APhase II Trial of Erlotinib in Combinationwith Bevacizumab in Patients withMetastatic Breast Cancer

To evaluate the efficacy and toxicity of erlotinib plus bevacizumab in patients with metastatic breast cancer (MBC), targeting the epidermal growth factor receptor (EGFR/HER1) and the vascular endothelial growth factor (VEGF) pathway. Thirty-eight patients with MBCwere enrolled and treated at two institutions with erlotinib, a small molecule EGFR tyrosine kinase inhibitor (150 mg p.o. daily) plus bevacizumab, an anti-VEGF antibody (15 mg/kg i.v. every 3 weeks). Patients had one to twoprior chemotherapy regimens for metastatic disease. The primary end point was response rate by Response Evaluation Criteria in Solid Tumors criteria using a Simon 2-stage design. Secondary end points included toxicity, time to progression, response duration, and stabilization of disease of z26 weeks. Correlative studies were done on tumor tissue, including EGFR expression and mutation analysis.  One patient achieved a partial response for 52+ months. Fifteen patients had stable disease at first evaluation at 9 weeks; 4 of these patients had stable disease beyond 26 weeks. Median time to progressionwas11weeks (95% confidence interval, 8-18weeks). Diarrhea of any grade was observed in 84% of patients (grade 3 in 3%); 76% experienced grade1or 2 skin rash, and18% developed hypertension (grade 3 in11%).The level of EGFR expression was not predictive of response to therapy. The combination of erlotinib and bevacizumab was well-tolerated but had limited activity in unselected patients with previously treated MBC. Biomarkers are needed to identify those MBC patients likely to respond to anti-EGFR/HER1plus anti-VEGF therapy. Breast cancer is the second leading cause of cancer-related mortality among women in the United States. Although a number of agents have activity in breast cancer, metastatic disease remains incurable. New targeted treatments that delay disease progression while reducing toxicity would therefore represent a significant advance in the care of women with breast cancer. Vascular endothelial growth factor (VEGF) is a central regulator of both normal and pathologic angiogenesis, which is essential for the growth and metastasis of solid tumors (1). VEGF therefore serves as a therapeutic target for inhibiting tumor growth. As proof of this concept, bevacizumab (Avastin; Genentech), a humanized monoclonal antibody that binds the VEGF-A ligand, improved overall survival when added to chemotherapy in patients with metastatic colorectal cancer (2) and non–small cell lung cancer (NSCLC; ref. 3). As a single agent, bevacizumab is also active in metastatic renal cell carcinoma (4) and ovary cancer (5). In metastatic breast cancer (MBC), single-agent bevacizumab produced objective responses in 9.3% of patients in a phase I/II trial (6). In combination with weekly paclitaxel, bevacizumab doubled response rate and significantly prolonged progression-free survival compared with chemotherapy alone as first-line treatment of MBC (progression-free survival, 11.8 versus 5.9 months; hazard ratio, 0.60, P < 0.001; ref. 7). Members of the human epidermal growth factor receptor (EGFR) family (ErbB family) are also proven therapeutic targets for cancer therapy (8). In breast cancer, targeting the human epidermal growth factor receptor 2 (HER2) with trastuzumab (Herceptin; Genentech) improves survival in patients with HER2-positive breast cancer in both the adjuvant (9) and metastatic setting (10). The EGFR or HER1 is another Cancer Therapy:  Breast Cancer Medicine Service and Departments of Pathology, Radiology, and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York ; University of California San Francisco Comprehensive Cancer Center San Francisco, California, Memorial Health University Medical Center, Savannah, Georgia; and National Cancer Institute Bethesda, Maryland Received1/18/08; revised 7/8/08; accepted 7/28/08.  The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact.  Previously presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5 to 8, 2004; and the 41st American Society of Clinical OncologyAnnual Meeting, Orlando, FL, May 13 to 17, 2005. Requests for reprints: Maura N. Dickler, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NewYork, NY10021. Phone: 646-888-4560; Fax: 646-888-4555; E-mail: dicklerm@mskcc.org. F2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-0141 www.aacrjournals.org Clin Cancer Res 2008;14(23) December1, 2008 7878 Research. on April 13, 2017.  Binding of the epidermal growth factor or transforming growth factor a ligand to EGFR triggers downstream signaling pathways that mediate a variety of cellular responses, including cellular proliferation, angiogenesis, and apoptosis (8). Anti-EGFR therapy with erlotinib (Tarceva; OSI Pharmaceuticals), an orally active EGFR tyrosine kinase inhibitor, improves survival in patients with NSCLC (12), and activating mutations in the EGFR gene are predictive of response to therapy in this disease (13, 14). In breast cancer, EGFR expression has ranged widely from 8.3% to 91% in the reported literature (15) and has been associated with a decrease in relapse-free and overall survival (16). However, recent studies using the anti-EGFR tyrosine kinase inhibitors erlotinib and gefitinib (Iressa; Astra-Zeneca) as monotherapy in patients with breast cancer have reported limited activity, with response rates of <5% (17, 18). Preclinical data suggest that the EGFR signaling pathway plays a role in the regulation of angiogenesis (19–22). AntiEGFR therapy with a monoclonal antibody decreases production of angiogenic factors including VEGF, basic fibroblast growth factor, and interleukin-8 (23). In xenograft models, anti-EGFR plus anti-VEGF therapy has increased activity compared with either agent alone (24, 25). We therefore hypothesized that targeting both the EGFR and VEGF pathways may suppress common downstream signaling pathways and increase and/or prolong antitumor activity. Phase II trials of bevacizumab plus erlotinib have reported promising results for patients with renal cell carcinoma (26), NSCLC (27), and carcinomas of unknown primary site (28); and phase I data in NSCLC showed no evidence of a negative pharmacokinetic interaction between these 2 agents (27). Our study sought to evaluate the combination of erlotinib and bevacizumab as targeted therapy in patients with MBC. Patients andMethods Patient eligibility. A total of 38 patients with MBC were enrolled at Memorial Sloan-Kettering Cancer Center, New York, NY, and the University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, from February 2003 to December 2004. Patients with histologically confirmed breast carcinoma were eligible if they had stage IV disease that was stable or progressing after treatment with 1 or 2 chemotherapy regimens. There was no limit on the number of prior endocrine therapies allowed in either the adjuvant or metastatic setting, nor was endocrine therapy required for eligibility. The use of prior adjuvant chemotherapy did not affect eligibility. Additional criteria included measurable disease by Response Evaluation Criteria in Solid Tumors (29), an Eastern Cooperative Oncology Group performance status of V2, and adequate hepatic, renal, and hematologic function. Additionally, if the patient’s tumor was HER2 positive, prior therapy with trastuzumab was required. Although EGFR positivity was not required for eligibility, a tissue sample of the patient’s breast cancer was obtained for retrospective EGFR assessment. Main exclusion criteria included chemotherapy, radiotherapy, immunotherapy, or investigational therapy within 3 wk or hormonal therapy within 2 wk of initiating study treatment. All patients had to have a baseline computed tomography or magnetic resonance imaging of the brain. Patients with central nervous system disease including primary brain tumor, brain metastases, or history of stroke were also ineligible. Prior treatment with VEGFR inhibitors and/or EGFR targeting therapies, major surgery occurring within 28 d before treatment, nonhealing wound or bone fracture, and baseline proteinuria >500 mg/24 h were additional exclusion criteria. Patients with clinically significant cardiovascular disease (e.g., uncontrolled hypertension, myocardial infarction, unstable angina) were excluded. Concurrent administration of bisphosphonates was allowed throughout the study period. The institutional review boards of the two participating centers reviewed and approved this study protocol. All patients gave written informed consent before