Randomized phase II study of fulvestrant plus palbociclib or placebo in endocrine-sensitive, hormone receptor-positive/HER2-advanced breast cancer: GEICAM/2014-12 (FLIPPER)

Abstract

Background: The potential benefit of adding palbociclib to fulvestrant as first-line treatment in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative endocrine-sensitive advanced breast cancer (ABC) patients remains uncharacterized.

Patients and methods: In this randomized (1:1), double-blind, phase II study, postmenopausal women with HR-positive, HER2-negative ABC with de novo metastatic disease or those who relapsed after >12 months of adjuvant endocrine therapy received palbociclib/fulvestrant or placebo/fulvestrant. Stratification was based on recurrent versus de novo metastatic disease and visceral involvement. The primary objective was one-year progression-free survival (PFS-1y) rate. The sample size was 190 patients. The two-sided alpha of 0.2, 80% of power to detect a difference between the arms, assuming PFS rates of 0.695 and 0.545 for palbociclib/fulvestrant and placebo/fulvestrant, respectively.

Results: In total, 189 patients were randomized to palbociclib/fulvestrant ([n = 94] or placebo/fulvestrant [n = 95]). 45.5% and 60.3% of patients had de novo metastatic disease and visceral involvement, respectively. PFS-1y rates were 83.5% and 71.9% in the palbociclib/fulvestrant and placebo/fulvestrant arms, (HR 0.55, 80% CI 0.36-0.83, P = 0.064). The median PFS were 31.8 and 22.0 months for the palbociclib/fulvestrant and placebo/fulvestrant arms (aHR 0.48, 80% CI 0.37-0.64, P = 0.001). The most frequent grade 3-4 adverse events were neutropenia (68.1% vs. 0%), leucopenia (26.6% vs. 0%), anemia (3.2% vs. 0%), and lymphopenia (14.9% vs. 2.1%) for the palbociclib/fulvestrant and placebo/fulvestrant, respectively. The most frequent non-hematologic grade 3-4 adverse event was fatigue (4.3% vs. 0%).

Conclusions: Palbociclib/fulvestrant demonstrated better PFS-1y rates and median PFS than placebo/fulvestrant in HR-positive/HER2-negative endocrine-sensitive ABC patients.

Trial registration: ClinicalTrials.gov NCT02690480.

Keywords: Breast cancer; CDK 4/6; Endocrine-sensitive; First-line; Fulvestrant; Metastatic; Palbociclib.

Conflict of interest statement

Conflict of interest statement Joan Albanell has received consulting or advisory role fees from Roche, Pfizer, Amgen, MSD, Lilly and Daiichi-Sankyo; research funding or grant support trials by Roche, Pfizer, Amgen, MSD, Lilly, Daiichi-Sankyo; and travel and accommodation support from Roche, Pfizer, Amgen, MSD, Lilly and Daiichi-Sankyo. Manuel Ramos has received honoraria from Novartis, Roche, and Pfizer. Luis de la Cruz-Merino has received consulting or advisory role fees from MSD-Merck, Roche Farma, Bristol-Myers-Squibb, Pierre-Fabré, Amgen and Novartis; research funding from MSD-Merck, Roche Farma and Celgene; speaker's honoraria from MSD-Merck, Roche-Farma, Bristol-Myers-Squibb and Amgen; and grant support by Roche Farma and Bristol-Myers-Squibb. Ana Santaballa has received consulting or advisory role fees from GSK, Clovis, MSD, AstraZeneca, Roche and Pfizer; speakers' honoraria from GSK, Clovis, Roche, MSD, AstraZeneca and Pfizer; and grant support by Pfizer, GSK and MSD. Noelia Martinez-Janez has received advisory board honorary from Roche, AstraZeneca, Daichi, Pfizer, Novartis, Lilly and Eisai. Fernando Moreno has received consulting or advisory fees from Roche/Genentech, Novartis, Pfizer, AstraZeneca, and MSD; speakers' honoraria from Pfizer and Roche/Genentech; research funding fees from Pfizer; travel and accommodation support from Roche/Genentech, Pfizer and Novartis. Isaura Fernández has received consulting or advisory role fees from AstraZeneca, MSD, GlaxoSmithKline and Roche; research funding from Roche; and speaker's honoraria from Clovis, Pfizer and Novartis. Jesús Alarcón has received honoraria by GSC, Clovis, Roche and AstraZeneca; consulting or advisory board honoraria by GSK and Clovis; speaker and expert testimony fees by GSK, Clovis and Roche; and travel and accommodation support from GSK. Juan de la Haba has received speaker's honoraria from AstraZeneca, Pfizer, Novartis and Lilly. Mireia Margelí has received advisory board fees from Roche, Novartis, Pfizer, and Eisai. Her institution, ICO -Badalona. B-ARGO (Badalona Applied Research Group in Oncology) Hospital Universitari Germans Trias i Pujol, Badalona, has received funding research from Roche, Pfizer, Novartis, Lilly, AstraZeneca, Eisai, and Kern. Antonio Antón has received advisory board fees from Bayer, Spain. Federico Rojo has received consulting or advisory role fees from Roche, Pfizer, Novartis, BMS, Pierre-Fabre, Incyte, Abbvie, Amgen, MSD, and Lilly; and travel and accommodation support from Roche. GEICAM has received research funding from Roche/Genentech, Bristol-Myers Squibb, Novartis, Pfizer, Celgene, AstraZeneca, Merck Sharp & Dohme, Pierre Fabre, and Takeda. All remaining authors have declared no conflicts of interest.

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