Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma.
OBJECTIVE
Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM.


METHODS
Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m(2) on days 1 and 8 every 21 days, cisplatin 75 mg/m(2) every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression.


RESULTS
One hundred fifteen patients were enrolled at 11 sites; 108 patients were evaluable. Median PFS time was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). Median overall survival (OS) times were 15.6 and 14.7 months in the bevacizumab and placebo arms, respectively (P = .91). Partial response rates were similar (24.5% for bevacizumab v 21.8% for placebo; P = .74). A higher pretreatment plasma VEGF concentration (n = 56) was associated with shorter PFS (P = .02) and OS (P = .0066), independent of treatment arm. There were no statistically significant differences in toxicity of grade 3 or greater.


CONCLUSIONS
The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM.
University of Chicago ComprehensiveCancer Center, Chicago, IL, USA. hkindler@medicine.bsd.uchicago.edu
Hedy L
HL
Kindler
Theodore G
TG
Karrison
David R
DR
Gandara
Charles
C
Lu
Lee M
LM
Krug
James P
JP
Stevenson
Pasi A
PA
Jänne
David I
DI
Quinn
Marianna N
MN
Koczywas
Julie R
JR
Brahmer
Kathy S
KS
Albain
David A
DA
Taber
Samuel G
SG
Armato
Nicholas J
NJ
Vogelzang
Helen X
HX
Chen
Walter M
WM
Stadler
Everett E
EE
Vokes
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D010919:Placebos; D010997:Pleural Neoplasms / Q000188:drug therapy*; D000093542:Gemcitabine
D061067:Antibodies, Monoclonal, Humanized; D010919:Placebos; D003841:Deoxycytidine; D000068258:Bevacizumab; D002945:Cisplatin; D000093542:Gemcitabine