New insights into renal toxicity of the B-RAF inhibitor, vemurafenib, in patients with metastatic melanoma.

Abstract

Vemurafenib (VMF) is a B-RAF inhibitor used in the treatment of B-RAF-V600-mutant metastatic melanomas. Reports of acute kidney injury (AKI) in patients treated with VMF are scarce. To investigate the incidence and severity of AKI, we conducted a retrospective, observational, monocentric study in the Lyon Sud Hospital University, France, which included 74 patients with metastatic B-RAF-mutated melanomas treated with VMF, between June 2011 and August 2014. According to the Kidney Disease Improving Global Outcomes Guidelines, AKI is defined as an increase in serum creatinine concentration exceeding the baseline concentration by 1.5 fold. Serum creatinine was thus determined before treatment, on a monthly basis during treatment, and 3months after treatment discontinuation. Patients were divided into two main groups: AKI-positive (AKI+) and AKI-negative (AKI-) and further subdivided into three groups according to AKI severity (stage 1, 2 or 3). To visualize the tissue damage caused by VMF, kidney biopsies were performed for two stage 1 AKI+ patients. Of the 74 patients, 30 (40.5%) were AKI-, and of the 44 AKI+ patients (59.5%), 29 (66%) were diagnosed within the first three months of treatment. There were significantly more men in the AKI+ group: n=33 (75%) versus n=12 (40%) women, p=0.004 with an odds ratio for developing AKI of 4.6 (95% CI 1.48-14.23). Most AKI+cases were considered as stage 1 (n=40; 91%) and the remaining four (9%) as stage 2 AKI. Kidney biopsies revealed interstitial fibrosis and acute focal tubular damage. However, renal failure was reversible in 80% of patients within 3months of VMF discontinuation. We observed frequent, reversible, moderately severe AKI with some histological evidence of tubular and interstitial damage in VMF-treated patients, suggesting that renal function should be carefully monitored in male patients, especially during the first 3months.