Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus. Oncotarget 2016 Apr 26;7(17):23227-38
Date
03/05/2016Pubmed ID
26933802Pubmed Central ID
PMC5029622DOI
10.18632/oncotarget.7594Scopus ID
2-s2.0-84966552475 (requires institutional sign-in at Scopus site) 22 CitationsAbstract
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.
PATIENTS AND METHODS: We analyzed safety and responses in 21 patients with advanced solid tumors treated with bevacizumab, cetuximab, and temsirolimus.
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%)).
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.
Author List
Liu X, Kambrick S, Fu S, Naing A, Subbiah V, Blumenschein GR, Glisson BS, Kies MS, Tsimberidou AM, Wheler JJ, Zinner RG, Hong DS, Kurzrock R, Piha-Paul SAAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Bevacizumab
Cetuximab
Female
Follow-Up Studies
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms
Prognosis
Sirolimus
Survival Rate