Metformin impact on progression-free survival in diabetic patients with advanced pancreatic neuroendocrine tumors (pNET) receiving everolimus and/or somatostatin analogues. The PRIME-NET (Pancreatic multicentric, Retrospective, Italian MEtformin) study

Background

In phase III trials, both everolimus (EVE), and somatostatin analogues (SA) have shown antitumor efficacy in pNETs. Some studies have identified diabetic patients (pts) as having increased risk for the development of cancer and have associated metformin (MET) treatment with a decrease of cancer risk. MET may have anti-proliferative activity due to its ability to decrease insulin and IGF1 levels; in addition, it promotes AMPK activation and TSC1-2/mTOR inhibition. This multicentric, retrospective study evaluates the impact of glycemic status (hyper vs normoglycemic pts) on progression-free survival (PFS); the impact of concomitant MET administered during EVE and/or SA therapy in diabetic pNETs is also assessed.

Methods

To obtain a 90% statistical power, with α error 0.05, and to detect an HR of progression (PD) of 0.67 for hyperglycemic vs normoglycemic pts, 267 events (PD or deaths without PD) were needed, and 445 pts were planned. With these numbers, 77% power was anticipated to detect HR 0.67 in each subgroup analysis (hyperglycemic pts on MET vs normoglycemic and hyperglycemic pts on INS vs normoglycemic pts).

Results

Between 1999 and 2016, 445 pts (median age 59, range 49-69; 53.5% males), were treated with EVE and/or SA in 24 Italian Centers. In total, 112 (25.2%) diabetic pts received MET, 91 (20.4%) received INS and 33 (7.7%) received dietetic counseling; 209 (46.7%) pts were normoglycemic. In the overall population, median PFS was 23.4 months (mo) (95%CI 19.1–27.9); mPFS was 32.0 mo in diabetic pts and 15.1 mo in normoglycemic pts (HR 0.63, 95%CI 0.50-0.80; p = 0.0002). Median PFS was 20.8 mo (95%CI 15.6-36.3) in pts receving INS (HR vs normoglycemic pts 0.81, 95%CI 0.60-1.1, p = 0.18) and 44.2 mo (95%CI 36.4-61.9) in pts on MET (HR vs normoglycemic pts 0.45, 95%CI 0.32-0.62, p 

Conclusions

With the limitations of any retrospective analysis, the results of this large study may suggest that the addition of MET to EVE and /or SA can provide clinical benefits in advanced diabetic pNETs pts. Prospective evaluations are required to confirm these preliminary findings.

Clinical trial identification

Protocol number INT 85/15, approved by Ethical committee of Fondazione IRCCS Istituto tumori Milano on 15 June 2015.

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale Tumori di Milano

Funding

Fondazione IRCCS Istituto Nazionale Tumori di Milano

Disclosure

S. Pusceddu: Ipsen, Novartis, Italfarmaco, Pfizer.

All other authors have declared no conflicts of interest.