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FDA Grants Priority Review to Palbociclib in Pretreated HR+/HER2- Breast Cancer

Jason M. Broderick @jasoncology
Published: Thursday, Dec 10, 2015

Nicholas C. Turner, MD, PhD

Nicholas C. Turner,
MD, PhD

The FDA has granted a priority review to a supplemental new drug application for palbociclib (Ibrance) for use in combination with fulvestrant in pretreated patients with HR-positive, HER2-negative metastatic breast cancer, according to Pfizer, the manufacturer of the CDK 4/6 inhibitor. The FDA is scheduled to make its approval decision by April 2016.

The priority review is based on findings from the phase III PALOMA-3 trial, in which adding palbociclib to standard fulvestrant more than doubled progression-free survival (PFS) in pretreated patients with HR-positive, HER2-negative breast cancer. Palbociclib delayed disease progression by over 5 months, according to study results presented at the 2015 ASCO Annual Meeting and published in The New England Journal of Medicine.1,2

“We look forward to continuing to work with the FDA to add the robust phase III data set from the PALOMA-3 trial to the available data in the Ibrance label,” said Liz Barrett, global president and general manager of Pfizer Oncology.

The double-blind, multicenter PALOMA-3 study randomized 521 patients with metastatic breast cancer whose disease progressed on or following endocrine treatment in a 2:1 ratio to fulvestrant plus either palbociclib (n = 347) or placebo (n = 174).

Fulvestrant was administered at 500 mg (IM) on days 1 and 15 of cycle 1, and then on day 1 of each cycle thereafter, and patients received oral palbociclib at 125 mg/day continuously for the first 3 weeks of each cycle, followed by 1 week off. Treatment cycles were 28 days for both arms. Goserelin was also administered to pre- and perimenopausal patients.

Baseline patient data were similar between the 2 arms. The median patient age was 57 and 56 years in the palbociclib and placebo arms, respectively. Patients were stratified by menopausal status, sensitivity to prior hormonal therapy, and visceral metastases. In both treatment arms, 79% of patients were sensitive to previous endocrine treatment, 60% had visceral disease, and 79% were postmenopausal. One previous line of chemotherapy for advanced disease was permitted, of which 33% of patients in the overall population had received.

PFS was the primary outcome measure, with secondary objectives focusing on overall survival (OS), response, and safety. Following 195 PFS events, the trial was halted in April 2015 after an independent panel determined the study had met its primary endpoint.

Median PFS was 9.2 months with the palbociclib combination versus 3.8 months in the placebo arm (HR, 0.422; 95% CI 0.318-0.560; P <.000001).

The PFS benefit was observed regardless of menopause status and remained consistent across all prespecified patient subgroups. OS data are not yet mature.

“Palbociclib and fulvestrant in combination was well tolerated,” lead PALOMA-3 author Nicholas C. Turner, MD, PhD, consultant medical oncologist at The Royal Marsden and Institute of Cancer Research in London, said when he presented the data at the ASCO Annual Meeting. The most frequently reported toxicities in the palbociclib arm versus the placebo group were neutropenia (78.8% vs 3.5%), leucopenia (45.5% vs 4.1%), and fatigue (38.0% vs 26.7%). “The incidence of febrile neutropenia…was very rare, and was 0.6% in both arms,” said Turner.

Turner noted that symptomatic adverse events (AEs) were “largely similar” in the placebo and palbociclib arms, with a small increase in fatigue, alopecia, and infections for patients receiving the CDK4/6 inhibitor. Rates of serious AEs were 9.6% versus 14.0% for the palbociclib versus placebo groups, respectively. Adverse events led to treatment discontinuation in 2.6% and 1.7% of the cohorts, respectively.

Palbociclib received an FDA accelerated approval in February 2015 as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer, based on findings from the phase II PALOMA-1 trial.

In the open-label phase II study, treatment with palbociclib plus letrozole reduced the risk of disease progression by 51% compared with letrozole alone. The median PFS with palbociclib was 20.2 versus 10.2 months for letrozole alone (HR, 0.488; P = .0004).

The confirmatory phase III trial for palbociclib’s accelerated frontline approval is PALOMA-2. This study is comparing the combination of palbociclib and letrozole with letrozole alone as a frontline treatment for postmenopausal women with ER-positive, HER2-negative advanced breast cancer (NCT01740427).

“Since FDA approval in February, more than 18,000 women have been treated with Ibrance by approximately 5000 prescribers in the United States. With approval of this indication, we hope to expand the role of Ibrance in combination with endocrine therapy for the treatment of HR+, HER2- metastatic breast cancer and to serve even more patients with this first-in-class medicine,” said Barrett.


  1. Turner NC, Ro J, Andre F, et al. PALOMA3: A double-blind, phase III trial of fulvestrant with or without palbociclib in pre- and post-menopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy. J Clin Oncol. 2015;33 (suppl; abstr LBA502).
  2. Turner NC, Ro J, André F, Loi S, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373(3):209-219.



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