Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus
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Xiaochun Liu1, Susan Kambrick1, Siqing Fu1, Aung Naing1, Vivek Subbiah1, George R. Blumenschein2, Bonnie S. Glisson2, Merrill S. Kies2, Apostolia M. Tsimberidou1, Jennifer J. Wheler1, Ralph G. Zinner1, David S. Hong1, Razelle Kurzrock3 and Sarina A. Piha-Paul1
1 Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
2 Department of Thoracic/Head & Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
3 Division of Hematology and Oncology, University of California San Diego, Moores Cancer Center, San Diego, CA, USA
Sarina A. Piha-Paul, email:
Keywords: solid tumors, bevacizumab, cetuximab, temsirolimus
Received: August 20, 2015 Accepted: February 05, 2016 Published: February 24, 2016
BACKGROUND: Bevacizumab and temsirolimus are active agents in advanced solid tumors. Temsirolimus inhibits mTOR in the PI3 kinase/AKT/mTOR pathway as well as CYP2A, which may be a resistance mechanism for cetuximab. In addition, temsirolimus attenuates upregulation of HIF-1α levels, which may be a resistance mechanism for bevacizumab.
RESULTS: The median age of patients was 60 years (range, 23-80 years). The median number of prior systemic therapies was 3 (range, 1-6). The maximum tolerated dose (MTD) was determined to be bevacizumab 10 mg/kg biweekly, temsirolimus 5 mg weekly and cetuximab 100/75 mg/m2 weekly. Grade 3 or 4 toxicities were seen in 52% of patients with the highest prevalence being hyperglycemia (14%) and hypophosphatemia (14%). Eighteen of the 21 patients were evaluable for response. Three patients were taken off the study before restaging for toxicities. Partial response (PR) was observed in 2/18 patients (11%) and stable disease (SD) lasting ≥ 6 months was observed in 4/18 patients (22%) (total = 6/18 (33%)). In 8 evaluable patients with squamous cell carcinoma of the head and neck (HNSCC) there were partial responses in 2/8 (25%) patients and SD ≥ 6 months in 1/8 (13%) patients (total = 3/8, (38%)).
PATIENTS AND METHODS: We analyzed safety and responses in 21 patients with advanced solid tumors treated with bevacizumab, cetuximab, and temsirolimus.
CONCLUSION: The combination of bevacizumab, cetuximab, and temsirolimus showed activity in HNSCC; however, there were numerous toxicities reported, which will require careful management for future clinical development.
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