The selective BRAF inhibitors vemurafenib (Zelboraf, Roche/Plexxikon) and dabrafenib (Tafinlar, GlaxoSmithKline) have significantly improved survival in patients with BRAFV600–mutant metastatic melanoma, when compared with standard therapy.
However, both of these drugs appear to be associated with an increased risk for acute kidney injury.
According to a new report published in the November issue of JAMA Oncology, data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) revealed that from July 2011 through June 2014, 132 cases of acute kidney injury were reported in patients receiving vemurafenib therapy. In addition, 13 cases of renal injury were reported in those receiving dabrafenib.
"The FDA adverse reporting system is a physician-based reporting directly to the agency," explained lead author, Kenar D. Jhaveri, MD, associate professor of medicine at Hofstra North Shore Long Island Jewish School of Medicine, Great Neck, New York. "It doesn't involve peer review or publication or detailed information, and it is a crude database that only provides a potential signal of potential toxicities post marketing."
"Published case series or case reports are obviously peer reviewed and are more reliable," he told Medscape Medical News.
However, even though FAERS is an unsophisticated database with scant demographic information, Dr Jhaveri and his coauthors note, the number of acute kidney injury cases reported with BRAF inhibitor therapy is "still alarming."
"Dermatologists, oncologists, and nephrologists need to be aware of this potential hazard," they write.
Scant Literature Available
A few cases studies have previously reported severe renal insufficiency in patients with melanoma receiving vemurafenib. A paper published last year (Cancer. 2014;120:2158-2163) outlined a case series of eight patients who experienced significant to severe renal insufficiency associated with vemurafenib treatment. The authors concluded that vemurafenib may induce potentially severe acute renal failure, including renal sequelae and persistent kidney disease in some cases, and they recommended that renal function should be closely monitored to detect early signs of renal dysfunction.
"Dabrafenib has no published case reports yet in the literature," said Dr Jhaveri. "At this point, based on both published literature and FAERS reporting, vemurafenib is more renal toxic."
The full prescribing information for each drug also does not contain any warnings about renal toxicity or list any type of renal problem as an adverse event.
Dr Jhaveri thinks the reason for that is the rarity of renal events in terms of the larger perspective. "If one takes the incidence of melanoma in US, and the rate or renal injury with these agents, the events are scarce," he said. "It is also possible that they do happen, but the renal injury is transient and not reported."
Need to Monitor Renal Function
In this study, the authors reviewed the FAERS data on renal toxic effects for both agents. A total of 132 cases of acute kidney injury were reported in patients receiving vemurafenib, which primarily occurred in men (n = 85).
Mean ages were 65 years for men and 59 years for women (P = .04). While the cases were reported from all over the world, France, the United States, and Germany accounted for most of them.
In addition, 14 cases of electrolyte disorders (6 cases of hypokalemia and 8 cases of hyponatremia) were also reported with vemurafenib. The FAERS data file also showed 13 reported cases of acute kidney injury in patients receiving dabrafenib during the study period. Similar to vemurafenib, most cases were in men (12 of 13). The mean age of the men was 55 years; the one female patient was aged 75 years (P = .002).
Eight cases of electrolyte disorders were also reported with dabrafenib: two cases of hypokalemia and six cases of hyponatremia.
"On the basis of our findings, there is a heightened need to monitor renal function and electrolyte levels in all patients who receive these drugs," conclude the authors. "Kidney biopsies are needed to elucidate the mechanism behind the toxicity."
The authors have disclosed no relevant financial relationships.
JAMA Oncol. 2015;1:1133-1134. Abstract