Frontline fulvestrant in combination with palbociclib demonstrated an improvement in progression-free survival at 1 year compared with fulvestrant and placebo alone in patients with endocrine-sensitive hormone receptor-positive, HER2-negative metastatic breast cancer, which met the primary end point of the phase 2 FLIPPER trial.
Joan Albanell, MD
Frontline fulvestrant (Faslodex) in combination with palbociclib (Ibrance) demonstrated an improvement in progression-free survival (PFS) at 1 year compared with fulvestrant and placebo alone in patients with endocrine-sensitive hormone receptor (HR)–positive, HER2-negative metastatic breast cancer, which met the primary end point of the phase 2 FLIPPER trial (GEICAM/2014-12; NCT02690480), according to findings from the first analysis of the trial that were presented at the 2020 European Society of Medical Oncology (ESMO) Virtual Congress.1
The doublet regimen led to improvements in median PFS, objective response rate (ORR), and clinical benefit rate (CBR) compared with fulvestrant alone and demonstrated a manageable toxicity profile.
“These data provide evidence for superiority of fulvestrant plus palbociclib versus fulvestrant plus placebo in the first-line treatment of [patients with] endocrine-sensitive disease,” said Joan Albanell, MD, during his presentation of the results at the virtual ESMO meeting.
Fulvestrant and palbociclib was previously proven to be a standard of care in the treatment of patients with HR-positive, HER2-negative metastatic breast cancer who have progressed on or relapsed during prior endocrine therapy based on the results of the phase 3 PALOMA-3 trial, which demonstrated a significant improvement in overall survival (OS) compared with fulvestrant alone.2 However, the trial did not include patients with endocrine-sensitive disease. The FLIPPER trial sought to explore the benefit of the addition of palbociclib to fulvestrant in the first-line setting in patients with HR-positive, HER2-negative metastatic breast cancer, including in those with endocrine-sensitive disease.
FLIPPER is an ongoing randomized, double-blind, parallel-group, multicenter, international trial. The trial enrolled women who were postmenopausal; had HR-positive, HER2-negative metastatic breast cancer; endocrine-sensitive disease, as defined by relapse after adjuvant endocrine therapy of at least 5 years and a disease-free interval of more than 12 months, or de novo metastatic disease; an ECOG performance status of 0 to 2; and no prior therapy for metastatic disease.
A total of 189 patients were enrolled and randomized to either the experimental arm of fulvestrant and palbociclib (n = 94) or the control arm of fulvestrant and placebo (n = 95). Patients were stratified by visceral versus nonvisceral metastases and metastatic de novo presentation versus recurrent presentation at study entry.
Fulvestrant was administered at 500 mg on days 1 and 15 of the first cycle and then once every 28 days thereafter. Palbociclib was given at 125 mg for 3 weeks on and 1 week off of every 28-day cycle. Treatment was given until disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent.
The primary end point was PFS rate at 1 year as assessed by the investigator using RECIST v1.1 criteria. Secondary end points included median PFS, OS, ORR, CBR, rate of OS at 1 and 2 years, safety and tolerability, and health-related quality of life. Investigators also looked to identify promising biomarkers of response, monitoring, or resistance.
With a sample size of 95 patients per treatment arm, per statistical assumptions, the study required a target hazard ratio of 0.6 for PFS at 1 year in order to be positive with 80% power and a 2-sided α of 0.2, as it was a phase 2 trial. The investigators estimated that 70 PFS events would be needed and the primary analysis could be completed after at least 12 months of follow-up.
At baseline, patient and disease characteristics were well balanced between the 2 groups. The median age was 64 years (range, 38-82) and more than half of the patients (54.0%) had a performance status of 0. At study entry about half of the patients had recurrent disease (54.5%), visceral disease (60.3%), and measurable lesions (67.2%). The most frequent site of disease was in the bone for 67.7% of patients, the lymph nodes for 54.0%, the breast for 35.4%, and the lung for 34.0%. About twenty percent of patients had at least 4 different involved sites.
A total of 81.5% of patients had estrogen receptor–positive, progesterone receptor–positive status, and the remainder had estrogen receptor–positive, progesterone receptor–negative disease. Additionally, 59.3% of patients had luminal B-like disease and 40.7% had luminal A-like disease.
Prior therapy consisted of adjuvant chemotherapy in 39.2%, and for early breast cancer, 37.0% received tamoxifen and 41.3% received aromatase inhibition. The disease-free interval was more than 3 years in 40.2%.
After a median follow-up of 28.6 months (range, 1.5-44.8), the PFS rate at 1 year was 83.5% with fulvestrant and palbociclib versus 71.9% with fulvestrant and placebo (HR, 0.55; 80% CI, 0.36-0.83; P = .064), meeting the primary end point.
Median PFS was 31.8 months (80% CI, 30.3-33.4) with the doublet and 22 months (80% CI, 18.5-25.1) with fulvestrant alone (adjusted HR, 0.52; 80% CI, 0.39-0.68; P = .002).
Those with visceral disease who were treated with fulvestrant and palbociclib (n = 57) had a median PFS of 30.9 months versus 19.4 months with fulvestrant and placebo (n = 57; HR, 0.53; 80% CI, 0.38-0.73; P = .013). At 1 year, the PFS rate was 81.8% versus 69.6% with the doublet and fulvestrant monotherapy, respectively (HR, 0.55; 80% CI, -.33-0.92; P = .1397).
Among those with nonvisceral disease, the median PFS was 33.4 months with fulvestrant and palbociclib (n = 37) versus 25.6 months with fulvestrant alone (n = 38) HR, 0.60; 80% CI, 0.38-0.94; P = .148). The PFS rate at 1 year was 85.9% with the combination regimen and 75.4% with fulvestrant alone (HR, 0.54; 80% CI, 0.26-1.01; P = .2688).
Those with de novo metastatic disease had a median PFS of 33.4 months with fulvestrant and palbociclib (n = 44) versus 16.4 months with fulvestrant alone (n = 42; HR, 0.30; 80% CI, 0.20-0.45; P <.001). At 12 months, the PFS rate was 90.5% with the palbociclib regimen versus 60.2% with single-agent fulvestrant (HR, 0.20; 80% CI, 0.10-0.41; P = .004).
Among those with recurrent disease, the median PFS was 30.5 months with fulvestrant and palbociclib (n = 50) versus 27.3 months with fulvestrant alone (n = 53; HR, 0.89; 80% CI, 0.62-1.28; P = .679). The 12-month PFS rate was 80.8% versus 77.3% with the doublet and monotherapy, respectively (HR, 1.21; 80% CI, 0.69-2.12; P = 1).
“In these exploratory trials, the results are hypothesis generating and have to be interpreted as such,” Albanell, head of medical oncology at the Hospital del Mar in Barcelona, Spain, said.
OS data were not yet mature at the time of the data cutoff and were not reported during the ESMO presentation.
Most subgroup analyses favored the addition of palbociclib to fulvestrant. Those with an ECOG performance status of 1 (HR, 0.32), metastatic de novo disease (HR, 0.30), multiple sites of metastasis (HR, 0.44), progesterone receptor–positive status (HR, 0.43), and luminal A-like disease (HR, 0.37) showed particular benefit from added palbociclib.
The ORR was 68.3% in the investigational arm compared with 42.2% in the control arm (odds ratio, 2.9; 80% CI, 1.79-4.62; P = .004). The CBR, which was defined as responses plus stable disease for at least 24 weeks, was 90.4% with the combination regimen versus 80.0% with fulvestrant alone (odds ratio, 2.3; 80% CI, 1.33-4.03; P = .048).
Treatment-related adverse events (AEs) were observed in 89.4% of patients who received fulvestrant and palbociclib compared with 62.1% in those who received fulvestrant alone. About fifteen percent of patients in the investigational arm discontinued palbociclib and 4.3% discontinued all study drugs whereas 4.2% in the control arm discontinued treatment. Serious AEs were reported in 26.6% of patients in the combination arm versus 20.0% in the monotherapy arm. Two on-study treatment deaths were reported in the fulvestrant and palbociclib arm, but neither were considered due to treatment.
In the investigational arm, the most frequent treatment-related hematological AEs were neutropenia in 68.1%, leukopenia in 26.6%, lymphopenia in 14.9%, and anemia in 3.2%, all of which were grade 3/4. No cases of febrile neutropenia were noted. The most frequent non-hematologic treatment-related AEs were fatigue (12.8%), diarrhea (3.2%), constipation (3.2%), and alanine aminotransferase increase (3.2%), which were all grades 2 through 4.
Albanell noted that there were 3 reported cases of pneumonitis—2 of grade 1 and 1 of grade 3—and 2 cases of thromboembolic events—1 grade 2 and 1 grade 3—in the palbociclib arm.