Metformin use and outcome of sunitinib treatment in diabetic patients with metastatic renal cell carcinoma.

Abstract

440 Background: Sunitinib (Su) is a standard treatment (tx) for metastatic renal cell carcinoma (mRCC). Pre-clinical and clinical studies in several cancer types suggest that the antidiabetic agent metformin (Met) has antitumor activity. Met may negatively regulate mTOR activity. Its effect on the outcome of targeted therapies in mRCC is poorly defined. We analyzed the effect of Met use on the outcome sunitinib tx in diabetic patients (pts) with mRCC. Methods: We performed a retrospective study of an unselected cohort of diabetic pts with mRCC, who were treated with Su in 7 centers across 2 countries. Pts were divided into 2 groups: (1) Met users and (2) Met naive. The effect of Met use on response rate (RR), progression free survival (PFS) and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chisquare test and partial likelihood test from Cox model. Furthermore, univariate and multivariate analyses of association between clinicopathologic factors and Met use, and outcome were performed using the entire pt cohort. Results: Between 2004-2014, 108 diabetic pts with mRCC were treated with sunitinib. There were 52 Met users (group 1) and 56 nonusers (group 2). The groups were balanced regarding the following clinicopathologic factors: age, gender, HENG risk, past nephrectomy, mRCC histology, ≥2 metastatic sites, lung/liver/bone metastasis, prior targeted tx, smoking status, use of angiotensin system inhibitors (ASIs), pre-tx neutrophil to lymphocyte ratio (NLR) >3, Su-induced hypertension (HTN), and Su dose reduction/tx interruption. Clinical benefit (partial response + stable disease) in group 1 vs. group 2 was 96% vs. 84%, while 4% vs. 16% had disease progression within the first 3 months of tx (p=0.054). Median PFS was 15 vs. 11.5 months (p=0.1). Median OS was 32 vs. 21 months (p=0.001). In multivariate analyses of the entire pt cohort (n=108), factors associated with PFS were active smoking (HR=2.7, p<0.0001) and pre-tx NLR >3 (HR 1.8, p=0.012). Factors associated with OS were Met use (HR 0.2, p<0.0001), HENG risk (HR 3.3, p=0.008), active smoking (HR=2.9, p<0.0001), liver metastases (HR 1.8, p=0.004), and pre-tx NLR >3 (HR 3.3, p<0.0001). Conclusions: Met use may improve the OS of diabetic pts with mRCC that are treated with Su.