Combining antivascular endothelial growth factor and anti-epidermal growth factor receptor antibodies: randomized phase II study of irinotecan and cetuximab with/without ramucirumab in second-line colorectal cancer (ECOG-ACRIN E7208)

J Natl Cancer Inst. 2024 Sep 1;116(9):1487-1494. doi: 10.1093/jnci/djae114.

Abstract

Background: Early studies showed promise of combined anti-epidermal growth factor receptor (EGFR) plus anti-vascular endothelial growth factor (VEGF) antibodies for advanced colorectal cancer (CRC), yet this was later rejected as toxic and ineffective in studies not selected for RAS status. We studied advanced KRAS wild-type CRC, as second-line treatment, using irinotecan-cetuximab with or without the anti-VEGF receptor antibody ramucirumab.

Methods: Patients with 1 prior regimen including fluoropyrimidine, oxaliplatin, and bevacizumab, with KRAS wild-type tumors were stratified by Eastern Cooperative Oncology Group Performance Score, time since last chemotherapy, and progression on oxaliplatin to irinotecan-cetuximab (IC) (180 mg/m2 and 500 mg/m2 every 2 weeks) vs modified ICR (irinotecan-cetuximab with ramucirumab 150 mg/m2 and 400 mg/m2 plus 6 mg/kg, respectively). A total of 102 patients were compared for progression-free survival (PFS) as primary endpoint (85% power for 70% improvement in median PFS from 4.5 to 7.65 months).

Results: Of the 102 enrolled, 44 treated with irinotecan-cetuximab and 45 with modified ramucirumab were evaluable. Median PFS was 6.0 months vs 9.2 months, respectively (hazard ratio = 0.75, P = .07; statistically significant by study design for P < .128). Response rate was 23% vs 36% (P = .27), and disease-control rate was 52% vs 73% (P = .05). Grade 3 or higher toxicity was equivalent. Overall survival was not significantly different at approximately 19 months.

Conclusion: Previous phase 3 trials without RAS genotyping rejected combining anti-epidermal growth factor receptor and anti-VEGF drugs. In this randomized multicenter phase 2 study for KRAS wild-type CRC (all previously bevacizumab treated), the addition of ramucirumab to irinotecan and cetuximab improved PFS and disease control rate, showing the combination is feasible and effective. Further, phase 3 trials with appropriate patient-selection are required. (NCT01079780).

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized* / administration & dosage
  • Antibodies, Monoclonal, Humanized* / adverse effects
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Cetuximab* / administration & dosage
  • Cetuximab* / adverse effects
  • Cetuximab* / therapeutic use
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / pathology
  • ErbB Receptors* / antagonists & inhibitors
  • ErbB Receptors* / genetics
  • Female
  • Humans
  • Irinotecan* / administration & dosage
  • Irinotecan* / therapeutic use
  • Male
  • Middle Aged
  • Progression-Free Survival
  • Ramucirumab*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors

Substances

  • Ramucirumab
  • Irinotecan
  • Antibodies, Monoclonal, Humanized
  • Cetuximab
  • ErbB Receptors
  • Vascular Endothelial Growth Factor A
  • EGFR protein, human

Associated data

  • ClinicalTrials.gov/NCT01079780