title: Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Randomized Clinical Trial.
abstract: Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves outcome in patients with ERBB2 (HER2)-positive metastatic breast cancer; a clinically effective biosimilar may help increase access to this therapy.
  
  
  
  To compare the overall response rate and assess the safety of a proposed trastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without prior treatment for ERBB2-positive metastatic breast cancer.
  
  
  
  Multicenter, double-blind, randomized, parallel-group, phase 3 equivalence study in patients with metastatic breast cancer. From December 2012 to August 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar or trastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred.
  
  
  
  Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane.
  
  
  
  The primary outcome was week 24 overall response rate (ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24 with a 90% CI for ORR ratio (proposed biosimilar/trastuzumab) and -15% to 15% with a 95% CI for ORR difference. Secondary outcome measures included time to tumor progression, progression-free and overall survival at week 48, and adverse events.
  
  
  
  Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The ORR was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%-70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974-1.211) and ORR difference (5.53; 95% CI, -3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; -1.7%; 95% CI, -11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; -0.4%; 95% CI, -9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, -2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%).
  
  
  
  Among women with ERBB2-positive metastatic breast cancer receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab resulted in an equivalent overall response rate at 24 weeks. Further study is needed to assess safety and long-term clinical outcome.
  
  
  
  clinicaltrials.gov Identifier: NCT02472964; EudraCT Identifier: 2011-001965-42.
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco.
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
authors.affiliation: Biocon Research Limited, Bangalore, India3Now with Mylan Inc, Canonsburg, Pennsylvania.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Barve
authors.affiliation: Department of Haematology, Oncology, and Stem Cell Transplantation, University Medical Centre Freiburg and Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Waller
authors.affiliation: Quiron-Dexeus, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Hernandez-Bronchud
authors.affiliation: Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Jay
authors.initials: J
authors.lastname: Herson
authors.affiliation: Mylan Inc, Canonsburg, Pennsylvania.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Mylan Inc, Canonsburg, Pennsylvania.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Mylan Inc, Canonsburg, Pennsylvania.
authors.forename: Mark
authors.initials: M
authors.lastname: Baczkowski
authors.affiliation: Biocon Research Limited, Bangalore, India.
authors.forename: Mudgal
authors.initials: M
authors.lastname: Kothekar
authors.affiliation: Biocon Research Limited, Bangalore, India.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Loganathan
authors.affiliation: City Clinical Oncology Dispensary, Saint Petersburg, Russia.
authors.forename: Alexey
authors.initials: A
authors.lastname: Manikhas
authors.affiliation: Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine.
authors.forename: Igor
authors.initials: I
authors.lastname: Bondarenko
authors.affiliation: Regional Clinical Oncological Center, Kazan, Russia.
authors.forename: Guzel
authors.initials: G
authors.lastname: Mukhametshina
authors.affiliation: Institute of Clinical Oncology, Tbilisi, Georgia.
authors.forename: Gia
authors.initials: G
authors.lastname: Nemsadze
authors.affiliation: St Luke's Medical Center Global City, Taguig City, Philippines.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Parra
authors.affiliation: Cardinal Santos Medical Center, Manila, Philippines.
authors.forename: Maria Luisa T
authors.initials: ML
authors.lastname: Abesamis-Tiambeng
authors.affiliation: Golden Fleece 21 Century Health House Ltd, Tbilisi, Georgia.
authors.forename: Kakhaber
authors.initials: K
authors.lastname: Baramidze
authors.affiliation: Siriraj Hospital, Bangkok, Thailand.
authors.forename: Charuwan
authors.initials: C
authors.lastname: Akewanlop
authors.affiliation: Sumy State University, Sumy, Ukraine.
authors.forename: Ihor
authors.initials: I
authors.lastname: Vynnychenko
authors.affiliation: King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Virote
authors.initials: V
authors.lastname: Sriuranpong
authors.affiliation: City Cancer Center, Vijayawada, India.
authors.forename: Gopichand
authors.initials: G
authors.lastname: Mamillapalli
authors.affiliation: Curie Manavata Cancer Centre, Nasik, India.
authors.forename: Sirshendu
authors.initials: S
authors.lastname: Ray
authors.affiliation: Instituto Clinico Oncologico del Sur, Temuco, Chile.
authors.forename: Eduardo P
authors.initials: EP
authors.lastname: Yanez Ruiz
authors.affiliation: Mylan Inc, Canonsburg, Pennsylvania.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pennella
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D059451:Biosimilar Pharmaceuticals / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D000077143:Docetaxel; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D008875:Middle Aged; D017239:Paclitaxel / Q000009:adverse effects / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases; D012074:Remission Induction; D016019:Survival Analysis; D043823:Taxoids / Q000009:adverse effects / Q000627:therapeutic use; D057212:Therapeutic Equipoise; D013997:Time Factors; D000068878:Trastuzumab / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D059451:Biosimilar Pharmaceuticals; D000077143:Docetaxel; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human