EURURO-6091; No. of Pages 2 EUROPEAN UROLOGY XXX (2015) XXX–XXX

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Research Letter Exceptional Response to Pazopanib in a Patient with Urothelial Carcinoma Harboring FGFR3 Activating Mutation and Amplification We report the case of a 67-yr-old woman who presented with intermittent gross hematuria. Cystoscopy showed a sessile bladder tumor, and biopsy demonstrated high-grade papillary urothelial carcinoma. Computed tomography (CT) imaging of the chest, abdomen, and pelvis revealed a 7-cm bladder mass and multiple pulmonary nodules ranging from 0.4 to 2.1 cm. The patient received four cycles of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC regimen) chemotherapy. Her course was complicated by neutropenic fever, and subsequent imaging showed Response Evaluation Criteria in Solid Tumor–defined progression, with multiple new pulmonary nodules emerging. The patient then received a combination of doxorubicin and ifosfamide, complicated by both neutropenic fever and renal impairment with no documented response. This was followed by sequential therapy with paclitaxel followed by methotrexate, gemcitabine, and cyclophosphamide. Treatment was interrupted to allow the patient to undergo a palliative cystectomy. Pathologic analysis of the cystectomy specimen revealed residual high-grade papillary urothelial carcinoma invading the lamina propria. CT imaging of the chest performed within 2 mo of the procedure showed further tumor progression, with enlargement of existing lung nodules and new pulmonary lesions. With patient permission, the formalin-fixed, paraffinembedded cystectomy specimen was submitted to a College of American Pathologists–accredited, Clinical Laboratory

Improvement Act–certified laboratory (Foundation Medicine, Cambridge, MA, USA) for genomic profiling by a clinical hybrid capture–based assay [1]. The tumor harbored amplification of FGFR3 (11 copies), CCND1 (21 copies), and FGF19 (21 copies) and an FGFR3 S249C mutation with estimated mutant allele frequencies of 58%. On the basis of these findings, the patient was initiated on pazopanib. After 3 mo of therapy, the patient achieved a partial response (PR) that has been maintained for >6 mo of follow-up. In contrast to the prior cytotoxic regimens given, the patient experienced only mild fatigue and diarrhea on pazopanib (Fig. 1 ). The present case underscores the potential value of genomic profiling in advanced urothelial carcinoma. Median overall survival (OS) for patients with this disease is approximately 14 mo for patients who can tolerate first-line cisplatin-based regimens [2]. For the roughly 45% of patients who receive salvage treatment, median progression-free survival (PFS) and OS with various regimens range from 3 to 5 mo and from 6 to 9 mo, respectively [3,4]. In an unselected population, the data for pazopanib are not markedly different. One phase 2 study suggested a median PFS of just 1.9 mo, with no responses among 16 patients enrolled [5]. In contrast, major patient benefit may occur from applying matched targeted therapies to patients harboring genomic alterations that may suggest response. In a phase 1 study, for example, the fibroblast growth factor receptor (FGFR) inhibitor BGJ398 has been explored in a limited series of bladder cancer patients bearing FGFR3 mutations (n = 5), with two patients achieving a prolonged PR and the remaining three patients achieving stable disease as a best

Fig. 1 – Representative pulmonary lesion showing response after initiation of pazopanib therapy.

http://dx.doi.org/10.1016/j.eururo.2015.02.023 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology.

Please cite this article in press as: Palma N, et al. Exceptional Response to Pazopanib in a Patient with Urothelial Carcinoma Harboring FGFR3 Activating Mutation and Amplification. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.02.023

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EUROPEAN UROLOGY XXX (2015) XXX–XXX

response after three or more cycles of therapy [6]. FGFR3 rearrangement and activating mutations are seen in an estimated 6% and 15%, respectively, of bladder cancer cases [7,8]. In a previous study using the same hybrid capture– based assay, FGFR3 alterations were identified in 11% of urothelial carcinomas of the bladder [9]. Although investigational agents with specific affinity for FGFR show promise in early trials, other existing multikinase inhibitors also have inhibitory activity. Pazopanib is one such agent, with affinity for a variety of transmembrane receptors including vascular endothelial growth factor receptors 1–3 (VEGFR1, VEGFR2, VEGFR3), platelet-derived growth factor receptor (PDGFR), c-KIT, and FGFR. Data from the present case support further study of pazopanib in advanced urothelial carcinoma, specifically among patients with relevant molecular aberrations.

[5] Pili R, Qin R, Flynn PJ, et al. A phase II safety and efficacy study of the

Conflicts of interest: Norma Palma, Siraj M. Ali, and Jeffrey S. Ross are

John C. Morrisb,y

employees of and have equity interest in Foundation Medicine, Inc.

Siraj M. Alia

vascular endothelial growth factor receptor tyrosine kinase inhibitor pazopanib in patients with metastatic urothelial cancer. Clin Genitourin Cancer 2013;11:477–83. [6] Sequist LV, Cassier P, Varga A. Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors [abstract CT326]. Presented at: American Association for Cancer Research annual meeting. San Diego CA USA 2014, April 5–9. [7] Williams SV, Hurst CD, Knowles MA. Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Genet 2013;22:795–803. [8] Tomlinson DC, Baldo O, Harnden P, Knowles MA. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol 2007;213:91–8. [9] Ross JS, Wang K, Al-Rohil RN, et al. Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy. Mod Pathol 2014;27:271–80. Norma Palmaa,y

Jeffrey S. Rossa,c

Sumanta Kumar Pal has a research collaboration with Foundation

Sumanta Kumar Pald,*

Medicine Inc. John C. Morris has nothing to disclose.

References

a b

Cincinnati, OH, USA

[1] Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical cancer genomic profiling test based

c

Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY, USA

on massively parallel DNA sequencing. Nat Biotechnol 2013;31: 1023–31. [2] von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival

Foundation Medicine, Cambridge, MA, USA

Division of Hematology-Oncology, University of Cincinnati Cancer Institute,

d

Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005;23:4602–8.

*Corresponding author. Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer

[3] Sonpavde G, Sternberg CN, Rosenberg JE, Hahn NM, Galsky MD,

Center, 1500 East Duarte Road, Duarte, CA 91010, USA.

Vogelzang NJ. Second-line systemic therapy and emerging drugs

Tel. +1 626 256 4673; Fax: +1 626 301 8233.

for metastatic transitional-cell carcinoma of the urothelium. Lancet

E-mail address: [email protected] (S.K. Pal).

Oncol 2010;11:861–70. [4] Galsky MD, Chowdhury S, Bellmunt J, et al. Treatment patterns and

y

These authors contributed equally to this work.

outcomes in ‘‘real world’’ patients (pts) with metastatic urothelial cancer (UC) [abstract 4525]. J Clin Oncol 2013;31(Suppl).

February 20, 2015

Please cite this article in press as: Palma N, et al. Exceptional Response to Pazopanib in a Patient with Urothelial Carcinoma Harboring FGFR3 Activating Mutation and Amplification. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.02.023

Exceptional Response to Pazopanib in a Patient with Urothelial Carcinoma Harboring FGFR3 Activating Mutation and Amplification.

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