Abstract P5-08-18: Biomarker (BM) results from MERiDiAN, a double-blind placebo (PLA)-controlled randomized phase 3 trial of 1st-line paclitaxel (PAC) with or without bevacizumab (BEV) for HER2-negative metastatic breast cancer (mBC)
Authors: Das Thakur M , Bais C , Estay I , Vaidyanathan R , O'Shaughnessy J , Cameron D , Hubeaux S , Quah C , Miles D 
Published: May 2016

Abstract
Background: In the MERiDiAN trial, progression-free survival (PFS) was significantly improved with the addition of BEV to 1st-line PAC for mBC in both the ITT population and the subgroup with high baseline plasma (p) vascular endothelial growth factor (VEGF)-A, meeting both co-primary objectives. However, a predictive effect of pVEGF-A was not seen (PFS pVEGF-A-by-treatment interaction p=0.46; secondary endpoint). We report exploratory analyses of additional candidate BMs.
Methods: Patients (pts) with HER2-negative mBC previously untreated with chemotherapy for mBC were randomized to receive PAC (90 mg/m2, days 1, 8 & 15 q4w) combined with either PLA or BEV 10 mg/kg q2w until disease progression or unacceptable toxicity. Plasma, blood and archival tumor sampling was mandatory. The BM-evaluable population (BEP) comprised all ITT pts with a baseline sample for ≥1 BM. Prespecified exploratory BM analyses included: tumor (t) CD31 (marker of microvascular density) and tVEGF-A (molecular target of BEV) by immunohistochemistry; tPAM50 gene expression; and pVEGF receptor (R)-2 by ELISA. For CD31, tVEGF-A and pVEGFR-2 analyses, the BEP was dichotomized using the median of each BM as the cutoff between low and high subgroups. BEV effect on PFS was assessed within these subgroups (unstratified analyses). Similar subgroup analyses were done for each tPAM50 molecular subtype. No adjustment was made for multiplicity of testing as the analyses were exploratory.
Results: The BEP included 467 (97%) of the 481 randomized pts. There was no correlation between CD31, tVEGF-A and pVEGFR-2. Correlations between BMs and PFS are shown below. The hazard ratio (HR) point estimate for BEV effect was lower in luminal B (0.59) than luminal A (0.96) or other smaller tPAM50 subgroups, but 95% CIs overlapped. pVEGFR-2 showed borderline significance for predictive potential using the median (10.2 ng/mL) as the cutoff. In further exploratory analyses using the 1st quartile (Q1; 8.7 ng/mL) as the cutoff, the PFS HR was 1.19 (95% CI 0.75–1.89) in the low (≤Q1) subgroup vs 0.60 (95% CI 0.46–0.79) in the high (&gt;Q1) subgroup (interaction p=0.01).
BMSubgroupNo. of events/ptsMedian PFS, mosPFS HR (95% Wald CI)Interaction p-value PAC–PLAPAC–BEVPAC–PLAPAC–BEV tPAM50 (N=421)Luminal A65/10367/10610.911.20.96 (0.68-1.35)Not applicable Luminal B46/6332/569.011.00.59 (0.38-0.93) HER2 enriched8/119/105.58.30.88 (0.33-2.32) Basal like29/3727/355.68.50.67 (0.39-1.14) tCD31 (N=410)Low69/9969/1067.610.80.71 (0.51-0.99)0.40 High78/11164/949.211.00.87 (0.62-1.22) tVEGF-A (N=434)Low78/10777/1107.411.00.68 (0.49-0.93)0.23 High76/11165/1069.210.90.89 (0.64-1.24) pVEGFR-2 (N=436)Low70/10773/1119.210.60.90 (0.64-1.25)0.06 High83/10968/1097.912.20.58 (0.42-0.81)
Conclusions: Of the 4 candidate BMs explored here, potential predictive value was suggested only for pVEGFR-2. Correlations between pVEGFR-2 levels and outcome have been observed in previous retrospective analyses of breast cancer trials. However, similar levels in healthy donors and breast cancer pts, as well as the narrow dynamic range, may limit the utility of pVEGFR-2 as a potential predictive BM for BEV efficacy.
Citation Format: Das Thakur M, Bais C, Estay I, Vaidyanathan R, O'Shaughnessy J, Cameron D, Hubeaux S, Quah C, Miles D. Biomarker (BM) results from MERiDiAN, a double-blind placebo (PLA)-controlled randomized phase 3 trial of 1st-line paclitaxel (PAC) with or without bevacizumab (BEV) for HER2-negative metastatic breast cancer (mBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-18.