61-0.86); median progression free survival (PFS): 7.2 and 4.8 months (adjusted HR = 0.68; 95% CI: 0.57-0.80); and objective response rate (ORR): 24% versus 11% respectively. Poorer efficacy subgroup comprised of adjuvant fast relapsers or patients with PS2 or PS1 with ≥ 2 metastatic sites. In poorer efficacy subgroup, no benefit was seen with aflibercept. Median OS for FOLFIRI-aflibercept and FOLFIRI-placebo: 10.4 and 9.6 months (adjusted HR = 0.97; 95% CI: 0.78-1.21) respectively with no improvement in PFS or ORR.
  
  
  CONCLUSIONS
  This analysis suggests that within VELOUR, patients in the better efficacy subgroup may derive enhanced benefit from treatment with FOLFIRI-aflibercept. These prognostic criteria may guide practitioners toward optimal use of targeted biologicals in appropriate second-line mCRC patients.
authors.affiliation: Department of Medicine, Royal Marsden Hospital, London and Surrey, UK. ian.chau@rmh.nhs.uk.
authors.forename: Ian
authors.initials: I
authors.lastname: Chau
authors.forename: Florence
authors.initials: F
authors.lastname: Joulain
authors.forename: Sheikh Usman
authors.initials: SU
authors.lastname: Iqbal
authors.forename: John
authors.initials: J
authors.lastname: Bridgewater
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000009:adverse effects / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin