Evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for hormone receptor-positive metastatic breast cancer: a pooled analysis from the LEA (GEICAM/2006-11_GBG51) and CALGB 40503 (Alliance) trials

Abstract

Background: Randomised trials comparing the efficacy of standard endocrine therapy (ET) versus experimental ET + bevacizumab (Bev) in 1st line hormone receptor-positive patients with metastatic breast cancer have thus far shown conflicting results.

Patients and methods: We pooled data from two similar phase III randomised trials of ET ± Bev (LEA and Cancer and Leukemia Group B 40503) to increase precision in estimating treatment effect. Primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety. Exploratory analyses were performed within subgroups defined by patients with recurrent disease, de novo disease, prior endocrine sensitivity or resistance and reported grades III-IV hypertension and proteinuria.

Results: The pooled sample consisted of 749 patients randomised to ET or ET + Bev. Median PFS was 14.3 months for ET versus 19 months for ET + Bev (unadjusted hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.66-0.91; p < 0.01). ORR and CBR with ET and ET + Bev were 40 versus 61% (p < 0.01) and 64 versus 77% (p < 0.01), respectively. There was no difference in OS (HR 0.96; 95% CI 0.77-1.18; p = 0.68). PFS was superior for ET + Bev for endocrine-sensitive patients (HR 0.68; 95% CI 0.53-0.89; p = 0.004). Grade III-IV hypertension (2.2 versus 20.1%), proteinuria (0 versus 9.3%), cardiovascular (0.5 versus 4.2%) and liver events (0 versus 2.9%) were significantly higher for ET + Bev (all p < 0.01). Hypertension and proteinuria were not predictors of efficacy (interaction test p = 0.33).

Conclusion: The addition of Bev to ET increased PFS overall and in endocrine-sensitive patients but not OS at the expense of significant additional toxicity.

Trials registration: ClinicalTrial.Gov NCT00545077 and NCT00601900.

Keywords: Advanced breast cancer; Bevacizumab; Endocrine therapy; Pooled-analysis.

Conflict of interest statement

Conflict of interest statement

All remaining authors have declared no conflicts of interest.

I confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. I further confirm that any aspect of the work covered in this manuscript that has involved human patients has been conducted with the ethical approval of all relevant bodies. Me, as the Corresponding Author I am the sole contact for the Editorial process and the responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs.

Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1.. Progression-free Survival

Abbreviations: ET, Endocrine Therapy; ET+Bev, Endocrine Therapy + bevacizumab; PFS, progression-free survival.

Figure 2.. Forest plot of subgroup analysis for progression-free survival

Abbreviations: ET, Endocrine Therapy; ET+Bev, Endocrine Therapy + bevacizumab; HR, hazard ratio; DFI, disease-free interval.