To the Editor:
Nephrotoxicity is an important adverse effect of BRAF inhibitors, a class of drugs
that are a mainstay for the treatment of advanced BRAF
V600
-mutant metastatic melanoma.1, 2, 3 Encorafenib, a new drug in this class, has recently
been approved in combination with binimetinib, a MEK inhibitor, for patients with
advanced metastatic melanoma.
4
,
5
In the phase 1 trial of this combination, the maximum tolerated doses of encorafenib
were 450 mg daily and 600 mg daily, but 450 mg became the US Food and Drug Administration–approved
dose because 3 patients had unexplained acute kidney injury (AKI) at the higher dose.
6
Up to 93% of participants in the phase 3 COLUMBUS trial of the combination in patients
with advanced melanoma experienced at least a 0.3-mg/dL increase in creatinine level.
4
,
5
We aimed to describe the incidence, timing, and clinical features of AKI in patients
receiving encorafenib-binimetinib for malignant melanoma.
We retrospectively analyzed data from all patients who received encorafenib-binimetinib
at Partners Healthcare between 2013 and 2019. Patients were identified using the Research
Patient Data Registry by both medication list and natural language processing of electronic
health records searching for “encorafenib,” “binimetinib,” or “enco-bini.” Using chart
review, we recorded baseline demographics, comorbid conditions, medications, laboratory
studies, and encorafenib-binimetinib dose and start date. Patients were followed up
for 1 year. The Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used
to diagnose and grade AKI.
7
The cause of AKI was determined by 2 nephrologists (H.S. and M.E.S.). Transient AKI
was defined as AKI that resolved with supportive measures in less than 48 hours. Sustained
AKI persisted longer than 48 hours despite supportive measures. Univariable logistic
regression was used to compare the baseline demographic and clinical characteristics
associated with AKI.
This study was approved by the Institutional Review Board at Partners Healthcare (2017P000501),
and the need for informed consent was waived.
Fifty-seven patients were included; average age was 60 ± 15 years, 53% were men, 89%
were white, 9% had diabetes mellitus, and 53% had hypertension at baseline (Table 1).
The majority (81%) of patients received encorafenib, 450 mg, daily and binimetinib,
45 mg, twice daily. Sixty-seven percent had prior immune checkpoint inhibitor exposure.
Fifteen (26%) patients experienced AKI. Median time to AKI was 27 (interquartile range,
10-53) days. Among the 15 patients, the KDIGO stages of AKI severity were 53% stage
1, 20% stage 2, and 27% stage 3. Use of diuretics and higher doses of encorafenib
were associated with AKI in a univariable logistic regression model.
Table 1
Baseline Characteristics of Patients Receiving Encorafenib and Binimetinib by AKI
Status
Baseline Characteristic
All (N = 57)
No AKI (n = 42)
AKI (n = 15)
P
Age, y
60 (15)
60 (15)
64 (15)
0.31
Male sex
29 (53%)
21 (53%)
8 (53%)
0.45
White race
51 (89%)
37 (88%)
14 (93%)
0.33
Pretreatment serum creatinine, mg/dL
0.9 (0.2)
0.9 (0.2)
0.8 (0.2)
0.35
Estimated glomerular filtration rate, mL/min
96 (26)
95 (25)
98 (29)
0.69
Chronic kidney disease
6 (11%)
5 (12%)
1 (7%)
0.57
Diabetes mellitus
5 (9%)
2 (5%)
3 (20%)
0.07
Hypertension
30 (53%)
23 (55%)
7 (47%)
0.59
Coronary artery disease
7 (12%)
4 (10%)
3 (20%)
0.29
Congestive heart failure
2 (4%)
2 (5%)
0 (0%)
0.39
Prior immune checkpoint inhibitor exposure
38 (67%)
28 (67%)
10 (67%)
1.00
Prior chemotherapy within 6 mo
10 (18%)
9 (21%)
1 (7%)
0.20
ACEi or ARB use
9 (16%)
7 (17%)
2 (13%)
0.76
NSAID use
7 (12%)
4 (10%)
3 (20%)
0.29
Diuretic use
4 (7%)
1 (2%)
3 (20%)
<0.01
Encorafenib dose (daily)
≥450 mg
46 (81%)
31 (74%)
15 (100%)
<0.01
<450 mg
11 (19%)
11 (26%)
0 (0%)
Binimetinib dose (daily)
90 mg
49 (86%)
34 (81%)
15 (100%)
<0.01
<90 mg
8 (14%)
8 (19%)
0 (0%)
Note: Overall cohort and univariable comparison of baseline characteristics in patients
with AKI compared with those without AKI. Chronic kidney disease was defined as estimated
glomerular filtration rate < 60 mL/min/1.73 m2. Values expressed as number (percent)
or mean (standard deviation). Conversion factors for units: creatinine in mg/dL to
μmol/L, ×88.4.
Abbreviations: AKI, acute kidney injury; ACEi, angiotensin-converting enzyme inhibitor;
ARB, angiotensin receptor blocker; NSAID, nonsteroidal anti-inflammatory drug.
Ten of 15 (67%) patients with AKI had transient AKI; this resulted from either side
effects of BRAF inhibitor (fever, vomiting, and diarrhea) in 8 patients or from a
documented infection (pyelonephritis or diverticulitis). Sustained AKI occurred in
5 (33%) patients; 3 experienced tubular toxicity attributed to encorafenib and 2 experienced
AKI from tumor lysis syndrome. Sustained AKI lasted a median of 10 (range, 3-37) days.
No patient had significant proteinuria (protein excretion > 0.3 g/g). Three (20%)
had microscopic hematuria (>10 red blood cells per high-power field) and 2 patients
had leukocyturia (>10 white blood cells per high-power field). All 3 patients with
tubular toxicity had normal urine sediment without cellular casts. Eleven (73%) patients
were hospitalized at the time of AKI. Four (27%) saw a nephrologist. None of the patients
underwent kidney biopsy. The majority required dose reduction or treatment discontinuation
(66%). Five (33%) patients continued full-dose encorafenib with eventual resolution
of AKI with supportive care. Kidney function recovered to within 0.3 mg/dL of pre-AKI
baseline in all but 2 patients. The 6-month mortality was 27% for patients with AKI
and 14% for patients without AKI.
Nephrotoxicity is a common and important side effect of encorafenib-binimetinib treatment.
Twenty-six percent of patients experienced clinically significant AKI, at a median
of 27 days after starting therapy. The majority required hospitalization and dose
reduction or treatment discontinuation due to AKI. We have determined that the clinical
features of AKI in patients receiving encorafenib-binimetinib ranged from transient
AKI resolving with hemodynamic support to sustained AKI events likely due to tubular
nephrotoxicity or tumor lysis syndrome. This is consistent with kidney biopsy findings
from patients receiving other BRAF inhibitors showing acute and chronic tubular injury
as the dominant finding, though interstitial nephritis may be concurrently found.
1
,
2
The incidence of AKI with encorafenib-binimetinib may be lower than in patients receiving
other BRAF inhibitors; a retrospective analysis of 74 patients with melanoma receiving
vemurafenib demonstrated 60% incidence of at least stage 1 AKI.
2
Our main limitations were the small sample size with only limited numbers experiencing
sustained AKI and lack of biopsy-confirmed diagnosis, relying on retrospective adjudication
by 2 nephrologists.
In conclusion, oncologists and nephrologists should be aware of the substantial incidence
of clinically significant AKI with encorafenib-binimetinib. It is reassuring that
the majority of AKI was transient and almost all patients had recovery to their baseline.
However, patients frequently required hospitalization and treatment interruption or
discontinuation; this may lead to higher treatment failure rates and mortality. Future
studies are needed to help improve AKI risk stratification for patients receiving
BRAF inhibitor therapies for melanoma and other cancers.