Targeted FGFR Blockade for the Treatment of Tumor-Induced Osteomalacia

To The Editor: Tumor-induced osteomalacia is a rare paraneoplastic syndrome caused by excessive secretion of fibroblast growth factor 23 (FGF23) by a phosphaturic mesenchymal tumor.¹ Through fibroblast growth factor receptor 1 (FGFR1) signaling, FGF23 decreases renal phosphate reabsorption and 1,25-dihydroxyvitamin D production.² The resulting hypophosphatemia causes rickets, osteomalacia, bone pain, muscle weakness, and fractures. Tumor-induced osteomalacia is usually cured by surgical resection of the phosphaturic mesenchymal tumor.³ However, in unlocalizable, unresectable, or metastatic disease, when surgical cure is not possible, medical therapy can limit the biochemical consequences of FGF23 excess.¹ These therapies do not target the tumor, and therefore a potential for local or metastatic spread remains. When fusion genes consisting of FGFR1 and the gene encoding fibronectin 1 (FN1) were identified in some phosphaturic mesenchymal tumors, FGFR1 became a potential therapeutic target in patients with tumor-induced osteomalacia.⁴

We report the use of the FGFR1–3 tyrosine kinase inhibitor infigratinib in a 66-year-old man with a phosphaturic mesenchymal tumor bearing the FN1–FGFR1 fusion gene. The patient’s medical history was previously reported in the Journal.⁵ A phosphaturic mesenchymal tumor was diagnosed when he was 42 years of age; the tumor persisted despite multiple surgeries. When he was 56 years of age, lung metastases developed. By the age of 61 years, widespread superficial and visceral metastases had appeared (Fig. 1C), and he began treatment with infigratinib within the context of a clinical trial (ClinicalTrials.gov number, NCT02160041). The immediate response was dramatic. Within 24 hours, the FGF23 level decreased from 15,500 relative units (RU) per milliliter to 1765 RU per milliliter (normal value, <180); after 2 weeks, the FGF23 level was normal and the phosphate level elevated (Fig. 1A). Positron-emission tomographic imaging with ¹⁸F-fluorodeoxyglucose in combination with computed tomography indicated that the metastatic lesions had regressed (Fig. 1C). With treatment, progressive calcification of several soft-tissue lesions was observed. Pretreatment and post-treatment biopsies of one lesion revealed that a previously sarcomatous tumor had been replaced with lamellar bone, a finding consistent with metaplastic transformation (Fig. 1B).

Figure 1. Response to Infigratinib Treatment.

Panel A shows the marked decreases in FGF23 levels (black curve) induced by infigratinib (gray bars indicate doses of the drug), which reversed when the patient was not receiving the drug. The timing of the imaging studies are indicated by arrows labeled a through e, which correspond to the images shown in Panel C. Panel B shows images of the lesions, obtained by computed tomography (CT) and microscopy. Calcification of the metastatic lesion over the scapula was seen in pretreatment and post-treatment noncontrast CT images (arrows). Biopsy of the pretreatment lesion revealed features consistent with a sarcomatous phosphaturic mesenchymal tumor. Biopsy of the calcified lesion after treatment revealed mature, lamellar bone, a finding consistent with infigratinib-induced metaplastic ossification. Panel C shows serial whole-body positron-emission tomographic imaging with ¹⁸F-fluorodeoxyglucose in combination with CT (¹⁸F-FDG-PET–CT); the scans show the response of metastatic tumors to infigratinib before treatment (a), during treatment (b), after discontinuation (c), after reinitiation (d), and during disease progression (e).

Despite dose adjustments, tyrosine kinase inhibitor–related side effects led to infigratinib being discontinued after 18 months of treatment. Immunotherapy with nivolumab and ipilimumab, given in the context ofa clinical trial (NCT02834013), was ineffective. The FGF23 level continued to increase to 78,800 RU per milliliter, and widespread metastases were noted (Fig. 1A and 1C). Severe anemia developed and was treated with a transfusion; granulocyte-colony stimulating factor-mediated paraneoplastic neutrophilia also developed (Fig. S7 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).

Treatment with infigratinib was reinitiated 28 months after the previous discontinuation. Again, the FGF23 level decreased rapidly, from 78,800 RU per milliliter to 670 RU per milliliter over a period of 100 days (Fig. 1A). Imaging showed marked improvement (Fig. 1C). The white-cell count normalized in parallel with the FGF23 levels. Blood transfusions, which had previously been given every 2 to 3 weeks, were avoided for 7 months.

Ultimately, the side effects necessitated intermittent dose interruptions. The patient’s disease progressed, and his functional status deteriorated. Ten months after resuming therapy, and 5 years since the initiation of infigratinib, the patient died. Additional details are provided in the Supplementary Appendix.

This case enabled us to identify a much-needed treatment for malignant tumor–induced osteomalacia; in addition, it shows how an approach based on personalized medicine, made possible by molecular diagnostics and mechanistically directed therapy, prolonged this patient’s life. The dramatic biochemical and structural response to this treatment confirms the role of FGFR1 signaling in phosphaturic mesenchymal tumor growth and FGF23 production. The metaplastic differentiation from sarcoma to differentiated bone suggests that these tumors are derived from skeletal stem cells with the capacity to differentiate into osteoblast-like cells and that the acquisition of gain-of-function FGFR1 signaling both promotes tumorigenesis and blocks differentiation, a phenomenon that is reversed by FGFR blockade. Infigratinib as a treatment for unresectable or nonlocalized phosphaturic mesenchymal tumors is currently being investigated (NCT03510455).

THIS WEEK’S LETTERS.

1387 Targeted FGFR Blockade for the Treatment of Tumor-Induced Osteomalacia

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