Avutometinib

Electrolyte Disturbance — representative incidence ~24%.

No discrete acute-kidney-injury incidence has been reported for avutometinib. The best-quantified kidney-relevant signal is marked creatine phosphokinase (CPK) elevation: in the registrational RAMP 201 combination cohort (avutometinib + defactinib, n=115), grade >=3 CPK elevation occurred in 24% of patients — the single most common grade >=3 treatment-related adverse event — with grade >=3 diarrhea in 8% and anemia in 5%. A CPK rise of this magnitude is a recognized rhabdomyolysis-risk surrogate, not a measured AKI rate: most CPK elevations are asymptomatic skeletal-muscle elevations that do not injure the kidney, but sustained rhabdomyolysis-range values can precipitate pigment (myoglobin-cast) tubular injury, and high-grade diarrhea can drive prerenal azotemia and electrolyte loss. Across the MEK-inhibitor class, direct AKI signals are modest (FAERS AKI reporting-odds-ratios roughly 1.3 for trametinib and 4.4 for cobimetinib). All figures derive from a small phase II dataset and are hedged accordingly.

Source: Banerjee, J Clin Oncol 2025 (RAMP 201: grade >=3 CPK elevation 24%)

Reported injury signatures: Electrolyte Disturbance, Acute Tubular Necrosis, Prerenal / Hemodynamic AKI.

1. Electrolyte DisturbancePrimary
2. Acute Tubular NecrosisSecondary
3. Prerenal / Hemodynamic AKISecondary

Subacute (~1–6 weeks) — CPK elevation and diarrhea emerge within the first one to two cycles (first weeks); treatment-associated AKI clustered within the first three months.

• Baseline chronic kidney disease or reduced renal reserve
• Volume depletion or ongoing grade >=3 diarrhea
• Concomitant myotoxic drugs (statins, fibrates) or other nephrotoxins
• Pre-existing muscle disease or baseline/exertional CPK elevation
• Diuretics or RAAS inhibitors (predispose to prerenal azotemia and electrolyte shifts)
• Baseline hypomagnesemia or hypokalemia
• Older age and limited physiologic reserve

• Baseline and serial CPK, with prompt evaluation of myalgia/weakness or a rising trend
• Baseline and on-treatment electrolytes (potassium, magnesium, sodium, calcium) and serum creatinine/eGFR
• Early, aggressive antidiarrheal therapy (e.g., loperamide) with oral rehydration to preserve euvolemia
• Proactive magnesium and potassium repletion during diarrhea
• Dose interruption/reduction for high or rising CPK per label before overt rhabdomyolysis develops
• Review and minimize concomitant myotoxic and nephrotoxic medications
• Counsel patients on dark-urine and muscle symptoms and on hydration

• Serum CPK at baseline and periodically (more frequently early and with any myalgia/weakness); investigate for rhabdomyolysis if markedly or persistently elevated
• Serum electrolytes — potassium, magnesium, sodium, calcium — during diarrhea and at each cycle
• Serum creatinine/eGFR and clinical volume status, especially during grade >=3 diarrhea
• Urinalysis and urine myoglobin when CPK is in the rhabdomyolysis range or urine is pigmented
• Clinical assessment for peripheral edema, and (per label) LVEF for MEK-class cardiac/fluid effects

• RAMP 201 / ENGOT-OV60 / GOG-3052 (NCT04625270): registrational randomized phase II of avutometinib +/- defactinib in recurrent low-grade serous ovarian cancer; go-forward combination confirmed ORR 31%, with grade >=3 CPK elevation 24% and grade >=3 diarrhea 8% as the leading grade >=3 treatment-related events
• FRAME (NCT03875820): first-in-human phase 1 of avutometinib + defactinib establishing the intermittent recommended phase 2 dose/schedule (avutometinib 3.2 mg twice weekly, 3 weeks on / 1 week off) that improved tolerability
• RAMP 301 (NCT06072781): ongoing randomized phase 3 of avutometinib + defactinib versus investigator's choice in recurrent low-grade serous ovarian cancer

• The 24% grade >=3 CPK elevation is the drug's signature laboratory abnormality — usually asymptomatic skeletal-muscle CPK rise, not rhabdomyolysis; most does not injure the kidney, but sustained rhabdomyolysis-range values can precipitate pigment-cast ATN.
• Kidney injury here is largely indirect: diarrhea drives prerenal/electrolyte losses and CPK/rhabdomyolysis drives tubular injury — avutometinib is not primarily a direct tubulotoxin.
• Repair magnesium proactively: diarrheal hypomagnesemia perpetuates refractory hypokalemia, and both compound MEK-class electrolyte shifts.
• Peripheral edema is a class MEK fluid-retention effect, not a marker of glomerular disease — manage with dose modification and cautious diuresis, not immunosuppression.
• Attribute the renal/electrolyte signal to the MEK arm (avutometinib); the companion FAK inhibitor defactinib is not nephrotoxic and FAK inhibition is renoprotective preclinically.
• Most CPK elevations and electrolyte disturbances reverse with dose interruption, hydration, and supportive care — track CPK before it climbs into the rhabdomyolysis range.

• ADQI (2026) — The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupProvides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.Nat Rev Nephrol · PMID 41361704
• SIRM (2022) — SIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.Radiol Med · PMID 35303246
• KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerIdentifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.Kidney Int · PMID 33126977
• KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationAddresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.Kidney Int · PMID 33276867
• ADDIKD (2025) — Integrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceProvides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.EClinicalMedicine · PMID 40290844
• ADDIKD (2025) — Aligning kidney function assessment in patients with cancer to global practices in internal medicineThree consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.EClinicalMedicine · PMID 40290845
• ADDIKD (2025) — A methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEstablishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.EClinicalMedicine · PMID 40290846
• KDIGO (2013) — Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.Crit Care · PMID 23394211
• KDIGO (2021) — Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesProvides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.Kidney Int · PMID 34556300
• KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisUpdates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.Kidney Int · PMID 38388147
• KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisUpdates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.Kidney Int · PMID 38182299
• KDIGO (2025) — Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.Kidney Int · PMID 40975525