In the TANIA trial (NCT01250379), adding BEV to 2nd-line chemotherapy (CT) significantly improved 2nd-line progression-free survival (PFS, primary endpoint; hazard ratio [HR] 0.75, 95% CI 0.61–0.93; p = 0.0068) in BEV-pretreated LR/mBC. No difference in 3rd-line PFS or overall survival (OS) was observed. Post hoc analyses explored potential associations between 6 candidate BMs (based on previous results/biological hypotheses) and 2nd-line PFS and OS.
Patients (pts) with BEV-pretreated HER2-negative LR/mBC were randomised to receive 2nd-line CT ± BEV until disease progression (PD), unacceptable toxicity or withdrawal. At 2nd PD, 3rd-line CT was given without BEV in the CT arm and with BEV in the BEV + CT arm. Archival primary or metastatic tumour samples collected before 2nd-line BEV from pts consenting to optional translational research were analysed by immunohistochemistry using median expression levels for each BM as the cut-off for high vs low BM subgroups.
Samples (mainly primary tumour) were available from 210 (43%) of 494 randomised pts. Baseline characteristics and efficacy in these pts were broadly representative of the ITT population. High CA9 and CD31 were associated with worse prognosis but larger BEV benefit, although neither was consistently predictive across endpoints (table). Pts with high CA9 had median PFS of 4.6 vs 1.9 mo with BEV + CT vs CT, respectively; pts with high CD31 had median OS of 19.3 vs 13.0 mo, respectively. No BM was associated with a detrimental BEV effect.
|BM||2nd-line PFS HR (95% CI)||Interaction p-valuea||OS HR (95% CI)||Interaction p-valuea|
|CD31 No. of vessels||1.02 (0.68–1.55)||0.60 (0.39–0.93)||0.110||1.42 (0.88–2.27)||0.60 (0.37–0.99)||0.016|
|CD31 volume fraction||0.85 (0.57–1.29)||0.74 (0.48–1.15)||0.585||1.20 (0.74–1.95)||0.75 (0.47–1.22)||0.179|
|tVEGF-A||1.10 (0.73–1.65)||0.63 (0.41–0.95)||0.091||0.99 (0.63–1.55)||0.86 (0.53–1.38)||0.626|
|CA9 cytoplasm H-score||0.92 (0.64–1.30)||0.49 (0.30–0.81)||0.064||0.93 (0.62–1.39)||0.93 (0.54–1.60)||0.878|
|CA9 membrane H-score||0.90 (0.65–1.27)||0.41 (0.23–0.74)||0.017||0.99 (0.67–1.47)||0.70 (0.38–1.27)||0.258|
|PD-L1 immune cell||0.84 (0.59–1.19)||0.61 (0.36–1.04)||0.357||1.01 (0.68–1.51)||0.68 (0.37–1.26)||0.196|
|PD-L1 tumour cell||0.79 (0.58–1.06)||0.96 (0.17–5.38)||0.795||0.92 (0.65–1.29)||0.36 (0.04–3.16)||0.469|
|CD8 invasive margin||0.77 (0.44–1.33)||1.07 (0.63–1.83)||0.357||0.87 (0.46–1.65)||1.35 (0.73–2.48)||0.313|
|CD8 tumour centre||0.61 (0.40–0.93)||0.97 (0.63–1.49)||0.155||0.87 (0.55–1.37)||1.00 (0.62–1.63)||0.711|
|CD163 invasive margin||1.00 (0.55–1.80)||0.96 (0.56–1.64)||0.891||0.76 (0.40–1.44)||1.65 (0.87–3.14)||0.094|
|CD163 tumour centre||1.09 (0.71–1.67)||0.71 (0.47–1.06)||0.262||0.91 (0.57–1.45)||0.93 (0.58–1.48)||0.886|
aNot adjusted for multiplicity. CA9 = carbonic anhydrase 9; PD-L1 = programmed cell death 1 ligand 1; tVEGF-A = tumour vascular endothelial growth factor-A.
Continued BEV significantly improved 2nd-line PFS irrespective of BM levels in LR/mBC. Exploratory analyses suggested potential predictive effects of CA9 (PFS) and CD31 (OS), suggesting involvement of tumour and endothelium characteristics in the therapeutic concept of anti-angiogenesis.
Clinical trial identification
Legal entity responsible for the study
F Hoffmann-La Roche
F Hoffmann La Roche
C. Zielinski: Honoraria (Advisory Boards): Roche J. Gligorov: Consultant for Roche/Genentech and Eisai and honoraria from Novartis/GlaxoSmithKline, Genomic Health and Teva. N. Marschner: Honoraria Roche for consultancy and advisory boards, as well as grants for scientific projects. F. Puglisi: Honoraria from AstraZeneca, Amgen, Celgene, Ipsen, Novartis, Pierre Fabre and Roche. E. Vrdoljak: Funding for clinical trials from Roche and Pfizer, and consulting honoraria from Bayer, AstraZeneca, Amgen, Merck, MSD, GlaxoSmithKline, Novartis, Pfizer and Roche. J. Cortes Castan: Consultancy fees from Roche, Celgene and AstraZeneca, and honoraria from Roche, Celgene, Novartis and Eisai. S. de Ducla, R. Deurloo: Employee of Roche and holds shares in Roche. V. Easton: Employee of Stamford Consultants AG contracted to Roche. G. von Minckwitz: Institution received research funds from Pfizer, GSK, Sanofi-Aventis, Amgen, Roche, Novartis, Celgene, Teva, Boehringer-Ingelheim, AstraZeneca and Myriad Genetics.