title: Randomized Phase II Study of Ramucirumab or Icrucumab in Combination with Capecitabine in Patients with Previously Treated Locally Advanced or Metastatic Breast Cancer.
abstract: Icrucumab (ICR) and ramucirumab (RAM) bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. This open-label, randomized phase II study evaluated their efficacy and safety in combination with capecitabine (CAP) in patients with previously treated unresectable, locally advanced or metastatic breast cancer.
  
  
  
  Patients were randomly assigned (1:1:1) to receive CAP (1,000 mg/m2orally twice daily, days 1-14) alone or in combination with RAM (10 mg/kg intravenously [IV], days 1 and 8) (RAM + CAP) or ICR (12 mg/kg IV, days 1 and 8) (ICR + CAP) every 21 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), tumor response, safety, and pharmacokinetics.
  
  
  
  Of 153 patients randomized, 150 received treatment. Median PFS (95% confidence interval) was 22.1 (12.1-36.1) weeks on RAM + CAP, 7.3 (6.3-13.0) weeks on ICR + CAP, and 19.0 (12.1-24.3) weeks on CAP (hazard ratios [HRs]: 0.691,p= .1315, RAM + CAP versus CAP; 1.480,p= .0851, ICR + CAP versus CAP). Median OS was 67.4 weeks on RAM + CAP, 62.1 weeks on ICR + CAP, and 71.6 weeks on CAP (HRs: 1.833,p= .0283, RAM + CAP versus CAP; 1.468,p= .1550, ICR + CAP versus CAP). There was no statistically significant difference in PFS or OS between either combination arm and CAP. Treatment-related adverse events more frequent (by ≥10%) on RAM + CAP than on CAP were constipation, decreased appetite, headache, epistaxis, and hypertension. Those more frequent (by ≥10%) on ICR + CAP than CAP were anemia, increased lacrimation, periorbital edema, nausea, vomiting, peripheral edema, facial edema, dehydration, and dyspnea.
  
  
  
  Combining RAM or ICR with CAP did not improve PFS in the targeted study population.The Oncologist2017;22:245-254 IMPLICATIONS FOR PRACTICE: Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. VEGFR-1 activation on endothelial and tumor cell surfaces increases tumor vascularization and growth and supports tumor growth via multiple mechanisms, including contributions to angiogenesis and direct promotion of cancer cell proliferation. Strong preclinical and clinical evidence suggests key roles for VEGF and angiogenesis in breast cancer growth, invasion, and metastasis. This randomized phase II study evaluated the efficacy and safety of each antibody in combination with capecitabine in patients with previously treated unresectable, locally advanced or metastatic breast cancer.
authors.affiliation: Weill Cornell Breast Center, Weill Cornell Medicine, New York, New York, USA ltv2001@med.cornell.edu.
authors.forename: Linda T
authors.initials: LT
authors.lastname: Vahdat
authors.affiliation: Ohio State University, Columbus, Ohio, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Layman
authors.affiliation: Tennessee Oncology, Nashville, Tennessee, USA.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Yardley
authors.affiliation: Northwestern University Feinburg School of Medicine, Chicago, Illinois, USA.
authors.forename: William
authors.initials: W
authors.lastname: Gradishar
authors.affiliation: Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia, USA.
authors.forename: Mohamad A
authors.initials: MA
authors.lastname: Salkeni
authors.affiliation: University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: Anil
authors.initials: AA
authors.lastname: Joy
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
authors.forename: Agustin A
authors.initials: AA
authors.lastname: Garcia
authors.affiliation: Oncology Hematology Care Incorporated, Cincinnati, Ohio, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ward
authors.affiliation: Virginia Cancer Institute, Richmond, Virginia, USA.
authors.forename: James
authors.initials: J
authors.lastname: Khatcheressian
authors.affiliation: Weiler Division, Montefiore Medical Center, Bronx, New York, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Sparano
authors.affiliation: South Texas Oncology and Hematology, San Antonio, Texas, USA.
authors.forename: Gladys
authors.initials: G
authors.lastname: Rodriguez
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: Shande
authors.initials: S
authors.lastname: Tang
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: Rita P
authors.initials: RP
authors.lastname: Dalal
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kauh
authors.affiliation: Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Miller
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000069287:Capecitabine / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D000096662:Ramucirumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069287:Capecitabine; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000096662:Ramucirumab; C000626257:Icrucumab
keywords: Breast cancer; Capecitabine; Drug resistance; Metastasis; Monoclonal antibodies