title: Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status.
abstract: OBJECTIVE
  Ovarian cancers (OCs) frequently have HER2 activation in the absence of HER2 overexpression. Pertuzumab, a humanized antibody that prevents HER2 dimerization and inhibits multiple HER-mediated pathways, was studied in a phase II, multicenter trial in advanced, refractory OC.
  
  
  METHODS
  Sixty-one patients (cohort 1) with relapsed OC received a loading dose of 840 mg pertuzumab intravenously followed by 420 mg every 3 weeks; 62 patients (cohort 2) received 1,050 mg every 3 weeks. Response rate was the primary end point. Fresh tumor biopsies were obtained in cohort 1 to assay for phosphorylated HER2 (pHER2).
  
  
  RESULTS
  Median age was 57 years and median number of prior chemotherapy regimens was five. Fifty-five patients in cohort 1 and 62 patients in cohort 2 were assessable for efficacy. There were five partial responses (response rate [RR] = 4.3%; 95% CI, 1.7% to 9.4%), eight patients (6.8%) with stable disease (SD) lasting at least 6 months, and 10 patients with CA-125 reduction of at least 50% (includes two partial responses and four patients with SD > or = 6 months; total clinical activity, 14.5%). Median progression-free survival (PFS) was 6.6 weeks. Eight of 28 tumor biopsies (28.6%) were pHER2+ by enzyme-linked immunosorbent assay (ELISA; without gene amplification). Median PFS for pHER2+ patients was 20.9 weeks (n = 8) versus 5.8 weeks for pHER2- (n = 20; P = .14) and 9.1 weeks for unknown pHER2 status (n = 27). Pertuzumab was well tolerated with diarrhea in 69.1% (11.4% grade 3, no grade 4). Five patients had asymptomatic left ventricular ejection fraction decreases to less than 50% (one confirmed by central facility).
  
  
  CONCLUSIONS
  Pertuzumab is well tolerated with a RR of 4.3% in heavily-pretreated OC patients. Further studies on pHER2 as a diagnostic are warranted.
authors.affiliation: Arizona Cancer Center, Tuscon and Scottsdale, AZ, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.forename: Daniela
authors.initials: D
authors.lastname: Matei
authors.forename: Carol
authors.initials: C
authors.lastname: Aghajanian
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
authors.forename: Molly
authors.initials: M
authors.lastname: Brewer
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.forename: John D
authors.initials: JD
authors.lastname: Hainsworth
authors.forename: Agustin A
authors.initials: AA
authors.lastname: Garcia
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pegram
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Schilder
authors.forename: David E
authors.initials: DE
authors.lastname: Cohn
authors.forename: Lynda
authors.initials: L
authors.lastname: Roman
authors.forename: Mika K
authors.initials: MK
authors.lastname: Derynck
authors.forename: Kimmie
authors.initials: K
authors.lastname: Ng
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lyons
authors.forename: David E
authors.initials: DE
authors.lastname: Allison
authors.forename: David A
authors.initials: DA
authors.lastname: Eberhard
authors.forename: Thinh Q
authors.initials: TQ
authors.lastname: Pham
authors.forename: Randall C
authors.initials: RC
authors.lastname: Dere
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011237:Predictive Value of Tests; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C485206:pertuzumab