Neratinib
Nerlynx · HER2 / pan-EGFR TKI
Severe diarrhea → prerenal AKI; loperamide prophylaxis.
PRELYTE
Moderate94% phenotype match
HER2/EGFR TKI
Sevabertinib
Hyrnuo · SEV
HER2/EGFR TKI · approved 2025 · 3 citations
Up to date· through 2026
Emerging evidence6/9 · 6 signals▾
- 3 citations
- Deep literature (12+ refs)
- Accrued over 15+ years
- Beyond single case reports
- High-impact journal
- Landmark reference
- Registrational / key trials
- Current through 2026
- Real-world FAERS signal
Grades the strength of the evidence base (volume, journal quality, landmark trials, recency, real-world corroboration) — not the drug's severity. A rule-based summary, not a formal certainty appraisal.
A reversible HER2/EGFR tyrosine kinase inhibitor whose kidney risk is indirect but real: near-universal diarrhea drives prerenal volume depletion, and EGFR-pathway blockade wastes magnesium in the distal tubule.
MildReversible HER2/EGFR tyrosine kinase inhibitor
Locally advanced or metastatic non-small-cell lung cancer with activating HER2 (ERBB2) mutations, including exon-20 insertions, in previously treated patients (accelerated approval)Studied across treatment-naive and antibody-drug-conjugate-pretreated HER2-mutant NSCLC cohorts
§01
Signature kidney injury
Signature lesion
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)
Onset & rechallenge
Time to injuryAcute (~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.
Distilled from: “Diarrhea and its prerenal consequences are typically early and recur with dosing across the first cycles; hypomagnesemia accrues over weeks of continued therapy (duration-related) and reverses over several weeks after interruption or discontinuation.” · PMID 41104928
§02
Renal toxicities, ranked
This agent's kidney lesions ordered by prominence — the #1 signature lesion first, then secondary and rare patterns. Cited incidence is shown where a citable figure exists; otherwise the tier stands qualitatively.
Renal hypoperfusion from capillary leak and cytokine storm — IL-2 and CAR-T cytokine release syndrome.
Renal electrolyte derangement — magnesium/potassium/calcium wasting (cisplatin, anti-EGFR antibodies) or retention (FGFR-inhibitor hyperphosphatemia, tumor-lysis hyperkalemia/hyperphosphatemia).
§03
Kidney injury
Mechanism of kidney injury
Two indirect, on-target mechanisms, neither a primary tubular poisoning. First, prerenal/volume-depletion AKI: HER-family inhibition in the gut epithelium produces frequent, sometimes severe secretory diarrhea; the resulting fluid and sodium losses reduce effective circulating volume and renal perfusion, and if uncorrected can progress from prerenal azotemia to ischemic acute tubular necrosis, accompanied by potassium, magnesium, and bicarbonate losses. Second, renal magnesium wasting: EGFR is expressed in the distal convoluted tubule where it supports magnesium reabsorption through the TRPM6 channel; inhibiting EGFR signaling produces a TRPM6-like defect with urinary magnesium (and calcium) wasting and hypomagnesemia, a reversible class effect of anti-EGFR therapy that is dose/duration-related and typically recovers weeks after stopping (Costa, Target Oncol 2011). The effect is strongest with EGFR monoclonal antibodies and attenuated with a HER2-selective TKI, but the mechanism applies. The drug itself is hepatically handled, so renal impairment is not its clearance route.
Clinical presentation
The usual sequence is a patient with frequent watery diarrhea who becomes volume-depleted — thirst, orthostasis, weight loss — with a rising creatinine and a low fractional excretion of sodium (prerenal), often with hypokalemia, hypomagnesemia, and a non-anion-gap or contraction picture. Isolated hypomagnesemia (cramps, tetany, arrhythmia risk, refractory hypokalemia/hypocalcemia) can also appear on routine labs without overt AKI. A bland urine sediment is expected; an active sediment or heavy proteinuria points elsewhere.
Management
Treat the diarrhea and its consequences. Control diarrhea aggressively (loperamide, hydration, dose interruption/reduction per label), restore volume with oral or IV fluids, and correct electrolytes — potassium and, importantly, magnesium (oral magnesium for mild cases; IV magnesium for symptomatic or severe hypomagnesemia, recognizing that repletion is slow because filtered magnesium is re-wasted). Correct hypokalemia and hypocalcemia, which often will not stay corrected until magnesium is replaced. Provide standard supportive AKI care, avoid additional nephrotoxins, and hold the drug for severe volume-depletion AKI until the patient is rehydrated. The hypomagnesemia and prerenal AKI are reversible with these measures and with reduced diarrhea; permanent discontinuation is driven by intolerable GI toxicity rather than by an isolated renal number.Lesion-level management framework
Risk factors
- 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
Prevention
- 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
Anticancer mechanism· how it treats cancer
Oral, reversible tyrosine kinase inhibitor that potently inhibits mutant HER2 (ERBB2), including exon-20 insertions and other activating HER2 mutations, while sparing wild-type EGFR relative to earlier pan-HER agents. By shutting down constitutive HER2 signaling in HER2-mutant non-small-cell lung cancer, it drives tumor-cell cycle arrest and apoptosis. Its activity spans the HER family (it also has anti-EGFR activity), which underlies both its on-target gastrointestinal toxicity and its renal magnesium-handling effect.
§04
Clinical depth
Renal dose adjustment
No validated pharmacokinetic renal dose adjustment is established; SOHO-01 required adequate organ function and dedicated data in severe renal impairment or dialysis are limited. Sevabertinib is a hepatically metabolized small molecule, so GFR is not the primary determinant of exposure. The practical dose levers are interruption and reduction for diarrhea (and other toxicity) per label, not a GFR-based change; pre-existing CKD raises the stakes of diarrheal volume depletion and warrants closer monitoring and earlier fluid/electrolyte support.
Dialyzability & ESKD dosing
Not characterized as dialyzable and not clinically relevant: as a protein-bound, hepatically cleared small molecule, sevabertinib is unlikely to be appreciably removed by hemodialysis, and there is no role for dialysis in managing the drug. Renal replacement therapy would only be relevant to support severe AKI, which in this setting is prerenal/volume-depletion physiology best treated by rehydration and diarrhea control.
Differential diagnosis
Attribute the AKI and electrolytes to the diarrhea/EGFR axis and exclude mimics. Prerenal AKI is favored by a clear diarrheal history, volume depletion, low fractional excretion of sodium, and a bland sediment that corrects with rehydration. Renal magnesium wasting is favored by hypomagnesemia with an inappropriately high urinary magnesium and refractory hypokalemia/hypocalcemia. Distinguish both from concomitant nephrotoxins, contrast, or sepsis, and from a primary tubular/interstitial lesion (which would show an active sediment or fail to correct with volume). Unlike platinum agents, sevabertinib does not directly poison the proximal tubule.
Monitoring
- 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
Key trials & series
- 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.
Clinical pearls
- 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.
Where it strikes· nephron segments & injury signatures
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Distal Tubule / Collecting Duct
Fine-tuning of Na, K, Mg, acid & water
Injury signatures
Beyond the kidney — non-renal toxicities· 3 organ systems
Class-level context for the major non-renal toxicities of her2/egfr tkis.
Dermatologic
Rash, HFS, SJS/TEN, vitiligo
- Acneiform rash, paronychia
Gastrointestinal
Diarrhea, colitis, mucositis, perforation
- Diarrhea
Pulmonary
Pneumonitis, ILD, effusions, hypertension
- Interstitial lung disease (EGFR TKIs)
§05
References
3 peer-reviewed references. Citation metadata via PubMed / NLM.
Evidence accrual
3 references · 2011–2026 · 2 since 2024Citations per year in this profile — a proxy for how actively the agent's renal literature is accruing. Recent years are highlighted. Reflects curation depth, not a systematic bibliometric count.
- 1.LandmarkSevabertinib in Advanced HER2-Mutant Non-Small-Cell Lung Cancer.Le X, Kim TM, Loong HH, et al. · N Engl J Med · 2025 · PMID 41104928Registrational SOHO-01 phase 1-2 trial: diarrhea was the most common adverse event (84-91%, grade >=3 5-23%) with grade 3+ drug-related events in 31% — establishing diarrhea-driven prerenal/electrolyte risk as sevabertinib's dominant, kidney-relevant toxicity.
- 2.LandmarkHypomagnesaemia and targeted anti-epidermal growth factor receptor (EGFR) agents.Costa A, Tejpar S, Prenen H, Van Cutsem E. · Target Oncol · 2011 · PMID 22113391Reviews the tubular EGFR-TRPM6 mechanism of renal magnesium and calcium wasting from anti-EGFR agents — a reversible, treatment-duration-related class effect — the basis for monitoring magnesium on the HER2/EGFR-active sevabertinib.
- 3.Sevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer.Siegel F, Siegel S, Kotynkova K, et al. · Cancer Discov · 2026 · PMID 41090369Characterizes sevabertinib as a potent, reversible dual EGFR-HER2 inhibitor selective over wild-type EGFR with early clinical responses — the HER-family pharmacology underlying both its efficacy and its gastrointestinal/renal-magnesium effects.
Guidelines & consensus· 12
General onco-nephrology references
ADQIThe nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupNat Rev Nephrol 2026 · PMID 41361704Provides 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.SIRMSIRM-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)Radiol Med 2022 · PMID 35303246Recommends 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.KDIGOKDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerKidney Int 2020 · PMID 33126977Identifies 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.KDIGOKDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationKidney Int 2020 · PMID 33276867Addresses 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.ADDIKDIntegrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceEClinicalMedicine 2025 · PMID 40290844Provides 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.ADDIKDAligning kidney function assessment in patients with cancer to global practices in internal medicineEClinicalMedicine 2025 · PMID 40290845Three 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.ADDIKDA methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEClinicalMedicine 2025 · PMID 40290846Establishes 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.KDIGODiagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Crit Care 2013 · PMID 23394211Defines/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.KDIGOExecutive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesKidney Int 2021 · PMID 34556300Provides 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.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisKidney Int 2024 · PMID 38388147Updates 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.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisKidney Int 2024 · PMID 38182299Updates 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.KDIGOExecutive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Kidney Int 2025 · PMID 40975525Encourages 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.
Where Sevabertinib sits in nephrotoxicity space — each dot is an anti-cancer agent, positioned so neighbors share a kidney-injury phenotype.
Phenotype-similar agents· nearest neighbors in nephrotoxicity space
Profile
Relacorilant
Lifyorli · Selective glucocorticoid-receptor antagonist
2026 GR antagonist (ovarian); hypokalemia via cortisol/mineralocorticoid receptor — the mifepristone effect, blunted by GR-selectivity.
LYTEPRE
Mild89% phenotype match
Darolutamide
Nubeqa · Androgen receptor inhibitor (ARSI)
Not nephrotoxic; exposure rises in severe renal impairment, so consider dose adaptation.
LYTEPRE
Mild89% phenotype match
Glasdegib
Daurismo · Hedgehog (SMO) inhibitor
QT prolongation and muscle spasms; AML.
PRELYTE
Mild88% phenotype match
Lanreotide
Somatuline · Somatostatin analog
Kidney-neutral (CLARINET: diarrhea dominant); increased exposure in renal impairment.
LYTEPRE
Mild87% phenotype match
Pacritinib
Vonjo · JAK2/ACVR1 inhibitor
JAK2/ACVR1 inhibitor; diarrhea-driven prerenal AKI and electrolyte loss.
PRELYTE
Moderate83% phenotype match
Nearest agents by kidney-injury phenotype (shared injuries, nephron target, severity, class) — a similarity approximation, not a claim of shared drug identity or mechanism.