Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
KRAS G12C inhibitor
Sotorasib
Lumakras · Sotor
The first KRAS-G12C inhibitor — renal injury is largely a rat-specific metabolite story, with sparse human signal.
MildKRAS G12C inhibitor · approved 2021
KRAS-G12C-mutated NSCLCKRAS-G12C-mutated colorectal cancer
Signature kidney injury
Prerenal / Hemodynamic AKI
Clinically significant nephrotoxicity is uncommon and case-level in humans (the dominant on-target/off-tumor toxicity is hepatotoxicity). Proximal tubular toxicity is prominent in rats via a reactive mercapturate-pathway metabolite. Human renal incidence is not well quantified.
Source: Werner et al., Toxicol Appl Pharmacol 2021 (rat mechanism)
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityMild
ReversibilityReversible
Evidence0 refs
Nephron map
Vasculature / EndotheliumGlomerular & peritubular capillaries
Proximal Tubule
Distal Tubule / Collecting Duct
Prerenal / Hemodynamic AKI
Renal hypoperfusion from capillary leak and cytokine storm — IL-2 and CAR-T cytokine release syndrome.
Mechanism of kidney injury
In Sprague-Dawley rats, sotorasib is bioactivated through the cysteine-conjugate β-lyase (mercapturate) pathway to a nephrotoxic thiol metabolite that concentrates in and damages the proximal tubule (outer-stripe degeneration/necrosis). Human relevance appears limited. Clinically observed AKI is largely hemodynamic/prerenal — from diarrhea/vomiting-related volume depletion — rather than the defining metabolite lesion.
Clinical presentation
Usually no clinically meaningful renal change; transient creatinine rises occur mainly in the setting of GI losses and dehydration. The clinically dominant adverse events are transaminase elevation/hepatotoxicity and diarrhea.
Onset
When AKI occurs, it is acute during the first weeks–months of therapy, typically tracking GI toxicity.
Reversibility
Reversible
Anticancer mechanism
First-in-class covalent inhibitor that binds the mutant cysteine-12 of KRAS G12C and locks the oncoprotein in its inactive GDP-bound state, blocking downstream RAF-MEK-ERK (MAPK) signaling in KRAS-G12C–mutated non-small cell lung cancer (NSCLC) and colorectal cancer.
Management
Supportive care, volume repletion, and hold/dose-modify for GI toxicity; monitor renal and liver function. Sotorasib carries a major hepatotoxicity signal, so liver monitoring is integral.
Risk factors
- Volume depletion from diarrhea/vomiting
- Concurrent nephrotoxins
- Pre-existing CKD
- Solid-organ transplant on calcineurin/mTOR inhibitors (drug-interaction risk)
Prevention
- Maintain hydration
- Manage GI toxicity early
- Avoid concurrent nephrotoxins
- In transplant recipients, monitor immunosuppressant levels closely (CYP3A/P-gp interactions)
Note · The defining renal toxicology is a rat-specific metabolite finding; human renal data remain sparse. A reported transplant drug interaction (markedly reduced tacrolimus/everolimus levels) is an onconephrology-relevant hazard to graft function.
Clinical depth
Renal dose adjustment
No renal dose adjustment is recommended; sotorasib pharmacokinetics were not meaningfully affected by mild-moderate renal impairment, and severe impairment/ESKD are not well studied. Dose modifications (from 960 mg daily) are driven by hepatotoxicity and GI toxicity, not CrCl.
Dialyzability & ESKD dosing
Not characterized; as a highly protein-bound, hepatically cleared small molecule it is unlikely to be substantially dialyzed. No ESKD dosing guidance is established.
Differential diagnosis
Separate true sotorasib-related AKI from prerenal azotemia of GI fluid loss (responds to volume) and from hepatotoxicity-driven changes; the rat proximal-tubule metabolite lesion has no validated human correlate, so unexplained AKI should prompt the usual onconephrology workup rather than attribution to the drug.
Monitoring
- AST/ALT and bilirubin before and during therapy (primary safety concern)
- Serum creatinine, especially with diarrhea/vomiting
- Hydration/volume status
- Immunosuppressant trough levels in transplant recipients
Key trials & series
- de Langen et al., Lancet 2023 — CodeBreaK 200 phase 3 (sotorasib vs docetaxel in NSCLC; safety base rate)
- Pietrantonio et al., JCO 2025 — CodeBreaK 300 (sotorasib + panitumumab in KRAS-G12C colorectal cancer)
Clinical pearls
- The headline sotorasib toxicity is hepatic, not renal — but watch volume status, because GI losses drive most observed creatinine bumps.
- The dramatic proximal-tubule injury is a Sprague-Dawley rat metabolite phenomenon; do not over-attribute human AKI to it.
- In transplant recipients, sotorasib can collapse tacrolimus/everolimus levels and threaten the graft — a true onconephrology pitfall.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Prerenal / Hemodynamic AKIAcute Tubular NecrosisPseudo-AKI
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkMercapturate pathway metabolites of sotorasib, a covalent inhibitor of KRAS, are associated with renal toxicity in the Sprague Dawley rat.Werner JA et al. · Toxicol Appl Pharmacol 2021 · PMID 34004237Mechanistic study of metabolite-mediated proximal tubular injury (rat-specific).PMIDSotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS G12C mutation: a randomised, open-label, phase 3 trial.de Langen AJ et al. · Lancet 2023 · PMID 36764316CodeBreaK 200 registrational phase 3; defines the clinical adverse-event base rate (hepatic/GI dominate).PMIDOverall Survival Analysis of the Phase III CodeBreaK 300 Study of Sotorasib Plus Panitumumab Versus Investigator's Choice in Chemorefractory KRAS G12C Colorectal Cancer.Pietrantonio F et al. · J Clin Oncol 2025 · PMID 40215429CodeBreaK 300 colorectal registrational phase 3 (overall survival, no new safety signals).PMIDThe Pharmacologic Inhibition of KRAS Mutants as a Treatment for Cancer: Therapeutic Principles and Clinical Results.Kasper S et al. · Dtsch Arztebl Int 2025 · PMID 40009739Cross-drug review of sotorasib/adagrasib efficacy and adverse-event profiles.PMIDAcute Kidney Injury Associated with Anticancer Therapies: Small Molecules and Targeted Therapies.Kala J et al. · Kidney360 2024 · PMID 39186376Onconephrology review situating KRAS-G12C inhibitor renal effects among targeted agents.PMIDOnconephrology: Update in Anticancer Drug-Related Nephrotoxicity.García-Carro C et al. · Nephron 2022 · PMID 35717937Practical onconephrology review covering targeted-therapy nephrotoxicity mechanisms and monitoring.
Related agents
Other agents sharing the same signature kidney injury.