Renal effects of BRAF inhibitors: a systematic review by the Cancer and the Kidney International Network

Abstract

Advanced melanoma has been traditionally unresponsive to standard chemotherapy agents and used to have a dismal prognosis. Genetically targeted small-molecule inhibitors of the oncogenic BRAF V600 mutation or a downstream signaling partner (MEK mitogen-activated protein kinase) are effective treatment options for the 40-50% of melanomas that harbor mutations in BRAF. Selective BRAF and MEK inhibitors induce frequent and dramatic objective responses and markedly improve survival compared with cytotoxic chemotherapy. In the past decade after discovery of this mutation, drugs such as vemurafenib and dabrafenib have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of V600-mutated melanomas. While the initial trials did not signal any renal toxicities with the BRAF inhibitors, recent case reports, case series and FDA adverse reporting systems have uncovered significant nephrotoxicities with these agents. In this article, we systematically review the nephrotoxicities of these agents. Based on recently published data, it appears that there are lower rates of kidney disease and cutaneous lesions seen with dabrafenib compared with vemurafenib. The pathology reported in the few kidney biopsies done so far are suggestive of tubulo interstitial damage with an acute and chronic component. Electrolyte disorders such as hypokalemia, hyponatremia and hypophosphatemia have been reported as well. Routine monitoring of serum creatinine and electrolytes and calculation of glomerular filtration rate prior to the first administration when treating with dabrafenib and vemurafenib are essential.

Keywords: BRAF inhibitors; dabrafenib; onconephrology; vemurafenib.

Fig. 1.

Mechanism of action of BRAF inhibitors.