Background: Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective tumor response. Retrospective and small, prospective studies suggest that the combination of capecitabine and temozolomide is associated with high response rates (RR) and relative long progression-free survival (PFS). This trial was conducted to establish a role for the combination of capecitabine and temozolomide. Methods: E2211 was a multicenter, randomized, phase II trial comparing temozolomide (200 mg/m2 PO QD days 1-5) vs. capecitabine/temozolomide (capecitabine 750 mg/m2 PO BID days 1-14; temozolomide 200 mg/m2 PO QD days 10-14) in patients with advanced pancreatic NETs. Eligibility criteria included: metastatic or unresectable, low or intermediate grade pancreatic NETs, progression within preceding 12 months, and no prior temozolomide, DTIC, capecitabine or 5-fluorouracil. The primary endpoint was PFS; secondary endpoints were Overall Survival (OS), RR, safety, and MGMT as evaluated by immunohistochemistry (IHC) and promoter methylation. Allowing for 5% ineligibility, 145 randomized patients were required to obtain 138 eligible patients to detect a difference in median PFS of 9 versus 14 months (hazard ratio of 0.64) using a two-sided log-rank test at the overall 0.20 significance level with 81% power. Results: 144 patients were enrolled between 4/2013 to 3/2016 to temozolomide (n = 72) or capecitabine/temozolomide (n = 72); the efficacy analysis population included 133 eligible patients. At the scheduled interim analysis in January 2018, median PFS was 14.4 months for temozolomide vs. 22.7 months for capecitabine/temozolomide (HR = 0.58), which was sufficient to reject the null hypothesis for this final primary endpoint (stratified log rank p = 0.022. In the final analysis (5/2021), median OS was 53.8 months for temozolomide and 58.7 months for capecitabine/temozolomide (HR = 0.82, p = 0.42) and RR was 34% for temozolomide and 40% for capecitabine/temozolomide (p = 0.59). Capecitabine/temozolomide was associated with higher rates of grade 3-4 AEs (45% vs. 22%, p = 0.005). MGMT deficiency, defined as either low IHC or positive promoter methylation, was associated with greater odds of response (OR [95% CI] = 6.38 [2.19, 18.60] and 9.79 [1.09, 87.71], respectively). Conclusions: E2211 is the first prospective randomized trial of capecitabine/temozolomide and shows the longest PFS and highest RR reported for patients with pancreatic NETs in a prospective randomized study. MGMT deficiency was associated with greater odds of objective response. Clinical trial information: NCT01824875.