Background: Patients with advanced pancreatic neuroendocrine tumors (pNETs) have few treatment options that yield objective tumor regression. Somatostatin analogues, everolimus, and sunitinib yield prolonged progression-free survival (PFS) but low response rates (RRs). Retrospective and small, prospective studies suggest that temozolomide-based therapies may have activity and the combination of temozolomide and capecitabine (TC) is associated with high RRs and relative long PFS. However, there are no randomized, prospective studies of these agents and this trial was initiated to establish a role for the combination of TC. Methods: E2211 was a two-arm, randomized, phase II trial comparing T (200 mg/m2 PO QD days 1-5) vs. TC (T 200 mg/m2 PO QD days 10-14; C 750 mg/m2 PO BID days 1-14) in patients with advanced pNETs. Eligibility criteria included: metastatic or unresectable, low or intermediate grade pNETs, progression within preceding 12 months, and no prior T, C, DTIC, or 5-FU. The primary endpoint was PFS; secondary endpoints were Overall Survival (OS), RR, safety, and predictive value of MGMT as evaluated by immunohistochemistry and promoter methylation. This trial had at least 81% power to detect a difference in median PFS of 9 vs. 14 months (hazard ratio of 0.64) using a two-sided log-rank test at the 0.20 significance level. Results: 144 patients were enrolled at 66 US sites between 8/2013 to 3/2016 to T (n = 72) or TC (n = 72) (intention to treat population). Median age, 62 years; women, 44%. Median PFS was 22.7 months for TC vs. 14.4 months for T (HR = 0.58, p = 0.023) and crossed the pre-specified protocol efficacy boundary. Median OS was 38.0 months for T and has not been reached for TC (HR = 0.41, p = 0.012). Median follow-up was 29 months. RR data will be presented at the meeting. The treatment was well-tolerated with expected AEs and higher rates in the combination arm. Conclusions: In E2211, TC was associated with improved PFS and OS compared to T alone in advanced low or intermediate grade pNETs. This is the first prospective randomized trial of these agents and shows the longest PFS reported for pNET-directed therapy. Clinical trial information: NCT01824875