Sevabertinib

Prerenal / Hemodynamic AKI.

No discrete published incidence of sevabertinib acute kidney injury exists as a standalone endpoint; the renal risk is inferred from its dominant on-target toxicity. In the registrational phase 1-2 SOHO-01 study (Le, N Engl J Med 2025; n=209), diarrhea was the single most common adverse event, occurring in 84-91% of patients depending on cohort, with grade 3 or higher diarrhea in 5-23%; grade 3+ drug-related adverse events overall were 31%, and only 3% discontinued for toxicity. Diarrhea of this frequency and severity is a well-recognized driver of prerenal, volume-depletion acute kidney injury and of electrolyte loss. Separately, HER/EGFR-pathway inhibition causes renal magnesium wasting through the tubular EGFR-TRPM6 axis (Costa, Target Oncol 2011); this is most pronounced with anti-EGFR monoclonal antibodies and is expected to be milder with a HER2-directed TKI, but hypomagnesemia remains a monitoring point.

Source: No drug-specific AKI incidence; risk inferred from diarrhea in 84-91% (grade >=3 5-23%) driving prerenal AKI (SOHO-01, Le 2025) plus EGFR-pathway renal Mg wasting (Costa 2011)

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

1. Prerenal / Hemodynamic AKIPrimary
2. Electrolyte DisturbanceSecondary

Acute (~1–7 days) — Diarrhea and its prerenal/volume-depletion consequences are early and recur across the first cycles; hypomagnesemia accrues over weeks of continued therapy and reverses weeks after interruption.

• Severe or poorly controlled diarrhea (the main driver of prerenal AKI)
• Older age, baseline CKD, or volume depletion
• Concurrent diuretics, RAAS blockers, or other nephrotoxins
• Prolonged treatment duration (cumulative magnesium wasting)
• Baseline hypomagnesemia or GI magnesium losses
• Inadequate antidiarrheal management or oral intake

• Proactive antidiarrheal management (early loperamide, dietary measures) and prompt dose interruption/reduction for higher-grade diarrhea per protocol
• Encourage hydration and oral rehydration during diarrheal episodes; give IV fluids when intake is inadequate
• Monitor magnesium (and potassium, calcium) periodically and replete proactively
• Review and minimize concurrent nephrotoxins and additional magnesium-wasting drugs
• Check renal function and electrolytes at baseline and during early cycles

• Diarrhea frequency/severity and volume status at each visit (the primary renal-risk driver)
• Serum creatinine/eGFR during early cycles and with diarrheal episodes
• Serum magnesium periodically (EGFR-pathway renal Mg wasting), plus potassium and calcium
• Body weight and orthostatic vitals during significant diarrhea
• ECG/QT when magnesium/potassium are low

• SOHO-01 (Le, N Engl J Med 2025) — registrational phase 1-2 study of sevabertinib in HER2-mutant NSCLC (n=209); objective responses of 38-71% across cohorts, with diarrhea the most common adverse event (84-91%; grade >=3 5-23%) and grade 3+ drug-related events in 31% — the trial that establishes diarrhea, and thus prerenal/electrolyte risk, as the dominant toxicity.
• Preclinical and early clinical characterization (Siegel, Cancer Discov 2026) — describes sevabertinib as a potent, reversible dual EGFR-HER2 inhibitor selective over wild-type EGFR, with early phase 1/2 patient responses; the HER-family activity that underlies both its efficacy and its GI/renal-magnesium effects.
• Anti-EGFR hypomagnesemia mechanism (Costa, Target Oncol 2011) — reviews the tubular EGFR-TRPM6 basis of renal magnesium and calcium wasting from anti-EGFR agents: a reversible, duration-related class effect that informs the magnesium-monitoring recommendation for sevabertinib.

• The kidney risk is downstream of the gut: near-universal diarrhea (84-91%) is the real driver of prerenal AKI — control the diarrhea and you protect the kidney.
• Check the magnesium: EGFR-pathway blockade wastes magnesium in the distal tubule, and low magnesium keeps potassium and calcium from correcting.
• Repletion of magnesium is slow because the kidney re-wastes it — expect to give more, and for longer, than the number suggests.
• It is milder than the anti-EGFR antibodies: a HER2-directed TKI wastes less magnesium than cetuximab, but the mechanism is the same, so still monitor.
• A rising creatinine here is usually volume, not a tubular toxin — rehydrate first and reassess.
• Both the prerenal AKI and the hypomagnesemia are reversible with hydration, diarrhea control, and repletion.

• 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