Combination therapy with capecitabine and temozolomide in patients with low and high grade neuroendocrine tumors, with an exploratory analysis of O 6 -methylguanine DNA methyltransferase as a biomarker for response

// Dwight H. Owen 1 , Andrew J. Alexander 2 , Bhavana Konda 1 , Lai Wei 3 , Jessica A. Hemminger 4 , Carl R. Schmidt 5 , Sherif R.Z. Abdel-Misih 5 , Mary E. Dillhoff 5 , Jennifer A. Sipos 6 , Lawrence S. Kirschner 6 and Manisha H. Shah 1 1 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 2 Division of Infectious Disease, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 3 Center for Biostatistics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 4 Department of Pathology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 5 Division of Surgical Oncology, Department of Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 6 Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA Correspondence to: Manisha H. Shah, email: Manisha.Shah@osumc.edu Keywords: neuroendocrine tumors; MGMT; temozolomide; capecitabine; immunohistochemistry Received: March 21, 2017      Accepted: October 05, 2017      Published: October 24, 2017 ABSTRACT Recent advances in the treatment of neuroendocrine tumors (NET), including the combination regimen of capecitabine and temozolomide (CAPTEM), have mostly focused on grade 1 and 2 pancreatic neuroendocrine tumors (pNET). We undertook a retrospective review of 38 patients with advanced NET treated with CAPTEM, including patients with non-pancreatic tumors as well as grade 2 and 3 tumors. O 6 -methylguanine DNA methyltransferase (MGMT) expression was assessed as a predictive biomarker. We found that CAPTEM demonstrated activity in patients with all grades and in pNET and non-pNET. Median progression free survival (mPFS) was 13.0 months (95% CI: 5.6-17.0) and median overall survival (mOS) 29.3 months (95% CI 17.7 - 45.3). Among evaluable patients, there were 11 (38%) partial responses, 15 (52%) stable disease, and 3 (10%) progressive disease for a disease control rate of 90%. A higher rate of partial responses occurred in patients whose tumors had low levels of MGMT expression (63%) compared to intermediate-high (17%) (p=0.19). Our results show that CAPTEM therapy is active in patients with NET including in previously treated patients and in those with poorly-differentiated histology. We observed a trend towards increased response rate, median PFS, and median OS in patients whose tumors had low MGMT protein expression.