Analysis of plasma biomarkers potentially associated with antiangiogenic resistance in NCIC CTG/AGITG CO.20: A phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy refractory, k-RAS wild-type (WT), metastatic colorectal carcinoma (mCRC).
Authors: Shapiro Jeremy David , Siu Lillian L. , O'Callaghan Christopher J , Zalcberg John Raymond , Moore Malcolm J. , Price Timothy Jay , Doyle Catherine , Simes John , Findlay Brian Peter , Cronk Michelle F. , Shaikh Asif , Joubert Warren Lance , Samson Benoit , Bonaventura Antonino , Underhill Craig , Wyld David , Walters Ian B. , Phillips Penny , Tu Dongsheng , Jonker Derek J. ,   NCIC CTG AND AGITG
Published: March 2020

3572 Notice of Retraction: "Analysis of plasma biomarkers potentially associated with antiangiogenic resistance in NCIC CTG/AGITG CO.20: A phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy refractory, k-RAS wild-type (WT), metastatic colorectal carcinoma (mCRC)." Abstract 3572, published in the 2012 Annual Meeting Proceedings Part I, a supplement to the Journal of Clinical Oncology, has been retracted by Jeremy Shapiro, MBBS, and Lillian Siu, MD, on behalf of the NCIC, AGITG, and all authors of the abstract. The authors have been unable to finalize their data presentation due to the complexity of the analysis, and difficulties with the statistical interpretation of the significance of several possible predictive biomarkers. Background: In the CO.20 trial, the addition of BRIV, a tyrosine kinase inhibitor targeting vascular endothelial and fibroblast growth factor receptors (VEGFR2,3 and FGFR 1,2,3), to CET, increased objective response rate and progression free survival, but did not significantly increase overall survival. Previous clinical studies demonstrated modulation of circulating angiogenic factors (CAF) in CRC which occur on therapy or upon progression (Kopetz JCO 2010). Methods: CO.20 pts were randomized 1:1 to CET plus either BRIV (Arm A) or placebo (ARM B) in a double-blind design. Pts may have had 1 prior anti-VEGF based therapy, but no prior anti-EGFR therapy. Primary endpoint was overall survival (OS). Baseline pre-treatment plasma samples were analyzed using commercial Multi-Analyte ELISAs to measure CAF, immunologic, and growth factors, with an initial discovery and subsequent validation data set. Results: 750 pts were randomized (376 in Arm A and 374 in Arm B). Median OS in the intent-to-treat population was 8.8 months in Arm A and 8.1 months in Arm B, hazard ratio (HR)=0.88; 95%CI=0.74-1.03; p=0.12. In an exploratory subgroup analysis, there is a statistically non-significant trend favoring the effect of brivanib on OS among the 41% pts who received prior anti-VEGF therapy versus those who did not.Baseline plasma samples were collected from 96% of pts, and analysis is ongoing. Results of the largest circulating biomarker analysis will be presented. CAF results will be compared with response and survival data to look for potential patient subgroups that may benefit more from the combination treatment. Conclusions: This large scale analysis will provide insights on the potential use of CAF or CAF profiles as predictive markers in CRC.