Randomized run-in study of bevacizumab (B) and everolimus (E) in low- to intermediate-grade neuroendocrine tumors (LGNETs) using perfusion CT as functional biomarker.

Abstract

4002 Background: Studies have shown promising results for mTOR inhibitor, E, and VEGF inhibitor, B, in LGNETs. In our prior study, decrease in tumor blood flow (BF) following B was proportional to baseline BF suggesting B decreased BF by a fixed percentage. Methods: LGNET patients with lesion(s) ≥ 3 cm were randomized to therapy with B or E for one 21-day cycle. On cycle 2 day 1, the alternate agent was added (B+E). Functional CTs (fCTs) assessing tumor BF, blood volume (BV), mean transit time (MTT), and permeability surface (PS) were mandatory. Primary objectives were to determine the effects of B or E as well as B+E on BF. Response was evaluated by RECIST every 9 weeks. Results: 112 fCTs were performed among 39 eligible (treated) patients. 64 lesions among 36 patients were evaluated at 3 time points. B alone led to a 32% decrease in BF (p<0.01) and no significant change in MTT. E alone was associated with increase in MTT (13%; p=0.02) but not with decrease in BF. Addition of E to B led to a further decrease in BF (15%; p=0.02) and increase in MTT (22%; p<0.01). Addition of B to E resulted in a 21% decrease in BF (p=0.01) and no significant change in MTT. By ITT analyses, there were 10 PR (26%), 27 SD (69%), 1 PD (3%), 1 not assessable (3%). PFS rate at 6-month was 92%; median was 14.4 months (95% CI, 12.7-16.1). The 12- and 24-month overall survival rates were 92% and 87% (median not reached). RECIST PR was associated with fCT parameters (all p<0.05) including: higher baseline permeability surface, higher post-treatment MTT, higher percentage decrease in BF, BV, and higher percentage increase in MTT. CTC G3/4 AE occurring in 2 or more patients included: neutropenia (15%), proteinuria (10%), hyperglycemia (10%), anemia (8%), and 5% in each of thrombocytopenia, elevated ALT, elevated AST, fatigue, GI bleed, hypertriglyceridemia, infection, nausea, vomiting, small bowel obstruction, pneumonitis, weight loss. Conclusions: B decreased tumor BF. Addition of E to B was associated with further decrease in BF. B+E demonstrated antitumor activity in LGNET. fCT is a promising surrogate marker for selection of patients likely to benefit from therapy. Confirmatory studies are warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis GE Healthcare, Genentech, Novartis