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FGFR inhibitor

Infigratinib

Truseltiq · INFI

FGFR inhibitor · approved 2021 · 7 references

An FGFR inhibitor whose hyperphosphatemia is an on-target pharmacodynamic biomarker — manage it, do not ignore it.

Signature injury
Electrolyte Disturbance
Severity
Moderate
Reversibility
Reversible
Onset
Early (first cycle); reversible and dose-dependent, normalizing during the 7-day off-drug interval of the 21-on/7-off cycle.

Signature kidney injury & incidence

Electrolyte Disturbance — representative incidence ~77%.

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

Reported injury signatures: Electrolyte Disturbance, Crystal / Obstructive Nephropathy.

Renal toxicity profile

  1. Electrolyte DisturbancePrimary~77%Hyperphosphatemia ~77% (83/108) - on-target FGFR class effect and most common AE
  2. Crystal / Obstructive NephropathyRare

Onset timing & rechallenge

Subacute (~1–6 weeks) — Early (first cycle); reversible and dose-dependent, normalizing during the 7-day off-drug interval.

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.

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
  • Avoid vitamin D loading
  • Start an oral phosphate binder when phosphate exceeds the label threshold (~7.0 mg/dL)

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.

Anticancer mechanism

Oral, selective, ATP-competitive inhibitor of FGFR1-3 that targets oncogenic FGFR2 fusions and rearrangements in cholangiocarcinoma.

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.

Guidelines & consensus

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.

  • ADQI (2026) — The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupProvides 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.Nat Rev Nephrol · PMID 41361704
  • SIRM (2022) — SIRM-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)Recommends 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.Radiol Med · PMID 35303246
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerIdentifies 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.Kidney Int · PMID 33126977
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationAddresses 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.Kidney Int · PMID 33276867
  • ADDIKD (2025) — Integrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceProvides 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.EClinicalMedicine · PMID 40290844
  • ADDIKD (2025) — Aligning kidney function assessment in patients with cancer to global practices in internal medicineThree 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.EClinicalMedicine · PMID 40290845
  • ADDIKD (2025) — A methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEstablishes 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.EClinicalMedicine · PMID 40290846
  • KDIGO (2013) — Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Defines/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.Crit Care · PMID 23394211
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknownsEvaluate 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.Kidney Int · PMID 38519239
  • KDIGO (2021) — Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesProvides 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.Kidney Int · PMID 34556300
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisUpdates 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.Kidney Int · PMID 38388147
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisUpdates 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.Kidney Int · PMID 38182299
  • KDIGO (2025) — Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Encourages 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.Kidney Int · PMID 40975525

References

7 peer-reviewed references. Citation metadata via PubMed / NLM.

  1. 1.Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study.Javle M et al. · Lancet Gastroenterol Hepatol · 2021 · PMID 34358484
  2. 2.Targeted Therapy for Advanced or Metastatic Cholangiocarcinoma: Focus on the Clinical Potential of Infigratinib.Yu J et al. · Onco Targets Ther · 2021 · PMID 34720591
  3. 3.The Klotho proteins in health and disease.Kuro-O M et al. · Nat Rev Nephrol · 2019 · PMID 30455427
  4. 4.Pleiotropic Actions of FGF23.Erben RG et al. · Toxicol Pathol · 2017 · PMID 29096595
  5. 5.Calcinosis Cutis With Selective Fibroblast Growth Factor Receptor Inhibitors: A Case Report and Review of Literature.Ghimire B et al. · Cureus · 2025 · PMID 40486452
  6. 6.Infigratinib in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF 301 trial.Makawita S et al. · Future Oncol · 2020 · PMID 32580579
  7. 7.Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations.Prud'homme GJ et al. · Front Aging · 2022 · PMID 35903083
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.