title: Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3).
abstract: Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit.
  
  
  
  Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data.
  
  
  
  A total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ≥3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3-4 neutropenia with palbociclib. Dose modifications for grade 3-4 neutropenia had no adverse effect on progression-free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1-2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients.
  
  
  
  Palbociclib plus fulvestrant treatment was well-tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy. This study appears at ClinicalTrials.gov, NCT01942135.
  
  
  
  Treatment with palbociclib in combination with fulvestrant was generally safe and well-tolerated in patients with hormone receptor (HR)-positive metastatic breast cancer. Consistent with the drug's proposed mechanism of action, palbociclib-related neutropenia differs in its clinical time course, patterns, and consequences from those seen with chemotherapy. Neutropenia can be effectively managed by a dose reduction, interruption, or cycle delay without compromising efficacy. A significant efficacy gain and a favorable safety profile support the consideration of incorporating palbociclib into the routine management of HR-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer.
authors.affiliation: University of Calgary, Alberta, Canada DrSunil.Verma@ahs.ca.
authors.forename: Sunil
authors.initials: S
authors.lastname: Verma
authors.affiliation: Pfizer Inc., Collegeville, Pennsylvania, USA.
authors.forename: Cynthia Huang
authors.initials: CH
authors.lastname: Bartlett
authors.affiliation: Pfizer Inc., New York, New York, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schnell
authors.affiliation: University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: DeMichele
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.affiliation: National Cancer Center, Goyang-si, Republic of Korea.
authors.forename: Jungsil
authors.initials: J
authors.lastname: Ro
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Colleoni
authors.affiliation: Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Hiroji
authors.initials: H
authors.lastname: Iwata
authors.affiliation: Brustzentrum der Universität München, Munich, Germany.
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
authors.affiliation: Pfizer Inc., San Diego, California, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Pfizer Inc., Cambridge, Massachusetts, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Thiele
authors.affiliation: Institute of Cancer Research and Royal Marsden Hospital, London, United Kingdom.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Turner
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004311:Double-Blind Method; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis
chemical_list: D004958:Estradiol; D000077267:Fulvestrant; D010879:Piperazines; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C508053:ERBB2 protein, human; C500026:palbociclib
keywords: Cyclin-dependent kinase 4; Cyclin-dependent kinase 6; Neutropenia; Palbociclib