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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1487-1494 |
| Number of pages | 8 |
| Journal | Journal of the National Cancer Institute |
| Volume | 116 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2024 |
Funding
The study was designed and approved by the relevant ECOG-ACRIN and National Cancer Institute (NCI) Cancer Therapy Evaluation Program committees and the US Food and Drug Administration. The study was approved by the NCI Central Institutional Review Board and institutional review boards as required for all sites. Drug supply for ramucirumab was provided by the manufacturer Eli Lilly through the NCI Cooperative Research and Development Agreements program. Drug was supplied for ramucirumab arms from NCI Pharmaceutical Management Branch, and commercial sources were used for irinotecan and cetuximab. This study was coordinated by the ECOG-ACRIN Cancer Research Group (Peter J. O\u2019Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under award numbers: U10CA180820, U10CA180794, U10CA180888, UG1CA233320, UG1CA233302, UG1CA233337, UG1CA189830, UG1CA180830, UG1CA233341 P30CA014089, and P30CA072720. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Previously presented at ASCO Annual meeting, June 2018.
ASJC Scopus subject areas
- Oncology
- Cancer Research
