Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: A phase 2 randomized study.
BACKGROUND
This phase 2 randomized study evaluated trebananib (AMG 386), a peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction of angiopoietin-1 and -2 with Tie2, in combination with paclitaxel with or without bevacizumab in previously untreated patients with HER2-negative locally recurrent/metastatic breast cancer.


METHODS
Patients received paclitaxel 90 mg/m(2) once weekly (3-weeks-on/1-week-off) and were randomly assigned 1:1:1:1 to also receive blinded bevacizumab 10 mg/kg once every 2 weeks plus either trebananib 10 mg/kg once weekly (Arm A) or 3 mg/kg once weekly (Arm B), or placebo (Arm C); or open-label trebananib 10 mg/kg once a week (Arm D). Progression-free survival was the primary endpoint.


RESULTS
In total, 228 patients were randomized. Median estimated progression-free survival for Arms A, B, C, and D was 11.3, 9.2, 12.2, and 10 months, respectively. Hazard ratios (95% CI) for Arms A, B, and D versus Arm C were 0.98 (0.61-1.59), 1.12 (0.70-1.80), and 1.28 (0.79-2.09), respectively. The objective response rate was 71% in Arm A, 51% in Arm B, 60% in Arm C, and 46% in Arm D. The incidence of grade 3/4/5 adverse events was 71/9/4%, 61/14/5%, 62/16/3%, and 52/4/7% in Arms A/B/C/D. In Arm D, median progression-free survival was 12.8 and 7.4 months for those with high and low trebananib exposure (AUCss ≥ 8.4 versus < 8.4 mg·h/mL), respectively.


CONCLUSIONS
There was no apparent prolongation of estimated progression-free survival with the addition of trebananib to paclitaxel and bevacizumab at the doses tested. Toxicity was manageable. Exposure-response analyses support evaluation of combinations incorporating trebananib at doses > 10 mg/kg in this setting.


BACKGROUND
ClinicalTrials.gov, NCT00511459.
Institut Curie, Paris, France. Electronic address: veronique.dieras@curie.net.
Véronique
V
Diéras
University Hospital Leuven, Leuven, Belgium. Electronic address: hans.wildiers@uzleuven.be.
Hans
H
Wildiers
Medical University of Gdańsk, Gdańsk, Poland. Electronic address: jjassem@gumed.edu.pl.
Jacek
J
Jassem
General Hospital Sint-Augustinus, Antwerp, Belgium. Electronic address: Luc.Dirix@gza.be.
Luc Y
LY
Dirix
Centre Léon Bérard, Lyon, France. Electronic address: GUASTALL@lyon.fnclcc.fr.
Jean-Paul
JP
Guastalla
Helsinki University Central Hospital, Helsinki, Finland. Electronic address: Petri.Bono@hus.fi.
Petri
P
Bono
UCLA School of Medicine, Los Angeles, CA, USA. Electronic address: SHurvitz@mednet.ucla.edu.
Sara A
SA
Hurvitz
Institut Paoli-Calmettes, Marseilles, France. Electronic address: GONCALVESA@marseille.fnclcc.fr.
Anthony
A
Gonçalves
C.R.L.C. Val D'Aurelle, Montpellier, France. Electronic address: gilles@romieu.info.
Gilles
G
Romieu
Levine Cancer Institute, Charlotte, NC, USA. Electronic address: Steven.Limentani@carolinashealthcare.org.
Steven A
SA
Limentani
CHU Sart Tilman, Liege, Belgium. Electronic address: g.jerusalem@chu.ulg.ac.be.
Guy
G
Jerusalem
Kidwai Memorial Institute of Oncology, Bangalore, India. Electronic address: kcluck@gmail.com.
K C
KC
Lakshmaiah
Institut Claudius Régaud, Toulouse, France. Electronic address: Roche.Henri@claudiusregaud.fr.
Henri
H
Roché
Complejo Hospitalario de Jaén, Jaén, Spain. Electronic address: oncojaen@telefonica.net.
Pedro
P
Sánchez-Rovira
European Health Centre Otwock, Warszawa, Poland. Electronic address: tadeusz.pienkowski@gmail.com.
Tadeusz
T
Pienkowski
Corporació Sanitària Parc Taulí, Sabadell, Spain. Electronic address: MSegui@tauli.cat.
Miguel Ángel
MÁ
Seguí Palmer
Amgen Inc., Thousand Oaks, CA, USA. Electronic address: ail@amgen.com.
Ai
A
Li
Amgen Inc., Thousand Oaks, CA, USA. Electronic address: yus@amgen.com.
Yu-Nien
YN
Sun
Amgen Inc., Thousand Oaks, CA, USA. Electronic address: cpickett@amgen.com.
Cheryl A
CA
Pickett
UCLA School of Medicine, Los Angeles, CA, USA. Electronic address: DSlamon@mednet.ucla.edu.
Dennis J
DJ
Slamon
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000068258:Bevacizumab / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D011993:Recombinant Fusion Proteins; D000068258:Bevacizumab; D017239:Paclitaxel; C551398:trebananib
AMG 386; HER2-negative; bevacizumab; paclitaxel; trebananib