title: Pharmacokinetic and exposure-response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer.
abstract: The NeoSphere trial evaluated pertuzumab in the neoadjuvant setting [early breast cancer (EBC)] with pathological complete response (pCR) as the primary efficacy end point. This analysis of pertuzumab aimed to (1) compare its pharmacokinetics (PK) in patients with EBC versus advanced cancers, (2) to further evaluate PK drug-drug interactions (DDIs) when given in combination with trastuzumab, and (3) to assess the relationship between exposure and efficacy to assess the clinical dosing regimen in the EBC patients.
  
  
  
  Pertuzumab serum concentration data from 180 patients in NeoSphere were compared to historical observations and potential DDI was assessed, by applying simulation techniques using a population PK model. The impact of pertuzumab exposure on pCR rate was evaluated using a logit response model (n = 88).
  
  
  
  The observed PK matched the population PK model simulations, confirming that the PK in neoadjuvant EBC appear to be in agreement with the historical observations. No evidence of a DDI effect of trastuzumab or docetaxel on pertuzumab was observed supporting the doses when given in combination. In NeoSphere >90% of EBC patients achieved the non-clinical target serum concentration. There was no association between the pertuzumab serum concentration and pCR within the range observed in this study (20-100 μg/mL) supporting no dose adjustments needed for patients with lower exposure.
  
  
  
  This analysis further supports the lack of DDI between the two therapeutic proteins and the appropriateness of the approved fixed non-body-weight-adjusted pertuzumab dose in the treatment of neoadjuvant EBC with pertuzumab in combination with trastuzumab and docetaxel.
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Angelica L
authors.initials: AL
authors.lastname: Quartino
authors.affiliation: Quantitative Solutions/Certara, Menlo Park, CA, USA.
authors.forename: Hanbin
authors.initials: H
authors.lastname: Li
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Jin Y
authors.initials: JY
authors.lastname: Jin
authors.affiliation: Quantitative Solutions/Certara, Menlo Park, CA, USA.
authors.forename: D Russell
authors.initials: DR
authors.lastname: Wada
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Benyunes
authors.affiliation: Roche Products Limited, Welwyn, UK.
authors.forename: Virginia
authors.initials: V
authors.lastname: McNally
authors.affiliation: San Raffaele Hospital - Research Institute, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Viganò
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Ihsan
authors.initials: I
authors.lastname: Nijem
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Bert L
authors.initials: BL
authors.lastname: Lum
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA. garg.amit@gene.com.
authors.forename: Amit
authors.initials: A
authors.lastname: Garg
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D000077143:Docetaxel; D005260:Female; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab / Q000008:administration & dosage
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077143:Docetaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab
keywords: Early breast cancer; Exposure–response; HER2; Neoadjuvant; Pertuzumab; Pharmacokinetics