title: A phase II multicentre study of ziv-aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer.
abstract: BACKGROUND
  This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC).
  
  
  METHODS
  This single arm, multicentre phase II trial enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6 mg kg(-1), pemetrexed 500 mg m(-2), and cisplatin 75 mg m(-2), every 21 days for up to six cycles. Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal. The co-primary end points were objective response rate (ORR) and progression-free survival (PFS). Planned sample size was 72 patients.
  
  
  RESULTS
  The study was closed prematurely because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 55% were male, 86% Caucasian and 50% had Eastern Cooperative Oncology Group performance status (ECOG PS)=0. A median of four cycles of ziv-aflibercept was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. Of the 38 evaluable patients, ORR was 26% and median PFS was 5 months.
  
  
  CONCLUSIONS
  Cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development programme but the rate observed in this study was higher than previously observed. This might be related to declining renal function and/or hypertension. Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Arizona Oncology/Arizona Clinical Research Center, 1620W. St Mary's Rd, Tucson, AZ 85745, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Modiano
authors.affiliation: Department of Medicine, Stanford University School of Medicine and Cancer Institute, 875 Blake Wilbur Dr, Stanford, CA 94305, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Neal
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting/Blaustein CRB, 1650 Orleans St., G94, Baltimore, MD 21231, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Brahmer
authors.affiliation: Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 03756, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Rigas
authors.affiliation: Rocky Mountain Cancer Centers, 1800 Williams Street, Suite 200, Denver, CO 80218, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Jotte
authors.affiliation: Department of Medicine, Princess Margaret Hospital and University of Toronto, 610 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: N B
authors.initials: NB
authors.lastname: Leighl
authors.affiliation: Department of Medicine, Stanford University School of Medicine and Cancer Institute, 875 Blake Wilbur Dr, Stanford, CA 94305, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Riess
authors.affiliation: Department of Medicine, Stanford University School of Medicine and Cancer Institute, 875 Blake Wilbur Dr, Stanford, CA 94305, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Kuo
authors.affiliation: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.affiliation: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
authors.forename: B
authors.initials: B
authors.lastname: Gao
authors.affiliation: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Dicioccio
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Adjei
authors.affiliation: Department of Medicine, Stanford University School of Medicine and Cancer Institute, 875 Blake Wilbur Dr, Stanford, CA 94305, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Wakelee
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D005260:Female; D005971:Glutamates / Q000008:administration & dosage* / Q000009:adverse effects; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage* / Q000009:adverse effects; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D005971:Glutamates; D011993:Recombinant Fusion Proteins; D000068437:Pemetrexed; C533178:aflibercept; D006147:Guanine; D040262:Receptors, Vascular Endothelial Growth Factor; D002945:Cisplatin