Phase II, randomized, placebo-controlled study of dovitinib in combination with fulvestrant in postmenopausal patients with HR+, HER2-breast cancer that had progressed during or after prior endocrine therapy.
Overexpression of fibroblast growth factor receptor 1 (FGFR1), found in ≤8% of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer cases, is correlated with decreased overall survival and resistance to endocrine therapy (ET). Dovitinib, a potent FGFR inhibitor, has demonstrated antitumor activity in heavily pretreated patients with FGFR pathway-amplified breast cancer.



In this randomized, placebo-controlled phase II trial, we evaluated whether the addition of dovitinib to fulvestrant would improve outcomes in postmenopausal patients with HR+, HER2-advanced breast cancer that had progressed during or after prior ET. Patients were stratified by FGF pathway amplification and presence of visceral disease, and they were randomized 1:1 to receive fulvestrant plus dovitinib or placebo. The primary endpoint was progression-free survival (PFS).



From 15 May 2012 to 26 November 2014, 97 patients from 36 centers were enrolled. The frequency of FGF pathway amplification was lower than anticipated, and the study was terminated early owing to slow accrual of patients with FGF pathway amplification. The median PFS (95% CI) was 5.5 (3.8-14.0) months vs 5.5 (3.5-10.7) months in the dovitinib vs placebo arms, respectively (HR, 0.68; did not meet predefined efficacy criteria). For the FGF pathway-amplified subgroup (n = 31), the median PFS (95% CI) was 10.9 (3.5-16.5) months vs 5.5 (3.5-16.4) months in the dovitinib vs placebo arms, respectively (HR, 0.64; met the predefined superiority criteria). Frequently reported adverse events in the dovitinib (diarrhea, nausea, vomiting, asthenia, and headache) and placebo (diarrhea, fatigue, nausea, and asthenia) arms were mostly low grade.



The safety profile of dovitinib plus fulvestrant was consistent with the known safety profile of single-agent dovitinib. Dovitinib in combination with fulvestrant showed promising clinical activity in the FGF pathway-amplified subgroup. However, the data reported herein should be interpreted with caution, given that fewer PFS events occurred in the FGF pathway-amplified patients than was expected and that an effect of dovitinib regardless of FGR pathway amplification status cannot be excluded, because the population was smaller than expected.



ClinicalTrials.gov identifier: NCT01528345 . Registered 31 January 2012.
Medical Oncology Unit, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14, 43126, Parma, Italy. amusolino@ao.pr.it.
Antonino
A
Musolino
Institut de Cancerologie de l'Ouest, René Gauducheau, Saint-Herblain, France.
Mario
M
Campone
Hospital Gasthuisberg, Leuven, Belgium.
Patrick
P
Neven
Virginia Cancer Specialists, US Oncology Research, Arlington, VA, USA.
Neelima
N
Denduluri
Pontificia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil.
Carlos H
CH
Barrios
Vall d'Hebron Institute of Oncology, Barcelona, Spain.|Ramon y Cajal University Hospital, Madrid, Spain.
Javier
J
Cortes
Duke University Medical Center, Durham, NC, USA.
Kimberly
K
Blackwell
Moffitt Cancer Center, Tampa, FL, USA.
Hatem
H
Soliman
University of Szeged, Szeged, Hungary.
Zsuzsanna
Z
Kahan
Institut Bergonié Comprehensive Cancer Centre, Université de Bordeaux, Bordeaux, France.
Hervé
H
Bonnefoi
Novartis Pharma AG, Basel, Switzerland.
Matthew
M
Squires
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Yong
Y
Zhang
Novartis Pharma AG, Basel, Switzerland.
Stephanie
S
Deudon
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Michael M
MM
Shi
Institut Gustave Roussy, Villejuif, France.
Fabrice
F
André
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D017698:Postmenopause; D015363:Quinolones / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D019233:Retreatment; D016019:Survival Analysis; D016896:Treatment Outcome
D001562:Benzimidazoles; D004958:Estradiol; D000077267:Fulvestrant; D015363:Quinolones; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
Breast cancer; Dovitinib; Endocrine resistance; FGF; FGFR; Fulvestrant; TKI285