Overexpression of tumor vascular endothelial growth factor A may portend an increased likelihood of progression in a phase II trial of bevacizumab and erlotinib in resistant ovarian cancer.
OBJECTIVE
This phase II trial evaluated bevacizumab plus erlotinib in platinum-resistant ovarian cancer; exploratory biomarker analyses, including that of tumor vascular endothelial growth factor A (VEGF-A), were also done.


METHODS
Forty heavily pretreated patients received erlotinib (150 mg/d orally) and bevacizumab (10 mg/kg i.v.) every 2 weeks until disease progression. Primary end points were objective response rate and response duration; secondary end points included progression-free survival (PFS), toxicity, and correlations between angiogenic protein levels, toxicity, and efficacy.


RESULTS
Grade 3 toxicities included skin rash (n = 6), diarrhea (n = 5), fatigue (n = 4), and hypertension (n = 3). Grade 4 toxicities were myocardial infarction (n = 1) and nasal septal perforation (n = 1). Only one grade 3 fistula and one grade 2 bowel perforation were observed. Nine (23.1%) of 39 evaluable patients had a response (median duration, 36.1+ weeks; one complete response), and 10 (25.6%) patients achieved stable disease, for a disease control rate of 49%. Median PFS was 4 months, and 6-month PFS was 30.8%. Biomarker analyses identified an association between tumor cell VEGF-A expression and progression (P = 0.03); for every 100-unit increase in the VEGF-A score, there was a 3.7-fold increase in the odds of progression (95% confidence interval, 1.1-16.6).


CONCLUSIONS
Bevacizumab plus erlotinib in heavily pretreated ovarian cancer patients was clinically active and well tolerated. Erlotinib did not seem to contribute to efficacy. Our study raises the intriguing possibility that high levels of tumor cell VEGF-A, capable of both autocrine and paracrine interactions, are associated with resistance to bevacizumab, emphasizing the complexity of the tumor microenvironment.
Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724-5024, USA. schambers@azcc.arizona.edu
Setsuko K
SK
Chambers
Mary C
MC
Clouser
Amanda F
AF
Baker
Denise J
DJ
Roe
Haiyan
H
Cui
Molly A
MA
Brewer
Kenneth D
KD
Hatch
Michael S
MS
Gordon
Mike F
MF
Janicek
Jeffrey D
JD
Isaacs
Alan N
AN
Gordon
Raymond B
RB
Nagle
Heather M
HM
Wright
Janice L
JL
Cohen
David S
DS
Alberts
D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D002277:Carcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D016013:Likelihood Functions; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D017671:Platinum Compounds / Q000627:therapeutic use; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017671:Platinum Compounds; D011799:Quinazolines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride