Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
EGFR exon20 TKI
Mobocertinib
Exkivity · MOBO
An EGFR exon-20 TKI whose kidney injury is GI-mediated — torrential diarrhea drives prerenal AKI, watched alongside QT.
MildEGFR exon-20 TKI · approved 2021
Metastatic non-small-cell lung cancer with EGFR exon 20 insertion mutations, after platinum-based chemotherapy (withdrawn 2023)
Signature kidney injury
Prerenal / Hemodynamic AKI
Diarrhea is near-universal: any-grade ~83% (up to ~93% pooled), grade >=3 ~20-21%, with median onset ~5 days. AKI is predominantly prerenal; a real-world cohort reported grade >=3 renal failure in ~6%. Precise drug-attributable AKI and QT rates are not robustly quantified beyond class warnings.
Source: Zhou et al., JAMA Oncol 2021 (83% any-grade diarrhea; grade ≥3 renal failure ~6%)
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
Predominantly indirect/prerenal. Severe secretory diarrhea (on-target EGFR inhibition of intestinal epithelium) causes fluid and electrolyte losses, hypovolemia and reduced renal perfusion, producing prerenal AKI that can progress to ischemic ATN if prolonged. Separately, off-target hERG/IKr block (IC50 ~5 microM) plus Cav1.2 inhibition prolongs QTc — relevant to the kidney because diarrhea-driven hypokalemia/hypomagnesemia worsens QT.
Clinical presentation
Early, frequent diarrhea (median onset ~5 days, each episode resolving in ~2 days) with a rising creatinine, low urine output and hypokalemia/hypomagnesemia; QTc prolongation is a recognized label warning.
Onset
Diarrhea early (within the first week); AKI follows. Prerenal AKI is typically reversible with early volume repletion and diarrhea control.
Reversibility
Reversible
Anticancer mechanism
Oral, irreversible (covalent acrylamide-warhead) EGFR tyrosine kinase inhibitor selective for in-frame EGFR exon 20 insertion mutations; structurally derived from osimertinib with a modification conferring exon-20-insertion selectivity.
Management
For diarrhea/AKI: loperamide, restore volume, hold nephrotoxins, and treat the diarrhea driver. For QT: monitor and correct potassium and magnesium, perform ECG monitoring, and hold for significant QTc prolongation. Note that dose reductions reduce duration of response — balance toxicity against efficacy.
Risk factors
- Baseline CKD and older age
- Concurrent diuretics, RAAS blockers or NSAIDs
- Inadequate antidiarrheal prophylaxis and baseline electrolyte abnormalities
- Concomitant QT-prolonging drugs, hypokalemia or hypomagnesemia
Prevention
- Pre-emptive antidiarrheal plan: early loperamide at the first loose stool, dietary measures
- Aggressive hydration with potassium/magnesium repletion
- Baseline and periodic ECG/QTc; correct electrolytes and avoid concomitant QT-prolonging agents
- Hold/dose-reduce for grade >=3 or persistent diarrhea
Note · Voluntarily withdrawn worldwide in 2023 after the confirmatory EXCLAIM-2 trial missed its primary endpoint; entry is of historical/teaching value. The renal mechanism is GI-driven prerenal AKI.
Clinical depth
Renal dose adjustment
Standard 160 mg PO daily. No fully established renal dose-adjustment scheme; renal management is mainly diarrhea/volume control plus dose interruption/reduction.
Dialyzability & ESKD dosing
Not characterized; a small-molecule TKI that is highly protein-bound and hepatically metabolized, so it is unlikely to be dialyzable.
Differential diagnosis
Prerenal/volume-depletion AKI from diarrhea (most likely) versus ischemic ATN, other nephrotoxins/contrast, sepsis, obstructive/tumor-related AKI and other drug-induced AKI.
Monitoring
- ECG/QTc at baseline and periodically (and after electrolyte shifts)
- Serum electrolytes (especially magnesium and potassium)
- Renal function during diarrheal episodes
- Stool frequency
Key trials & series
- Phase 1/2 (PPP + EXCLAIM; Zhou, JAMA Oncol 2021) — registrational data supporting 2021 accelerated approval
- EXCLAIM-2 phase 3 (Janne, J Clin Oncol 2025) — first-line vs platinum; failed, leading to withdrawal
Clinical pearls
- Kidney injury is GI-mediated — mostly prerenal from torrential diarrhea, not direct tubulotoxicity; fix the gut and volume and the kidney recovers.
- Diarrhea is near-universal (~83-93%) and fast (median ~5 days) — a pre-emptive loperamide plus hydration/electrolyte plan from day 1 is essential.
- Watch the potassium/magnesium-QTc loop: diarrhea-induced hypokalemia/hypomagnesemia compounds intrinsic hERG-mediated QT prolongation.
- Historical caveat: withdrawn in 2023 after EXCLAIM-2 failed — a cautionary example of an unconfirmed accelerated approval.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Prerenal / Hemodynamic AKIAcute Tubular NecrosisElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of egfr exon20 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)
Evidence
7 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkTreatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic NSCLC: A Phase 1/2 Open-label Nonrandomized Clinical Trial.Zhou C et al. · JAMA Oncol 2021 · PMID 34647988Registrational phase 1/2 supporting 2021 accelerated approval.PMIDActivity and Safety of Mobocertinib (TAK-788) in Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations from a Phase I/II Trial.Riely GJ et al. · Cancer Discov 2021 · PMID 33632775First-in-human study defining the 160 mg/day dose; any-grade diarrhea ~83%.PMIDFirst-Line Mobocertinib Versus Platinum-Based Chemotherapy in Patients With EGFR Exon 20 Insertion-Positive Metastatic NSCLC in the Phase III EXCLAIM-2 Trial.Janne PA et al. · J Clin Oncol 2025 · PMID 39879577Confirmatory phase 3 that failed, precipitating worldwide withdrawal.PMIDCharacterization and management of adverse events observed with mobocertinib (TAK-788) treatment for EGFR exon 20 insertion-positive NSCLC.Yang JC et al. · Expert Rev Anticancer Ther 2022 · PMID 36537204Best diarrhea data: pooled diarrhea ~93%, median onset ~5 days, per-episode resolution ~2 days.PMIDMobocertinib: Mechanism of action, clinical, and translational science.Hanley MJ et al. · Clin Transl Sci 2024 · PMID 38511563Mechanism/PK review documenting the accelerated approval, EXCLAIM-2 failure and voluntary withdrawal.PMIDReal-world efficacy and safety of mobocertinib in EGFR exon 20 insertion-mutated lung cancer.Kian W et al. · Front Oncol 2022 · PMID 36203432Real-world cohort: grade >=3 diarrhea ~19% and grade >=3 renal failure ~6% (links GI to renal).PMIDSevere Acute Kidney Injury in Hospitalized Cancer Patients: Epidemiology and Predictive Model of Renal Replacement Therapy and In-Hospital Mortality.Calcas Marques R et al. · Cancers (Basel) 2024 · PMID 38339312Onconephrology context for prerenal/drug-induced AKI in cancer patients.
Related agents
Other agents sharing the same signature kidney injury.