title: The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study.
abstract: BACKGROUND
  Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 with preclinical evidence of growth-inhibitory activity in oestrogen receptor-positive breast cancer cells and synergy with anti-oestrogens. We aimed to assess the safety and efficacy of palbociclib in combination with letrozole as first-line treatment of patients with advanced, oestrogen receptor-positive, HER2-negative breast cancer.
  
  
  METHODS
  In this open-label, randomised phase 2 study, postmenopausal women with advanced oestrogen receptor-positive and HER2-negative breast cancer who had not received any systemic treatment for their advanced disease were eligible to participate. Patients were enrolled in two separate cohorts that accrued sequentially: in cohort 1, patients were enrolled on the basis of their oestrogen receptor-positive and HER2-negative biomarker status alone, whereas in cohort 2 they were also required to have cancers with amplification of cyclin D1 (CCND1), loss of p16 (INK4A or CDKN2A), or both. In both cohorts, patients were randomly assigned 1:1 via an interactive web-based randomisation system, stratified by disease site and disease-free interval, to receive continuous oral letrozole 2.5 mg daily or continuous oral letrozole 2.5 mg daily plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over 28-day cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an unplanned interim analysis of cohort 1 and the statistical analysis plan for the primary endpoint was amended to a combined analysis of cohorts 1 and 2 (instead of cohort 2 alone). The study is ongoing but closed to accrual; these are the results of the final analysis of progression-free survival. The study is registered with the ClinicalTrials.gov, number NCT00721409.
  
  
  RESULTS
  Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165 patients, 84 to palbociclib plus letrozole and 81 to letrozole alone. At the time of the final analysis for progression-free survival (median follow-up 29.6 months [95% CI 27.9-36.0] for the palbociclib plus letrozole group and 27.9 months [25.5-31.1] for the letrozole group), 41 progression-free survival events had occurred in the palbociclib plus letrozole group and 59 in the letrozole group. Median progression-free survival was 10.2 months (95% CI 5.7-12.6) for the letrozole group and 20.2 months (13.8-27.5) for the palbociclib plus letrozole group (HR 0.488, 95% CI 0.319-0.748; one-sided p=0.0004). In cohort 1 (n=66), median progression-free survival was 5.7 months (2.6-10.5) for the letrozole group and 26.1 months (11.2-not estimable) for the palbociclib plus letrozole group (HR 0.299, 0.156-0.572; one-sided p<0.0001); in cohort 2 (n=99), median progression-free survival was 11.1 months (7.1-16.4) for the letrozole group and 18.1 months (13.1-27.5) for the palbociclib plus letrozole group (HR 0.508, 0.303-0.853; one-sided p=0.0046). Grade 3-4 neutropenia was reported in 45 (54%) of 83 patients in the palbociclib plus letrozole group versus one (1%) of 77 patients in the letrozole group, leucopenia in 16 (19%) versus none, and fatigue in four (4%) versus one (1%). Serious adverse events that occurred in more than one patient in the palbociclib plus letrozole group were pulmonary embolism (three [4%] patients), back pain (two [2%]), and diarrhoea (two [2%]). No cases of febrile neutropenia or neutropenia-related infections were reported during the study. 11 (13%) patients in the palbociclib plus letrozole group and two (2%) in the letrozole group discontinued the study because of adverse events.
  
  
  CONCLUSIONS
  The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer. A phase 3 trial is currently underway.
  
  
  BACKGROUND
  Pfizer.
authors.affiliation: University of California Los Angeles, Los Angeles, CA, USA.
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: Orszagos Onkologiai Intezet, Budapest, Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Lang
authors.affiliation: Szent Margit Korhaz, Onkologia, Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Boer
authors.affiliation: Dnipropetrovsk Medical Academy, City Multiple-Discipline Clinical Hospital 4, Dnipropetrovsk, Ukraine.
authors.forename: Igor M
authors.initials: IM
authors.lastname: Bondarenko
authors.affiliation: Municipal Treatment and Prophylactic Institution, Donetsk, Ukraine.
authors.forename: Sergey O
authors.initials: SO
authors.lastname: Kulyk
authors.affiliation: Technical University of Munich, Munich, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Ettl
authors.affiliation: Comprehensive Blood and Cancer Center, Bakersfield, CA, USA.
authors.forename: Ravindranath
authors.initials: R
authors.lastname: Patel
authors.affiliation: Petz Aladar Megyei Oktato Korhaz, Gyor, Hungary.
authors.forename: Tamas
authors.initials: T
authors.lastname: Pinter
authors.affiliation: University Hospital Mainz, Mainz, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Lviv State Oncologic Regional Treatment and Diagnostic Centre, Lviv, Ukraine.
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Shparyk
authors.affiliation: Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA.
authors.forename: Anu R
authors.initials: AR
authors.lastname: Thummala
authors.affiliation: Kyiv City Clinical Oncology Centre, Kyiv, Ukraine.
authors.forename: Nataliya L
authors.initials: NL
authors.lastname: Voytko
authors.affiliation: Pfizer Oncology, Milan, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Fowst
authors.affiliation: Pfizer Oncology, San Diego, CA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Pfizer Oncology, San Diego, CA, USA.
authors.forename: Sindy T
authors.initials: ST
authors.lastname: Kim
authors.affiliation: Pfizer Oncology, San Diego, CA, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Randolph
authors.affiliation: University of California Los Angeles, Los Angeles, CA, USA. Electronic address: dslamon@mednet.ucla.edu.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D000077289:Letrozole; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009570:Nitriles / Q000008:administration & dosage; D009656:North America; D010879:Piperazines / Q000008:administration & dosage; D017698:Postmenopause; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000235:genetics; D011960:Receptors, Estrogen / Q000032:analysis*; D056910:Republic of Korea; D013019:South Africa; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000077289:Letrozole; D009570:Nitriles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D014230:Triazoles; C530104:CCND1 protein, human; C508053:ERBB2 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C500026:palbociclib