Abstract P3-06-08: Plasma (p) biomarker results from the TANIA trial evaluating continued or reintroduced bevacizumab (BEV) after 1st-line BEV for HER2-negative metastatic breast cancer (mBC)
Authors: Cortes Javier , Vrdoljak Eduard , Puglisi Fabio , Marschner Norbert , Gligorov Joseph , Zielinski Christoph , Villanueva Cristian , Romieu Gilles , Lang István , Ciruelos Eva , Veyret Corinne , Fontana Andrea , Oestergaard Mikkel , de Ducla Sabine , Freudensprung Ulrich , von Minckwitz Gunter 
Published: May 2015

Abstract
BACKGROUND: A potential predictive and prognostic effect of pretreatment pVEGF-A concentrations was suggested in exploratory analyses of phase III trials in HER2-negative mBC (AVADO), gastric cancer (AVAGAST), and pancreatic cancer (AViTA). This led to initiation of the MERiDiAN trial evaluating pVEGF-A prospectively in patients (pts) receiving 1st-line paclitaxel ± BEV in HER2-negative mBC. Potential predictive value was also noted for pVEGFR-2 in AVADO, AViTA, and in early BC in BEATRICE. We report prespecified pVEGF-A and pVEGFR-2 analyses in TANIA.
METHODS: TANIA is an open-label randomized phase III trial evaluating the addition of BEV (15 mg/kg q3w or 10 mg/kg q2w) to the investigator’s choice of chemotherapy (CT) in pts with HER2-negative mBC who experience disease progression (PD) on/after 1st-line BEV-containing therapy. Allocation to BEV or no BEV is continued with 3rd-line therapy after 2nd PD (ie no crossover permitted). The primary endpoint is PFS from randomization to 2nd-line PD/death. Pts consenting to the optional biomarker substudy provided 6 mL plasma samples in EDTA before drug administration at randomization, at wks 7 and 13, every 12 wks thereafter, and at 2nd PD. pVEGF-A and shedded pVEGFR-2 were measured using the IMPACT assay (v2.03). The median concentration for each marker before 2nd-line treatment was prespecified as the cut-off between low (≤ median) and high (&gt; median) biomarker subgroups. 2nd-line PFS was analyzed in each subgroup.
RESULTS: The PFS benefit from BEV seen in the ITT population (N=494; stratified hazard ratio [HR] 0.75, 95% CI 0.61–0.93) was observed consistently within subgroups of the biomarker population (N=312). However, there was no differential BEV effect according to pVEGF-A or shedded pVEGFR-2 concentrations. The stratified HR for PFS was 0.69 (95% CI 0.46–1.04) in pts with low pVEGF-A (≤1010.6 pg/mL [median]) and 0.80 (95% CI 0.54–1.18) in pts with high pVEGF-A (interaction p=0.47). As all pts had received prior BEV, unlike earlier trials showing a potential predictive effect of pVEGF-A, we explored pVEGF-A concentrations according to BEV-free interval. The BEV-free interval was ≤12 wks in 117/150 pts (78%) in the CT arm and 136/162 pts (84%) in the BEV+CT arm. Median pVEGF-A was much lower in the subgroup of 59 pts with a BEV-free interval &gt;12 wks (45.1 pg/mL) than in pts with a BEV-free interval ≤12 wks (1135.3 pg/mL). Analyses of 2nd-line PFS according to shedded pVEGFR-2 concentration showed stratified PFS HRs of 0.68 (95% CI 0.45–1.02) for low pVEGFR-2 (≤9.6 ng/mL [median]) and 0.90 (95% CI 0.60–1.34) for high pVEGFR-2 (interaction p=0.49).
CONCLUSIONS: The potential predictive effect of pVEGF-A in AVADO was not observed in TANIA, although high pVEGF-A concentrations in pts recently treated with BEV complicate interpretation. pVEGF-A is being evaluated prospectively in BEV-naïve pts in the ongoing MERiDiAN trial. Shedded pVEGFR-2 showed no predictive effect in TANIA and the suggested trend was in the opposite direction to the effect seen in AVADO and BEATRICE. Further analyses are planned to evaluate the impact of gene expression, cell-free DNA, protein expression, and DNA mutations on treatment effect in TANIA.
Citation Format: Javier Cortes, Eduard Vrdoljak, Fabio Puglisi, Norbert Marschner, Joseph Gligorov, Christoph Zielinski, Cristian Villanueva, Gilles Romieu, István Lang, Eva Ciruelos, Corinne Veyret, Andrea Fontana, Mikkel Oestergaard, Sabine de Ducla, Ulrich Freudensprung, Gunter von Minckwitz. Plasma (p) biomarker results from the TANIA trial evaluating continued or reintroduced bevacizumab (BEV) after 1st-line BEV for HER2-negative metastatic breast cancer (mBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-08.