Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study

L. Gianni, G. Bisagni, M. Colleoni, L. Del Mastro, C. Zamagni, M. Mansutti, M. Zambetti, A. Frassoldati, R. De Fato, P. Valagussa, G. Viale

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Background: In the neoadjuvant setting, blockade of HER2 plus use of an aromatase inhibitor in patients with HER2-positive and oestrogen receptor (ER)-positive breast cancer leads to a pathological complete response in 21% of patients. Convergence of HER2 and ER signals on RB1 suggests that a combined pharmacological intervention directed to these targets could be synergistic. To test this approach, we combined palbociclib to block RB1, fulvestrant to block ER, and trastuzumab with pertuzumab to block HER2 in patients with HER2-positive, ER-positive breast cancer. Methods: NA-PHER2 is a multicohort, open-label, exploratory, phase 2 study done at seven sites in Italy. Patients were eligible for the first cohort if they had previously untreated, histologically confirmed, unilateral, invasive, HER2-positive, ER-positive breast cancer and were suitable for neoadjuvant therapy. Patients were treated every 3 weeks with intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and intravenous pertuzumab (840 mg loading dose in the first cycle and then at 420 mg) for six cycles plus oral palbociclib (125 mg once a day for 21 days in a 4-week cycle) and intramuscular fulvestrant (500 mg) every 4 weeks for five cycles. The coprimary endpoints were change from baseline in Ki67 expression at 2 weeks of treatment and at surgery (16 weeks after treatment) and changes in apoptosis from baseline to surgery. Secondary endpoints were clinical objective response (according to modified Response Evaluation Criteria in Solid Tumors) and pathological complete response. All patients who met eligibility criteria were assessed for the primary and secondary endpoints. All patients who received at least one cycle of therapy were assessed for safety. This trial is registered with, number NCT02530424. The trial is ongoing and two further cohorts are being enrolled. Findings: Between May 20, 2015, and Feb 8, 2016, we enrolled 36 patients, of whom one was deemed ineligible for the study and five were found to be HER2-negative on retrospective analysis. Thus, 35 patients were included in safety analyses and 30 were assessed for the primary and secondary endpoints. At baseline, geometric mean Ki67 expression was 31·9 (SD 15·7), versus 4·3 (15·0) at week 2 (n=25; p
Original languageEnglish
Pages (from-to)249-256
Number of pages8
JournalThe Lancet Oncology
Issue number2
Publication statusPublished - 2018


  • alanine aminotransferase
  • fulvestrant
  • Ki 67 antigen
  • palbociclib
  • pertuzumab
  • retinoblastoma protein
  • retinoblastoma protein 1
  • trastuzumab
  • unclassified drug
  • antineoplastic agent
  • epidermal growth factor receptor 2
  • estrogen receptor
  • monoclonal antibody
  • piperazine derivative
  • pyridine derivative
  • adult
  • aged
  • alanine aminotransferase blood level
  • allergic reaction
  • apoptosis
  • Article
  • axillary lymph node
  • breast surgery
  • cancer grading
  • clinical article
  • cohort analysis
  • diarrhea
  • drug safety
  • drug toxicity
  • drug withdrawal
  • estrogen receptor positive breast cancer
  • exploratory research
  • female
  • human
  • human epidermal growth factor receptor 2 positive breast cancer
  • human tissue
  • Italy
  • loading drug dose
  • multicenter study
  • multiple cycle treatment
  • neoadjuvant therapy
  • neutropenia
  • open study
  • outcome assessment
  • phase 2 clinical trial
  • priority journal
  • protein expression
  • protein targeting
  • repeated drug dose
  • side effect
  • stomatitis
  • WERI-Rb-1 cell line
  • breast tumor
  • clinical trial
  • disease free survival
  • intramuscular drug administration
  • intravenous drug administration
  • Kaplan Meier method
  • middle aged
  • mortality
  • oral drug administration
  • pathology
  • procedures
  • prognosis
  • proportional hazards model
  • response evaluation criteria in solid tumors
  • survival analysis
  • treatment outcome
  • Administration, Oral
  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols
  • Breast Neoplasms
  • Disease-Free Survival
  • Female
  • Fulvestrant
  • Humans
  • Infusions, Intravenous
  • Injections, Intramuscular
  • Kaplan-Meier Estimate
  • Middle Aged
  • Neoadjuvant Therapy
  • Piperazines
  • Prognosis
  • Proportional Hazards Models
  • Pyridines
  • Receptor, ErbB-2
  • Receptors, Estrogen
  • Response Evaluation Criteria in Solid Tumors
  • Survival Analysis
  • Trastuzumab
  • Treatment Outcome


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