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

Setsuko K Chambers, Mary C. Clouser, Amanda F Baker, Denise Roe, Haiyan Cui, Molly A. Brewer, Kenneth D Hatch, Michael S. Gordon, Mike F. Janicek, Jeffrey D. Isaacs, Alan N. Gordon, Raymond B Nagle, Heather M. Wright, Janice L. Cohen, David S Alberts

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)5320-5328
Number of pages9
JournalClinical Cancer Research
Volume16
Issue number21
DOIs
StatePublished - Nov 1 2010

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Ovarian Neoplasms
Vascular Endothelial Growth Factor A
Disease-Free Survival
Neoplasms
Nasal Septal Perforation
Biomarkers
Angiogenic Proteins
Tumor Microenvironment
Exanthema
Platinum
Fistula
Fatigue
Disease Progression
Diarrhea
Research Design
Myocardial Infarction
Confidence Intervals
Hypertension
Bevacizumab
Erlotinib Hydrochloride

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / Chambers, Setsuko K; Clouser, Mary C.; Baker, Amanda F; Roe, Denise; Cui, Haiyan; Brewer, Molly A.; Hatch, Kenneth D; Gordon, Michael S.; Janicek, Mike F.; Isaacs, Jeffrey D.; Gordon, Alan N.; Nagle, Raymond B; Wright, Heather M.; Cohen, Janice L.; Alberts, David S.

In: Clinical Cancer Research, Vol. 16, No. 21, 01.11.2010, p. 5320-5328.

Research output: Contribution to journalArticle

Chambers, Setsuko K ; Clouser, Mary C. ; Baker, Amanda F ; Roe, Denise ; Cui, Haiyan ; Brewer, Molly A. ; Hatch, Kenneth D ; Gordon, Michael S. ; Janicek, Mike F. ; Isaacs, Jeffrey D. ; Gordon, Alan N. ; Nagle, Raymond B ; Wright, Heather M. ; Cohen, Janice L. ; Alberts, David S. / 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. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 21. pp. 5320-5328.
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abstract = "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.",
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T1 - 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

AU - Chambers, Setsuko K

AU - Clouser, Mary C.

AU - Baker, Amanda F

AU - Roe, Denise

AU - Cui, Haiyan

AU - Brewer, Molly A.

AU - Hatch, Kenneth D

AU - Gordon, Michael S.

AU - Janicek, Mike F.

AU - Isaacs, Jeffrey D.

AU - Gordon, Alan N.

AU - Nagle, Raymond B

AU - Wright, Heather M.

AU - Cohen, Janice L.

AU - Alberts, David S

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N2 - 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.

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