Abstract P4-15-12: Results from a randomized phase II study of the Dutch Breast Cancer Research Group (BOOG 2008-03): Concomitant trastuzumab, bevacizumab and paclitaxel (HAT) versus trastuzumab and bevacizumab, followed by trastuzumab, bevacizumab and paclitaxel (HA-HAT) a
Authors: Drooger Jan C , van Tinteren Harm , de Groot Steffen M , ten Tije Albert J , de Graaf Hiltje , Portielje Johanneke EA , Jager Agnes , Honkoop Aafke H , Linn Sabine C , Kroep Judith R , Erdkamp Frans LG , Hamberg Paul , Heijns Joan B , van Leeuwen-Stok A Elise , Sleijfer Stefan 
Published: May 2015

Abstract
Background
Until recently, trastuzumab (H) combined with a taxane was standard first line systemic therapy for patients with Her2 positive metastatic breast cancer (MBC) who are not candidates for endocrine therapy. Clinical studies have shown that bevacizumab (A) enhances the activity of weekly paclitaxel (T), while preclinical data suggest that A can also augment anti-tumor activity of H. Here we report outcome data of a randomized phase II study in Her2 positive MBC on the combination of HAT versus sequential treatment starting with a chemotherapy-free approach with H and A (HA), followed by adding T at progression (HA-HAT).
Methods
Patients with Her2 positive MBC, eligible for first-line systemic therapy, were randomized (1:1) between HAT (3-weekly H 6 mg/kg (first dose 8/mg/kg) plus A 15 mg/kg both until progression and T 90mg/m2, day 1,8,15 every 4 weeks for a maximum of 6 cycles) and HA-HAT (doses HA were the same as in HAT with T for a maximum of 6 cycles added to HA at progression). Primary endpoint was progression-free survival rate at 1 year after randomization (PFR-1yr). A regimen yielding a PFR-1yr of around 40% was decided to warrant further exploration (p1). A Fleming one-stage design was, therefore, applied to both arms with p2=20%, alpha=0.05 and beta=0.10. Secondary endpoints included PFS, defined as the time from randomization to documented disease progression (PD) or death from any cause after patients had received HAT. In addition for the HA-HAT group, a PFS1 and PFS2 was established. PFS1 was defined as the time from randomization to PD or death from any cause, PFS2 as the time from starting treatment with HAT to PD or death from any cause.
Results
Between April 2009 and September 2013, 84 patients were randomized, 39 to HAT and 45 to HA-HAT. Baseline characteristics were similar for both arms: mean age 55 years (range 29-80 years), prior adjuvant chemotherapy in 35% and hormone receptor positive disease in 63%. The primary endpoint was met in both arms. At a median follow-up of 22 months, 26 patients in the HAT arm had progressed of whom 14 had died. The median PFS for the HAT arm was 19.4 months (95% confidence interval (CI) 14.6-25.2). In the HA-HAT arm 23 patients progressed under HA of whom 3 still have no 2nd progression after adding T. Eleven patients of the HA-HAT arm died of whom 2 due to toxicity (1 sigmoid perforation, 1 pneumonia). The median PFS1 was 14.9 months (95% CI 10.9-NA) The median PFS2 was 8.2 months (95% CI 5.9-NA). Overall PFS in the HA-HAT arm was 22.6 months (95% CI 15.4-NA). Grade 3 or higher toxicity was 3 times more often seen during treatment including T. More detailed information regarding toxicity will be shown at the meeting.
Conclusion
Both HAT and HA-HAT are active regimens in Her2 positive MBC. In particular the sequential approach with starting monoclonal antibodies only, yielding a median PFS of more than 1 year and a relatively mild toxicity profile, and adding chemotherapy at progression is worthwhile to be further explored.
Financial support Roche Netherlands.
Citation Format: Jan C Drooger, Harm van Tinteren, Steffen M de Groot, Albert J ten Tije, Hiltje de Graaf, Johanneke EA Portielje, Agnes Jager, Aafke H Honkoop, Sabine C Linn, Judith R Kroep, Frans LG Erdkamp, Paul Hamberg, Joan B Heijns, A Elise van Leeuwen-Stok, Stefan Sleijfer. Results from a randomized phase II study of the Dutch Breast Cancer Research Group (BOOG 2008-03): Concomitant trastuzumab, bevacizumab and paclitaxel (HAT) versus trastuzumab and bevacizumab, followed by trastuzumab, bevacizumab and paclitaxel (HA-HAT) a [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 P4-15-12.