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Thyroid dysfunction from inhibitor of fibroblast growth factor receptor.

ABSTRACT: Background:Thyroid dysfunction has not been previously reported in clinical trials of selective fibroblast growth factor receptor (FGFR) inhibitors including AZD4547. Herein, we report a case of worsening hypothyroidism in a patient with advanced urothelial cancer treated with AZD4547. Case presentation:An 80-year-old Caucasian female with metastatic urothelial carcinoma failed first-line chemotherapy with gemcitabine and carboplatin and second-line treatment with atezolizumab, an inhibitor of programmed cell death ligand 1. She developed hypothyroidism at completion of atezolizumab treatment and responded to levothyroxine. Subsequently she was enrolled to a phase II study and received AZD4547 due to an actionable mutation at FGFR3 found in tumor biopsy. Two months later, she experienced recurrent hypothyroidism symptoms, and was hospitalized twice for small bowel obstruction. Her thyroid stimulating hormone level was significantly increased to 2957 uIU/mL (reference range 0.8-7.7 uIU/mL). Her levothyroxine dose was increased accordingly. Her thyroid function returned to normal 1 month afterwards, and small bowel obstruction did not recur. Conclusion:Further reports and studies will be needed to confirm the relationship between AZD4547 and hypothyroidism. Based on this observation and possible mechanisms for thyroid dysfunction discussed in this paper, routine thyroid function monitoring in patients receiving FGFR inhibitor should be considered.

SUBMITTER: Ahn J

PROVIDER: S-EPMC6379924 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Thyroid dysfunction from inhibitor of fibroblast growth factor receptor.

Ahn Jeffrey J Moyers Justin J Wong John J Hsueh Chung-Tsen CT

Experimental hematology & oncology 20190218

<h4>Background</h4>Thyroid dysfunction has not been previously reported in clinical trials of selective fibroblast growth factor receptor (FGFR) inhibitors including AZD4547. Herein, we report a case of worsening hypothyroidism in a patient with advanced urothelial cancer treated with AZD4547.<h4>Case presentation</h4>An 80-year-old Caucasian female with metastatic urothelial carcinoma failed first-line chemotherapy with gemcitabine and carboplatin and second-line treatment with atezolizumab, an ...[more]

PMID: 30820365

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Project description:ImportanceFibroblast growth factor receptor (FGFR) 1 to 4 inhibitors are approved by the US Food and Drug Administration and suppress the mitogen-activated protein kinase (MAPK) pathway, with a potential for treatment-related retinopathy. To date, implications of FGFR inhibitor-associated ocular toxic effects are poorly described. Therefore, more detailed clinical descriptions of this ocular toxic effect could help explain visual symptoms while receiving drug therapy.ObjectiveTo describe the clinical and morphologic characteristics of serous retinal disturbances associated with FGFR inhibitors.Design, setting, and participantsIn this retrospective case series, 146 patients receiving FGFR inhibitors as cancer treatment at a single tertiary referral center were included. This study included 40 eyes of 20 patients with retinopathy by optical coherence tomography (OCT). OCTs were obtained on the remaining patients and the results were judged normal. Patients were recruited from March 2012 to January 2021.Main outcomes and measuresCharacteristics of treatment-emergent choroidal and retinal OCT abnormalities as compared with baseline OCT, associated with visual acuity at presentation and at fluid resolution.ResultsA total of 20 of 146 patients (13.7%) exhibited FGFR inhibitor-associated retinopathy. Of these 20 patients, 11 (55%) were female, and the median (range) age was 62.6 (42.7-86.0) years. The median (range; mean) time from medication start to initial subretinal fluid detection was 21 (5-125; 32) days. The median (interquartile range [IQR]) baseline logMAR best-corrected visual acuity (BCVA) was 0 (0-0.1). At fluid accumulation, 11 eyes had decreased vision: the median (IQR) subgroup baseline BCVA was 0 (0-0.1); and the median (IQR) BCVA change from baseline to accumulation was -0.1 (-0.2 to -0.1). For 26 eyes (65%) with follow-up, the subretinal fluid resolved without medical intervention or drug interruption in all but 1 patient. At fluid resolution, the median (IQR) BCVA was 0.1 (0-0.1), and the change in median (IQR) BCVA from baseline to fluid resolution was 0 (-0.03 to 0). No patient discontinued drug therapy on account of their retinopathy.Conclusions and relevanceFGFR inhibitors result in subretinal fluid foci similar to other drugs that inhibit the MAPK pathway. In this series, FGFR inhibitors did not cause irreversible loss of vision; the retinopathy was self-limited and did not require medical intervention. These results may explain visual symptoms while taking the drug, although the precise frequency or magnitude of this adverse effect cannot be determined with certainty from this retrospective investigation.

Project description:BackgroundInfigratinib (BGJ398) is a potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor with significant activity in metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations. It can cause hyperphosphatemia due to the "on-target" class effect of FGFR1 inhibition.ObjectiveTo investigate the relationship between hyperphosphatemia and treatment response in patients with mUC.InterventionOral infigratinib 125 mg/d for 21 d every 28 d.Design, setting, and participantsData from patients treated with infigratinib in a phase I trial with platinum-refractory mUC and activating FGFR3 alterations were retrospectively analyzed for clinical efficacy in relation to serum hyperphosphatemia. The relationship between plasma infigratinib concentration and phosphorous levels was also assessed.Outcome measurements and statistical analysisClinical outcomes were compared in groups with/without hyperphosphatemia.Results and limitationsOf the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on one or more laboratory tests. Findings in patients with versus without hyperphosphatemia were the following: overall response rate 33.3% (95% confidence interval [CI] 20.4-48.4) versus 5.3% (95% CI 0.1-26.0); disease control rate 75.0% (95% CI 60.4-86.4) versus 36.8% (95% CI 16.3-61.6). This trend was maintained in a 1-mo landmark analysis. Pharmacokinetic/pharmacodynamic analysis showed that serum phosphorus levels and physiologic infigratinib concentrations were correlated positively. Key limitations include retrospective design, lack of comparator, and limited sample size.ConclusionsThis is the first published study to suggest that hyperphosphatemia caused by FGFR inhibitors, such as infigratinib, can be a surrogate biomarker for treatment response. These findings are consistent with other reported observations and will need to be validated further in a larger prospective trial.Patient summaryTargeted therapy is a new paradigm in treating bladder cancer. In a study using infigratinib, a drug that targets mutations in a gene called fibroblast growth factor receptor 3 (FGFR3), we found that elevated levels of phosphorous were associated with greater clinical benefit. In the future, these data may help inform treatment strategies.

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Thyroid dysfunction from inhibitor of fibroblast growth factor receptor.

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Thyroid dysfunction from inhibitor of fibroblast growth factor receptor.

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