Cetuximab & Panitumumab
Erbitux · Vectibix · Anti-EGFR antibody
TRPM6 magnesium wasting.
LYTE
MildOpen →
FGFR inhibitor
Infigratinib
Truseltiq · INFI
An FGFR inhibitor whose hyperphosphatemia is an on-target pharmacodynamic biomarker — manage it, do not ignore it.
ModerateFGFR inhibitor · approved 2021
Previously treated, unresectable or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement
Signature kidney injury
Electrolyte Wasting
Representative incidence77%
Hyperphosphatemia is the most common adverse event and the defining FGFR class effect — it occurred in 83 of 108 patients (~77%, any grade) in the pivotal trial. Infigratinib-specific nephrocalcinosis/calciphylaxis rates are not quantified (case reports/series only).
Source: Javle et al., Lancet Gastroenterol Hepatol 2021
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeverityModerate
ReversibilityReversible
Evidence0 refs
Nephron map
Proximal Tubule
Distal Tubule / Collecting DuctFine-tuning of Na, K, Mg, acid & water
Tubular Lumen
Electrolyte Wasting
Renal loss of magnesium, potassium or calcium — cisplatin and the anti-EGFR antibodies.
Mechanism of kidney injury
On-target disruption of the FGF23-alpha-Klotho axis. Normally bone-derived FGF23 binds the FGFR1/alpha-Klotho complex in the proximal tubule, downregulating apical sodium-phosphate cotransporters NaPi-2a (SLC34A1) and NaPi-2c (SLC34A3) to promote urinary phosphate excretion. FGFR inhibition blocks this signal, so NaPi-2a/2c are no longer suppressed and renal phosphate reabsorption rises, producing class-effect hyperphosphatemia. Sustained elevation (raised calcium-phosphate product) drives nephrocalcinosis, calcinosis cutis and vascular calcification. This is a metabolic/transporter effect, not primary tubular cytotoxicity.
Clinical presentation
Usually an asymptomatic rise in serum phosphate; severe or prolonged elevation can cause cramps and soft-tissue/cutaneous calcification (rarely calcinosis cutis/calciphylaxis). Onset is early — within the first cycle (days to weeks); cutaneous calcification has been reported as early as ~10 days.
Onset
Early (first cycle); reversible and dose-dependent, normalizing during the 7-day off-drug interval of the 21-on/7-off cycle.
Reversibility
Reversible
Anticancer mechanism
Oral, selective, ATP-competitive inhibitor of FGFR1-3 that targets oncogenic FGFR2 fusions and rearrangements in cholangiocarcinoma.
Management
Stepwise: intensify the phosphate binder (e.g. sevelamer) → if still markedly elevated, hold the drug → dose-reduce on rechallenge (125 mg to 100 to 75 mg) → discontinue for refractory/severe (e.g. >10 mg/dL) or symptomatic hyperphosphatemia or soft-tissue calcification. Keep the calcium-phosphate product down and avoid vitamin D loading.
Risk factors
- Higher dose/exposure
- Pre-existing CKD or reduced GFR and baseline hyperphosphatemia
- High dietary phosphate
- Concurrent vitamin D or phosphate supplementation
Prevention
- Low-phosphate diet (~600-800 mg/day) from the start
- Serial phosphate monitoring with a threshold-based algorithm
- Avoid vitamin D loading
- Start an oral phosphate binder when phosphate exceeds the label threshold (~7.0 mg/dL)
Note · The 2021 accelerated approval was contingent on confirmatory PROOF 301; infigratinib was subsequently withdrawn from the US cholangiocarcinoma market — verify current availability before clinical use. The hyperphosphatemia mechanism remains reference-grade and class-defining.
Clinical depth
Renal dose adjustment
Standard 125 mg daily for 21 of 28 days. No dedicated adjustment is established for mild-moderate renal impairment, but reduced GFR raises hyperphosphatemia risk and warrants closer monitoring; severe-impairment data are limited.
Dialyzability & ESKD dosing
Not established; highly protein-bound and CYP3A4-metabolized, so it is not expected to be meaningfully dialyzable.
Differential diagnosis
Distinguish from other FGFR inhibitors (pemigatinib, erdafitinib, futibatinib — same class effect), CKD/AKI phosphate retention, tumor lysis, exogenous phosphate load, hypoparathyroidism, vitamin D toxicity and pseudohyperphosphatemia (paraprotein/hemolysis).
Monitoring
- Serum phosphate at baseline and regularly (at least monthly) with a threshold-based binder/hold algorithm
- Serum calcium and renal function
- Ophthalmologic monitoring for serous retinopathy (FGFR class effect; outside renal scope)
Key trials & series
- Pivotal phase 2 (Javle, Lancet Gastroenterol Hepatol 2021) — hyperphosphatemia in ~77%
- PROOF 301 confirmatory phase 3 (Makawita, Future Oncol 2020) — design/rationale
Clinical pearls
- Hyperphosphatemia is an on-target pharmacodynamic biomarker of FGFR inhibition, not idiosyncratic — but it must be managed.
- It is the most common adverse event (~77% any grade) and the defining class effect of all FGFR1-3 inhibitors.
- Manage proactively with a low-phosphate diet plus threshold-triggered binders; the 7-day off-drug window aids reversal.
- The feared downstream harm is calcium-phosphate deposition (nephrocalcinosis, calcinosis cutis, calciphylaxis) — keep the calcium-phosphate product down and avoid vitamin D loading.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Electrolyte WastingCrystal / Obstructive Nephropathy
Beyond the kidney
Class-level context for the major non-renal toxicities of fgfr inhibitors.
Ophthalmic
Keratopathy, uveitis, retinopathy
- Central serous retinopathy
Dermatologic
Rash, HFS, SJS/TEN, vitiligo
- Nail/skin changes, hand-foot syndrome
Evidence
7 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkInfigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a single-arm, multicentre, phase 2 study.Javle M et al. · Lancet Gastroenterol Hepatol 2021 · PMID 34358484Pivotal/registrational phase 2; hyperphosphatemia the most common adverse event (83/108).PMIDTargeted Therapy for Advanced or Metastatic Cholangiocarcinoma: Focus on the Clinical Potential of Infigratinib.Yu J et al. · Onco Targets Ther 2021 · PMID 34720591Drug-focused review of mechanism, program and approval context.PMIDThe Klotho proteins in health and disease.Kuro-O M et al. · Nat Rev Nephrol 2019 · PMID 30455427Authoritative review of the FGF23-alpha-Klotho-FGFR axis governing renal phosphate handling.PMIDPleiotropic Actions of FGF23.Erben RG et al. · Toxicol Pathol 2017 · PMID 29096595FGF23/FGFR1/alpha-Klotho in the proximal tubule suppressing NaPi-2a/2c — basis of hyperphosphatemia.PMIDCalcinosis Cutis With Selective Fibroblast Growth Factor Receptor Inhibitors: A Case Report and Review of Literature.Ghimire B et al. · Cureus 2025 · PMID 40486452FGFR-inhibitor hyperphosphatemia-driven soft-tissue calcification with binder/hold management.PMIDInfigratinib in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF 301 trial.Makawita S et al. · Future Oncol 2020 · PMID 32580579Design/rationale of the confirmatory phase 3 PROOF 301 (first-line vs gemcitabine/cisplatin).PMIDPathobiology of the Klotho Antiaging Protein and Therapeutic Considerations.Prud'homme GJ et al. · Front Aging 2022 · PMID 35903083Klotho as an obligate FGF23 co-receptor regulating renal phosphate excretion.