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

Clin Cancer Res. 2010 Nov 1;16(21):5320-8. doi: 10.1158/1078-0432.CCR-10-0974.


Purpose: 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.

Experimental design: 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.

Trial registration: ClinicalTrials.gov NCT00696670.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bevacizumab
  • Carcinoma / diagnosis
  • Carcinoma / drug therapy*
  • Carcinoma / genetics
  • Disease Progression
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Erlotinib Hydrochloride
  • Female
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Likelihood Functions
  • Ovarian Neoplasms / diagnosis
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Platinum Compounds / therapeutic use
  • Prognosis
  • Quinazolines / administration & dosage*
  • Quinazolines / adverse effects
  • Treatment Outcome
  • Tumor Microenvironment / genetics
  • Up-Regulation / genetics
  • Up-Regulation / physiology
  • Vascular Endothelial Growth Factor A / genetics*
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor A / physiology


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Platinum Compounds
  • Quinazolines
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Bevacizumab
  • Erlotinib Hydrochloride

Associated data

  • ClinicalTrials.gov/NCT00696670