Cetuximab & Panitumumab
Erbitux · Vectibix · Anti-EGFR antibody
TRPM6 magnesium wasting.
LYTE
MildOpen →
PI3Kα inhibitor
Inavolisib
Itovebi · PI3Kalpha inhibitor
PI3Kalpha inhibitor whose renal-relevant toxicity is metabolic, hyperglycemia and electrolyte shifts, not a defined kidney lesion
ModerateSelective PI3Kalpha (p110alpha) inhibitor/degrader · approved 2024
In combination with palbociclib and fulvestrant for PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer with disease relapse during or within 12 months of completing adjuvant endocrine therapy
Signature kidney injury
Electrolyte Wasting
Representative incidence5.6%
Direct nephrotoxicity from inavolisib is not prominent and renal-specific data are limited; the headline metabolic toxicity is on-target hyperglycemia. In the INAVO120 phase 3 trial, grade 3 or 4 hyperglycemia occurred in 5.6 percent of the inavolisib group versus 0 percent with placebo, alongside higher rates of stomatitis and diarrhea (which can secondarily cause volume and electrolyte loss). A defined inavolisib-specific kidney lesion with an established incidence rate is not characterized, so the incidence percentage shown reflects the grade 3 or higher hyperglycemia rate as the renal-relevant metabolic signal.
Source: 39476340
Mechanism of kidney injury
PI3Kalpha is a central mediator of insulin signaling, so on-target inhibition causes insulin resistance and hyperglycemia as a class effect, the dominant metabolic toxicity rather than a structural renal lesion. Secondary electrolyte disturbances can arise from the hyperglycemia itself (osmotic shifts and glucosuria-driven losses) and from GI toxicity (stomatitis and diarrhea causing volume depletion with potassium and magnesium loss). True direct tubular or glomerular injury is not a recognized feature of inavolisib.
Clinical presentation
Most commonly new or worsened hyperglycemia detected on glucose monitoring, occasionally severe and recalcitrant, with associated risk of dehydration. Electrolyte abnormalities and prerenal-pattern changes, when present, generally track with hyperglycemia severity and GI fluid losses rather than with an intrinsic kidney lesion.
Anticancer mechanism
Inavolisib is a highly potent, selective small-molecule inhibitor of the p110alpha catalytic subunit of PI3K (encoded by PIK3CA) that also promotes degradation of mutant p110alpha. By blocking and depleting oncogenic PI3Kalpha signaling it suppresses the PI3K/AKT/mTOR pathway that drives PIK3CA-mutated, HR-positive/HER2-negative breast cancer. It is used in combination with palbociclib and fulvestrant to overcome endocrine resistance.
Management
Manage hyperglycemia per protocol with lifestyle measures and antihyperglycemics (metformin is commonly first-line; insulin's effect may be partly blunted by ongoing PI3K inhibition), and interrupt or dose-modify inavolisib for severe or refractory hyperglycemia. Correct electrolyte abnormalities and replete volume losses driven by GI toxicity. Monitor renal function in the context of these metabolic and volume disturbances rather than expecting a primary nephrotoxic lesion.Lesion-level management framework
Risk factors
- Pre-existing diabetes, prediabetes, or impaired fasting glucose
- Obesity and metabolic syndrome
- Concurrent glucocorticoids
- Volume depletion from stomatitis/diarrhea (amplifies electrolyte and prerenal risk)
Prevention
- Baseline fasting glucose and HbA1c with optimization before starting
- Regular glucose monitoring during treatment, especially early
- Dietary counseling and early involvement of endocrinology for at-risk patients
- Proactive management of stomatitis and diarrhea to limit volume and electrolyte losses
Clinical depth
Renal dose adjustment
No CrCl-based renal-impairment dose thresholds are established in the cited literature; refer to current product labeling. Dose modification in practice is driven by hyperglycemia and GI toxicity rather than by measured renal function.
Dialyzability & ESKD dosing
Not characterized. As a small-molecule oral agent, dialytic clearance data are not available; management of hyperglycemic emergencies follows standard metabolic principles.
Differential diagnosis
Distinguish on-target PI3Kalpha-inhibitor hyperglycemia from new-onset diabetes, steroid-induced hyperglycemia, and stress hyperglycemia. Electrolyte and creatinine changes should be attributed to hyperglycemia and GI fluid losses (prerenal physiology) rather than to a primary inavolisib nephrotoxic lesion, which is not an established entity.
Monitoring
- Fasting glucose and HbA1c at baseline and periodically
- Frequent glucose monitoring early in treatment and after dose changes
- Serum electrolytes (including potassium and magnesium) and volume status, especially with stomatitis/diarrhea
- Renal function in the setting of hyperglycemia or volume depletion
Key trials & series
- INAVO120 (NCT04191499; Jhaveri/Turner et al., N Engl J Med 2024): phase 3, inavolisib plus palbociclib-fulvestrant vs placebo plus palbociclib-fulvestrant in PIK3CA-mutated HR-positive/HER2-negative advanced breast cancer; median PFS 15.0 vs 7.3 months (HR 0.43), with grade 3 or 4 hyperglycemia 5.6 percent vs 0 percent
- Phase I/Ib dose-finding (NCT03006172; Jhaveri et al., J Clin Oncol 2024): established the inavolisib plus palbociclib plus endocrine therapy combination; most frequent treatment-related AEs were stomatitis, hyperglycemia, and diarrhea
Clinical pearls
- The renal-relevant toxicity of inavolisib is metabolic, on-target hyperglycemia, not a defined kidney lesion; frame it honestly as an electrolyte/metabolic signal.
- Hyperglycemia is an inevitable consequence of inhibiting PI3Kalpha, a core insulin-signaling node; metformin is generally preferred and exogenous insulin may be partly counteracted by the drug.
- Watch for secondary electrolyte and volume problems from stomatitis and diarrhea, which can produce prerenal changes that mimic kidney injury.
- Renal-specific literature for inavolisib is limited; the class hyperglycemia evidence (e.g., alpelisib) carries most of the mechanistic weight.
Where it strikes
Nephron segments
Distal Tubule / Collecting Duct
Fine-tuning of Na, K, Mg, acid & water
Injury signatures
Electrolyte Wasting
Evidence
4 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkInavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer.Jhaveri KL, Im SA, Saura C, et al. · N Engl J Med 2024 · PMID 39476340INAVO120 registrational phase 3 trial; source for the metabolic toxicity profile including grade 3 or 4 hyperglycemia 5.6 percent vs 0 percent, the renal-relevant incidence figure, and the absence of a defined nephrotoxic lesion.PMIDPhase I/Ib Trial of Inavolisib Plus Palbociclib and Endocrine Therapy for PIK3CA-Mutated, Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer.Jhaveri KL, Accordino MK, Bedard PL, et al. · J Clin Oncol 2024 · PMID 39236276Dose-finding trial confirming hyperglycemia (with stomatitis and diarrhea) as a leading treatment-related toxicity of the inavolisib combination, supporting the metabolic/electrolyte framing.PMIDOncogenic activation of PIK3CA in cancers: Emerging targeted therapies in precision oncology.Wang Y, Rozen V, Zhao Y, Wang Z · Genes Dis 2024 · PMID 39717717Mechanistic review establishing hyperglycemia as an on-target, dose-limiting side effect of PI3Kalpha inhibition because PI3Kalpha is a critical mediator of insulin signaling.PMIDAlpelisib-Induced Hyperglycemia.Ekanayake PS, Gerwer J, McCowen K · Acta Endocrinol (Buchar) 2022 · PMID 35975254Class case series demonstrating that PI3Kalpha-inhibitor hyperglycemia can be severe and recalcitrant, that it reverses on drug cessation, and that exogenous insulin may be theoretically counteracted by PI3K inhibition, informing inavolisib management.
Guidelines & consensus· 12
General onco-nephrology references
Acute Disease Quality InitiativeThe 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.Cancer Institute NSWIntegrating 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.Cancer Institute NSWAligning 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.Cancer Institute NSWA 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.