TY - JOUR
T1 - Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus
AU - Liu, Xiaochun
AU - Kambrick, Susan
AU - Fu, Siqing
AU - Naing, Aung
AU - Subbiah, Vivek
AU - Blumenschein, George R.
AU - Glisson, Bonnie S.
AU - Kies, Merrill S.
AU - Tsimberidou, Apostolia M.
AU - Wheler, Jennifer J.
AU - Zinner, Ralph G.
AU - Hong, David S.
AU - Kurzrock, Razelle
AU - Piha-Paul, Sarina A.
PY - 2016/4/26
Y1 - 2016/4/26
N2 - 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.
AB - 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.
KW - Bevacizumab
KW - Cetuximab
KW - Solid tumors
KW - Temsirolimus
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UR - http://www.scopus.com/inward/citedby.url?scp=84966552475&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.7594
DO - 10.18632/oncotarget.7594
M3 - Article
C2 - 26933802
AN - SCOPUS:84966552475
SN - 1949-2553
VL - 7
SP - 23227
EP - 23238
JO - Oncotarget
JF - Oncotarget
IS - 17
ER -