Cisplatin
Platinol · Platinum agent
Proximal tubular ATN + magnesium wasting; the archetype.
ATNLYTEPRE
SevereOpen →
BRAF inhibitor
Encorafenib
Braftovi · Enco
A BRAF inhibitor whose kidney signal is a mild, usually class-shared tubular/interstitial effect.
MildBRAF inhibitor · approved 2018
BRAF V600-mutant melanomaBRAF V600E-mutant metastatic colorectal cancer
Signature kidney injury
Acute Tubular Necrosis
Renal injury with BRAF/MEK therapy is uncommon and largely case-level (tubular injury and acute interstitial nephritis reported); usually mild and reversible with drug interruption. In COLUMBUS, grade 3-4 creatine-phosphokinase elevation (7%) and hypertension (6%) were the renally relevant grade 3-4 events with encorafenib plus binimetinib.
Source: Sanagawa et al., Anticancer Drugs 2021
Mechanism of kidney injury
BRAF/MEK pathway inhibition has been associated in case reports, real-world pharmacovigilance, and human kidney-cell models with proximal tubular injury and acute interstitial nephritis; the precise mechanism is not fully defined and the signal is typically mild relative to vemurafenib. Indirect injury can also arise from MEK-inhibitor-related CK elevation/rhabdomyolysis when binimetinib is co-administered.
Clinical presentation
Modest creatinine rise, occasionally with electrolyte changes; biopsy-proven acute interstitial nephritis (sometimes with eosinophilia, sterile pyuria, or sub-nephrotic proteinuria) has been described with BRAF/MEK regimens. Often reversible after holding therapy, with or without corticosteroids.
Onset
Weeks into therapy when it occurs.
Reversibility
Reversible
Anticancer mechanism
Selective inhibitor of mutant BRAF V600E/K kinase with a long target-residence time, blocking constitutive MAPK pathway signaling. Used (with binimetinib) in BRAF V600-mutant melanoma and (with cetuximab) in BRAF V600E-mutant colorectal cancer.
Management
Hold drug for significant AKI; supportive care and volume repletion; corticosteroids if biopsy-proven (or strongly suspected) interstitial nephritis; rechallenge cautiously — case data describe successfully switching to the alternative BRAF/MEK regimen after AIN.
Risk factors
- Concurrent nephrotoxins or other AIN-associated drugs (PPIs, NSAIDs)
- Volume depletion
- Pre-existing CKD
Prevention
- Baseline and periodic creatinine/electrolytes
- Avoid concurrent nephrotoxins
- Maintain volume status
Note · Renal signal is largely extrapolated from the BRAF/MEK class; encorafenib-specific nephrotoxicity data are limited.
Clinical depth
Renal dose adjustment
No dedicated renal dose adjustment established; no change recommended for mild-moderate impairment, and severe impairment/dialysis are not studied (use with caution). Dose modifications are driven mainly by CK, hepatic, and cardiac (QT) toxicity.
Dialyzability & ESKD dosing
Highly protein-bound oral small molecule; not expected to be appreciably removed by dialysis. No validated ESKD dosing.
Differential diagnosis
BRAF/MEK-associated AIN vs prerenal azotemia (volume status, FENa), vs ATN from co-nephrotoxins or rhabdomyolysis (check CK, urine myoglobin), vs immune-checkpoint-inhibitor AIN if prior/concurrent ICI. Eosinophiluria and sterile pyuria favor AIN but are neither sensitive nor specific.
Monitoring
- Serum creatinine and electrolytes at baseline and periodically
- Creatine phosphokinase periodically (with binimetinib) and with any myalgia
- ECG/QTc and LVEF per label given the combined cardiac signal
Key trials & series
- COLUMBUS (encorafenib + binimetinib vs vemurafenib in BRAF-mutant melanoma)
- BEACON CRC (encorafenib + cetuximab in BRAF V600E colorectal cancer)
- Sanagawa 2021 real-world BRAF/MEK nephrotoxicity analysis
Clinical pearls
- Encorafenib's renal signal is largely extrapolated from the BRAF/MEK class — drug-specific data are limited, so keep the differential broad.
- With a binimetinib partner, a rising creatinine plus myalgia should prompt a CK to exclude rhabdomyolysis.
- Biopsy-proven AIN can sometimes be managed by switching to the alternative BRAF/MEK combination rather than abandoning targeted therapy.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Interstitium
Supporting tissue around the tubules
Injury signatures
Acute Tubular NecrosisAcute Interstitial Nephritis
Beyond the kidney
Class-level context for the major non-renal toxicities of braf inhibitors.
Dermatologic
Rash, HFS, SJS/TEN, vitiligo
- Rash, photosensitivity, squamous-cell carcinomas (BRAF)
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- Reduced LVEF (MEK)
Ophthalmic
Keratopathy, uveitis, retinopathy
- Retinopathy / retinal vein occlusion (MEK)
Vascular
Hypertension, VTE/ATE, bleeding, aneurysm
- Pyrexia syndrome, hypertension
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkBRAF/MEK inhibitor-associated nephrotoxicity in a real-world setting and human kidney cells.Sanagawa A et al. · Anticancer Drugs 2021 · PMID 34232935Real-world pharmacovigilance plus in vitro data characterizing BRAF/MEK inhibitor renal injury.PMIDTruth or dare: switching BRAF/MEK inhibitors after acute interstitial nephritis in a patient with metastatic melanoma - A case report and review of the literature.De Ryck L et al. · Acta Clin Belg 2022 · PMID 35996969Case report and literature review of acute interstitial nephritis with BRAF/MEK therapy and successful rechallenge by switching agents.PMIDEncorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial.Dummer R et al. · Lancet Oncol 2018 · PMID 29573941Pivotal COLUMBUS trial: grade 3-4 CK elevation and hypertension among the most common severe AEs with encorafenib + binimetinib.PMIDOverall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial.Dummer R et al. · Lancet Oncol 2018 · PMID 30219628COLUMBUS overall-survival analysis confirming the CK-elevation and hypertension safety signal.PMIDEncorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer.Kopetz S et al. · N Engl J Med 2019 · PMID 31566309Pivotal BEACON CRC trial: registrational safety dataset for encorafenib in colorectal cancer.PMIDCurrent Trends in Anti-Cancer Molecular Targeted Therapies: Renal Complications and Their Histological Features.Tonooka A et al. · J Nippon Med Sch 2021 · PMID 34840210Onconephrology review of renal complications of targeted small-molecule therapies.