Capecitabine–Temozolomide Therapy for Pancreatic Neuroendocrine Tumors

Low- and intermediate-grade pancreatic neuroendocrine tumors (NETs) that progress on somatostatin analogue therapy are responsive to systemic therapies, which include sunitinib, everolimus, and streptozotocin- or temozolomide-based chemotherapy. Many chemotherapy case series have been retrospective single-institution reports. Investigators now report results from an open-label, multicenter, randomized, phase 2 trial comparing temozolomide versus the combination of capecitabine and temozolomide in patients with low- or intermediate-grade pancreatic NETs that progressed on prior therapy (somatostatin analogues, everolimus and/or sunitinib).

Of 133 patients, the median age was 61 years, 55% were men, 94% had liver metastases, 35% had received prior everolimus, and 52% received concurrent octreotide therapy. More patients in the temozolomide arm than the combination-therapy arm had intermediate-grade NETs (55% vs. 31%).

The primary endpoint of progression-free survival (PFS) was superior with combination therapy compared with temozolomide at the first interim analysis (median, 22.7 vs. 14.4 months; hazard ratio, 0.58; P=0.022) and in the final analysis (23.2 vs. 15.1 months; HR, 0.71). Adjustment for tumor grade did not impact the PFS benefit (HR, 0.61). A trend towards improved overall survival in the combination-therapy arm compared with the temozolomide arm did not reach statistical significance (median, 58.7 vs. 53.8 months; P=0.42). Response rates were similar for the two regimens (39.7% and 33.7%, respectively). Incidence of grade 3–4 toxicities was higher in the combination-therapy arm (45% vs. 22%). Methyl guanyl methyl transferase (MGMT) deficiency (defined as low immunohistochemistry staining or positive gene promoter methylation leading to gene silencing) correlated with a higher response.