Sevabertinib
Hyrnuo · HER2/EGFR TKI
2025 reversible HER2/EGFR TKI; profuse diarrhea (84-91%) → prerenal AKI, plus EGFR-pathway renal magnesium wasting.
PRELYTE
Mild#1 · 89% phenotype match
Gedatolisib
Revtorpyk · GDL
Pan-PI3K inhibitor · approved 2026 · 3 citations
Up to date· through 2026
Fairly sourced4/9 · 4 signals
- Not met: 3 citations
- Not met: 12+ references
- Not met: Accrued over 10+ years (span: 1y)
- Met: Beyond single case reports
- Met: High-impact journal
- Met: Landmark reference
- Met: Current through 2026
- Not met: Real-world FAERS signal
Describes how this page is sourced, not how dangerous the drug is. Thinly sourced means fewer of the sourcing signals are met — not that the agent is kidney-safe. A rule-based summary, not a formal certainty appraisal.
An intravenous pan-PI3K plus mTORC1/2 inhibitor whose kidney-relevant effects are metabolic and electrolyte — on-target hyperglycemia and low-grade sodium, potassium and magnesium drift — rather than a structural kidney lesion.
MildPan-PI3K/mTOR dual inhibitor
HR-positive, HER2-negative, PIK3CA wild-type advanced or metastatic breast cancer, with fulvestrant with or without palbociclib, after progression on CDK4/6-inhibitor and aromatase-inhibitor therapy (VIKTORIA-1)Studied first-line with palbociclib and letrozole and in HER2-positive disease with trastuzumab in PI3K-pathway-altered cohorts
§01
Signature kidney injury
Signature lesion
No discrete drug-specific incidence of gedatolisib acute kidney injury is published; the renal-relevant signal is laboratory-level. In the VIKTORIA-1 triplet arm the FDA label's laboratory table reports increased creatinine in 14% (grade 3-4 0.8%) versus 8% (0.8%) on fulvestrant alone, decreased sodium in 21% (grade 3-4 1.6%), decreased potassium in 19% (1.6%) and decreased magnesium in 19% (0%) — all-grade drift, with severe events rare. The dominant metabolic effect is on-target hyperglycemia: increased fasting glucose in 46% of triplet-arm and 57% of doublet-arm patients on the label's laboratory table, while grade >=3 treatment-related hyperglycemia in the VIKTORIA-1 publication was 2.3% in both gedatolisib arms (Hurvitz, J Clin Oncol 2026) — markedly gentler than daily oral PI3K-alpha inhibition. In a phase II HER2-positive combination, any-grade hyperglycemia was 25.0% with grade 3 in 2.3% (Kim, ESMO Open 2026).Source: No drug-specific AKI incidence; label lab-table electrolyte/creatinine drift is all-grade and low-grade. Grade >=3 hyperglycemia 2.3% in VIKTORIA-1 (Hurvitz 2026); any-grade 25% in a HER2+ phase II (Kim 2026)
Onset & rechallenge
Time to injurySubacute (~1–6 weeks)
Fasting glucose moves within the first weekly infusions; electrolyte drift appears on routine chemistries across early cycles rather than as an acute event.
Distilled from: “Hyperglycemia is an early, exposure-linked effect — fasting glucose moves within the first infusions and tracks the weekly dosing cycle; electrolyte drift appears on routine monitoring across early cycles rather than as an acute event.”
§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 electrolyte derangement — magnesium/potassium/calcium wasting (cisplatin, anti-EGFR antibodies) or retention (FGFR-inhibitor hyperphosphatemia, tumor-lysis hyperkalemia/hyperphosphatemia).
Renal hypoperfusion from capillary leak and cytokine storm — IL-2 and CAR-T cytokine release syndrome.
§03
Kidney injury
Mechanism of kidney injury
There is no evidence of direct tubular, interstitial or glomerular toxicity. The kidney-relevant physiology is on-target: PI3K signaling is the effector arm of insulin action, so pan-PI3K blockade produces hyperglycemia during exposure — and severe hyperglycemia can drive osmotic diuresis, volume depletion and prerenal azotemia, the same indirect route the catalog documents for alpelisib. The low-grade sodium, potassium and magnesium decreases on the label's laboratory table are consistent with pathway effects on distal electrolyte handling plus GI losses (stomatitis, diarrhea, decreased appetite), and were almost never grade 3-4. The modest all-grade creatinine excess over the fulvestrant control (14% vs 8%) with near-absent severe events reads as hemodynamic/laboratory drift on an intermittent intravenous schedule, not cumulative structural injury.
Clinical presentation
The typical picture is biochemical: rising fasting glucose in the first cycles, with or without polyuria and thirst if it escapes control, and low-grade electrolyte abnormalities on routine chemistries. A creatinine rise is usually modest and accompanies volume depletion from hyperglycemic diuresis, stomatitis-limited intake or diarrhea; an isolated severe creatinine rise or an active urine sediment should redirect the workup away from gedatolisib.
Management
Manage the metabolic effect and the kidney follows: treat hyperglycemia per the label's threshold-based instructions — dietary modification, hydration and anti-hyperglycemic therapy, with dose hold/reduction for higher grades — and replete potassium, magnesium and sodium as needed. A prerenal creatinine rise responds to volume restoration and glycemic control. There is no gedatolisib-specific renal rescue; a progressive creatinine rise, heavy proteinuria or an active sediment warrants an independent renal workup rather than attribution to the drug.Lesion-level management framework
Risk factors
- Pre-existing diabetes, prediabetes or elevated baseline HbA1c (amplifies on-target hyperglycemia)
- Volume depletion from stomatitis-limited intake, diarrhea or decreased appetite
- Concurrent diuretics or other electrolyte-wasting drugs
- Baseline CKD — the label reports no clinically significant pharmacokinetic differences at eGFR >=45 mL/min/1.73 m2 (MDRD equation) and states the effect of eGFR <45, or dialysis, on pharmacokinetics is unknown
- Concurrent corticosteroids or other hyperglycemia-promoting medications
Prevention
- Assess fasting glucose and HbA1c before the first infusion and optimize glycemic control before starting — the baseline gate the label builds dosing on
- Correct baseline electrolyte abnormalities before starting therapy
- Ensure adequate hydration when fasting glucose rises, per the label's hyperglycemia management instructions
- Initiate or intensify anti-hyperglycemic treatment early rather than after osmotic symptoms develop
- Review co-medications for additive electrolyte loss or hyperglycemia before each cycle
Anticancer mechanism· how it treats cancer
Intravenous small molecule that potently inhibits all four class I PI3K isoforms and both mTOR complexes (mTORC1 and mTORC2), blocking the PI3K/AKT/mTOR pathway more comprehensively than isoform-selective agents. Given as a 30-minute infusion once weekly on days 1, 8 and 15 of a 28-day cycle, in combination with fulvestrant with or without palbociclib, for hormone receptor-positive, HER2-negative advanced breast cancer that has progressed on CDK4/6-inhibitor plus aromatase-inhibitor therapy. The intermittent intravenous schedule is part of the tolerability design relative to continuous oral pathway inhibitors.
§04
Clinical depth
Renal dose adjustment
No renal dose adjustment is established for eGFR >=45 mL/min/1.73 m2 — the range in which the label reports no clinically significant pharmacokinetic differences (MDRD equation); the label states the effect of eGFR <45, or dialysis, on gedatolisib pharmacokinetics is unknown, so use below that threshold is uncharted rather than dose-banded. Dose modifications are driven by hyperglycemia, stomatitis and hematologic toxicity, not by GFR.
Dialyzability & ESKD dosing
Not characterized as dialyzable and not clinically relevant: no dialysis-based removal scenario applies, and patients on dialysis fall below the eGFR range in which the drug's pharmacokinetics have been studied at all.
Differential diagnosis
Attribute a creatinine rise on gedatolisib by checking glucose and volume first: hyperglycemic osmotic diuresis and intake-limiting stomatitis produce prerenal physiology that corrects with fluids and glycemic control. Distinguish pathway-driven electrolyte drift (low-grade, chemistry-panel finding) from GI potassium/magnesium loss and diuretic effect. Gedatolisib is not an established tubular toxin — a severe or progressive creatinine rise, heavy proteinuria or active sediment should prompt a search for another cause rather than reflexive attribution.
Monitoring
- Fasting glucose before each infusion during early cycles, then periodically per label; HbA1c to track control
- Basic chemistries including sodium, potassium, magnesium and creatinine on the routine schedule
- Volume status during stomatitis, diarrhea or poor intake
- Blood counts per the palbociclib partner's requirements (the dominant grade 3-4 toxicity in the triplet)
Key trials & series
- VIKTORIA-1 (Hurvitz, J Clin Oncol 2026) — phase III, n=392: gedatolisib triplet median PFS 9.3 vs 2.0 months for fulvestrant (HR 0.24), doublet 7.4 months (HR 0.33); grade >=3 treatment-related hyperglycemia 2.3% in both gedatolisib arms — the registrational trial and the source of the label's laboratory table.
- Phase Ib first-line triplet (Wesolowski, Clin Cancer Res 2025) — gedatolisib plus palbociclib and letrozole, n=41: median PFS 48.4 months; most frequent grade 3/4 events neutropenia 61%, rash 39%, stomatitis 29% — no renal signal.
- HER2-positive phase II (Kim, ESMO Open 2026) — trastuzumab plus gedatolisib, n=44: oral mucositis 90.9% (grade >=3 15.9%) and hyperglycemia 25.0% (grade 3 2.3%) as the leading toxicities.
Clinical pearls
- Think glucose first: pan-PI3K blockade inhibits insulin signaling, and the kidney trouble it causes is downstream of hyperglycemia and volume, not a lesion in the nephron.
- The intermittent IV schedule is why its grade >=3 hyperglycemia (2.3% in VIKTORIA-1) sits far below daily oral PI3K-alpha inhibition — same target, different exposure shape.
- Label lab tables show creatinine up 14% all-grade versus 8% on fulvestrant alone, with grade 3-4 essentially absent — drift, not injury.
- Sodium, potassium and magnesium each dip in roughly a fifth of patients; replete and move on — severe derangement is rare.
- Below eGFR 45 the pharmacokinetics are unstudied — that is an evidence gap, not a dose band.
Where it strikes· nephron segments & injury signatures
Nephron segments
Distal Tubule / Collecting Duct
Fine-tuning of Na, K, Mg, acid & water
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
§05
References
3 primary references — trials, cohorts, mechanism, and reviews. Citation metadata via PubMed / NLM.
Evidence accrual
3 references · 2025–2026 · 3 since 2024Primary (non–case-report) references per year — 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.LandmarkVIKTORIA-1 Trial of Gedatolisib Plus Fulvestrant With or Without Palbociclib in Hormone Receptor-Positive/HER2-/PIK3CA Wild-Type Advanced Breast Cancer.Hurvitz SA, Layman RM, Curigliano G, et al. · J Clin Oncol · 2026 · PMID 41802242Registrational phase III trial: PFS 9.3 (triplet) and 7.4 (doublet) vs 2.0 months on fulvestrant; grade >=3 treatment-related hyperglycemia 2.3% in both gedatolisib arms with no renal toxicity signal — the trial behind the label whose laboratory table quantifies the creatinine and electrolyte drift.
- 2.Gedatolisib Combined with Palbociclib and Letrozole in Patients with No Prior Systemic Therapy for Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer.Wesolowski R, Rugo HS, Specht JM, et al. · Clin Cancer Res · 2025 · PMID 40711480First-line phase Ib triplet (n=41): median PFS 48.4 months with grade 3/4 toxicity led by neutropenia (61%), rash (39%) and stomatitis (29%) — an extended-exposure safety picture without a renal signal.
- 3.Phase II study of trastuzumab-pkrb plus gedatolisib in patients with HER2-positive metastatic breast cancer who progressed after two or more HER2-directed therapies.Kim JW, Park YH, Lee S, et al. · ESMO Open · 2026 · PMID 42419085Source of the quantified hyperglycemia rate outside the registrational setting: any-grade 25.0% with grade 3 in 2.3% (oral mucositis 90.9% the leading toxicity) — supports the on-target metabolic framing of the renal-relevant risk.
Guidelines & consensus· 13
Each recommendation below is this atlas's faithful summary of the source, not a quotation from it — follow the PubMed link for the wording the society published. Summaries may be superseded; consult the current full text and individualize to the patient.
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 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknownsKidney Int 2024 · PMID 38519239Evaluate and risk-stratify CKD, manage to delay progression and its complications, and practise explicit medication management and drug stewardship — the framework the atlas's G1–G5 eGFR banding and every renal dose-adjustment recommendation sit inside. Because the guideline excludes dialysis and transplant recipients by its own statement of scope, its recommendations do not carry to those settings, where this atlas's dialyzability and post-transplant guidance rests on other sources.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 Gedatolisib sits in nephrotoxicity space — each dot is an anti-cancer agent, positioned so neighbors share a kidney-injury phenotype. Its 6 closest are filled and lead to a numbered marker, matching the numbered cards below.
Phenotype-similar agents· the numbered markers on the map above
Profile
Darolutamide
Nubeqa · Androgen receptor inhibitor (ARSI)
Not nephrotoxic; exposure rises in severe renal impairment, so consider dose adaptation.
LYTEPRE
Mild#2 · 88% phenotype match
Glasdegib
Daurismo · Hedgehog (SMO) inhibitor
QT prolongation and muscle spasms; AML.
PRELYTE
Mild#3 · 88% phenotype match
Lanreotide
Somatuline · Somatostatin analog
Kidney-neutral (CLARINET: diarrhea dominant); increased exposure in renal impairment.
LYTEPRE
Mild#4 · 87% phenotype match
Octreotide
Sandostatin · Somatostatin analog
Kidney-neutral/possibly renoprotective; renally cleared, caution in severe CKD/dialysis.
LYTEPRE
Mild#5 · 86% phenotype match
Capivasertib
Truqap · AKT inhibitor
2023 breast-cancer AKT inhibitor; AKI with diarrhea/hyperglycemia.
PRELYTE
Moderate#6 · 83% 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.
Kidney risk across PI3K / AKT inhibitors
Same-class agents ordered by their documented kidney-injury profile — atlas severity, an acute-kidney-injury FAERS signal, and how many injury types each is documented to cause. Agents nearer the top carry the lighter documented renal profile.
- 1DuvelisibPRE — Prerenal / Hemodynamic AKIMild
- 2Gedatolisib· this agentLYTE — Electrolyte DisturbanceMild
- 3IdelalisibPRE — Prerenal / Hemodynamic AKIMild
- 4CopanlisibHTN — HypertensionModerate
- 5CapivasertibPRE — Prerenal / Hemodynamic AKIModerate
- 6AlpelisibPRE — Prerenal / Hemodynamic AKIModerate
- 7InavolisibLYTE — Electrolyte DisturbanceFAERS AKIModerate
A comparison of documented kidney-injury data within one drug class — not a substitution recommendation. Efficacy, indication, and non-renal toxicity differ between these agents and are out of scope here. Educational only, not medical advice.