title: Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18.
abstract: Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6. In the randomized, open-label, phase II PALOMA-1/TRIO-18 trial, palbociclib in combination with letrozole improved progression-free survival (PFS) compared with letrozole alone as first-line treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced breast cancer (20.2 months versus 10.2 months; hazard ratio (HR) = 0.488, 95 % confidence interval (CI) 0.319-0.748; one-sided p = 0.0004). Grade 3-4 neutropenia was the most common adverse event (AE) in the palbociclib + letrozole arm. We now present efficacy and safety analyses based on several specific patient and tumor characteristics, and present in detail the clinical patterns of neutropenia observed in the palbociclib + letrozole arm of the overall safety population.
  
  
  
  Postmenopausal women (n = 165) with ER+, HER2-negative, advanced breast cancer who had not received any systemic treatment for their advanced disease were randomized 1:1 to receive either palbociclib in combination with letrozole or letrozole alone. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary endpoint was PFS. We now analyze the difference in PFS for the treatment populations by subgroups, including age, histological type, history of prior neoadjuvant/adjuvant systemic treatment, and sites of distant metastasis, using the Kaplan-Meier method. HR and 95 % CI are derived from a Cox proportional hazards regression model.
  
  
  
  A clinically meaningful improvement in median PFS and clinical benefit response (CBR) rate was seen with palbociclib + letrozole in every subgroup evaluated. Grade 3-4 neutropenia was the most common AE with palbociclib + letrozole in all subgroups. Analysis of the frequency of neutropenia by grade during the first six cycles of treatment showed that there was a downward trend in Grade 3-4 neutropenia over time. Among those who experienced Grade 3-4 neutropenia, 71.7 % had no overlapping infections of any grade and none had overlapping Grade 3-4 infections.
  
  
  
  The magnitude of clinical benefit seen with the addition of palbociclib to letrozole in improving both median PFS and CBR rate is consistent in nearly all subgroups analyzed, and consistent with that seen in the overall study population. The safety profile of the combination treatment in all subgroups was also comparable to that in the overall safety population of the study.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA. RFinn@mednet.ucla.edu.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.affiliation: Irish Cooperative Oncology Research Group, Dublin, Ireland.
authors.forename: John P
authors.initials: JP
authors.lastname: Crown
authors.affiliation: Technical University of Munich, Munich, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Ettl
authors.affiliation: University Hospital Mainz, Mainz, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Dnipropetrovsk Medical Academy, City Multiple-Discipline Clinical Hospital, Dnipropetrovsk, Ukraine.
authors.forename: Igor M
authors.initials: IM
authors.lastname: Bondarenko
authors.affiliation: Orszagos Onkologiai Intezet, Budapest, Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Lang
authors.affiliation: Petz Aladar Megyei Oktato Korhaz, Gyor, Hungary.
authors.forename: Tamas
authors.initials: T
authors.lastname: Pinter
authors.affiliation: Department of Medical Oncology, Szent Margit Korhaz, Onkologia, Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Boer
authors.affiliation: Comprehensive Blood and Cancer Center, Bakersfield, CA, USA.
authors.forename: Ravindranath
authors.initials: R
authors.lastname: Patel
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Randolph
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: Sindy T
authors.initials: ST
authors.lastname: Kim
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Pfizer Oncology, New York, NY, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schnell
authors.affiliation: Pfizer Oncology, Groton, CT, USA.
authors.forename: Sashi
authors.initials: S
authors.lastname: Nadanaciva
authors.affiliation: Pfizer Oncology, Collegeville, PA, USA.
authors.forename: Cynthia Huang
authors.initials: CH
authors.lastname: Bartlett
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia / Q000175:diagnosis / Q000209:etiology; D009570:Nitriles / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D019233:Retreatment; D016019:Survival Analysis; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D000077289:Letrozole; D009570:Nitriles; D010879:Piperazines; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D014230:Triazoles; C500026:palbociclib
keywords: Breast cancer; Cyclin-dependent kinase; Estrogen receptor-positive; HER2-negative; Neutropenia