Rationale for mTOR Inhibition in pNETs

Genomic studies have shown that select individuals with pancreatic neuroendocrine tumors (pNETs) express mutations in the mTOR pathway. Building upon this, results from the phase III, placebo-controlled RADIANT-3 study demonstrated improvements in progression-free survival in patients with advanced pNETs who received everolimus, an mTOR inhibitor, compared with those who received best supportive care.

In the study, median progression-free survival was 11 months in the everolimus arm versus 4.6 months in the placebo arm, says James C. Yao, MD. Other studies have suggested that patients who do not have mutations in these pathways can still benefit from treatment with mTOR inhibitors, states Matthew H. Kulke, MD.

Selection of which targeted agents to use in patients with pNETs depends on the safety profile of the medications, comments Yao. For example, everolimus may be favored over sunitinib, a tyrosine kinase inhibitor, in individuals with hypertension or history of cardiovascular disease and heart failure, while sunitinib may be preferred in patients with uncontrolled diabetes or oxygen-dependent COPD.

Everolimus may also be preferred in the setting of functional tumors because data indicate that everolimus delays disease progression and reduces tumor-secreted hormones from pNETs. The data for gastrin and glucagon are quite strong in this setting, notes Yao, and other data suggest that everolimus may be effective in controlling malignant hypoglycemia among patients with metastatic insulinomas.