Tyrosine Kinase Inhibitors in Clinical Practice: Case Reports

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1 european urology supplements 7 (2008) available at journal homepage: Tyrosine Kinase Inhibitors in Clinical Practice: Case Reports Vincenzo Ficarra a, *, Antonio Galfano a, Marco Cosentino a, Manfred Johannsen b a Clinica Urologica, Dipartimento di Scienze Oncologiche e Chirurgiche, Università degli Studi di Padova, Padua, Italy b Department of Urology, Campus Mitte, Charité-Universitätsmedizin Berlin, Germany Article info Keywords: Metastases Multitargeted Renal cell carcinoma Sunitinib malate Tyrosine kinase inhibitor This paper summarizes a presentation at a Pfizersponsored satellite symposium at the European Association of Urology (EAU) Congress on March 27, Abstract Context: Sunitinib malate is an oral, multitargeted receptor tyrosine kinase inhibitor approved multinationally for the treatment of metastatic renal cell carcinoma (mrcc). Objective: Experience of sunitinib use in clinical practice is demonstrated using real-life examples. Evidence acquisition: The use of sunitinib in two representative patients with mrcc is described. Evidence synthesis: The first patient, classified as intermediate risk according to the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic criteria, was treated with sunitinib following the occurrence of multiple soft-tissue and lung metastases. After 12 mo of follow-up, despite no reduction in the size of the metastases, the contrast enhancement was lower and patient s symptoms had resolved. Increased hypertension was effectively managed using antihypertensive treatment, and no dose reductions were required. The second patient, stratified into the MSKCC poor risk category, had synchronous multiple liver metastases and received sunitinib as a firstline treatment. After 13 mo, a partial response was achieved with minimal toxicity. Adverse events observed included grade 1 diarrhea and grade1/2 hand foot syndrome. No sunitinib dose reductions were required. In addition, the patient reported improvements in quality of life. Conclusions: The case studies reported in this paper confirm the effectiveness of sunitinib for the treatment of patients with mrcc stratified into different risk groups, with manageable adverse events. There is a need for additional stratification tools and new definitions for tumor responses for the new targeted therapies. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Clinica Urologica, Dipartimento di Scienze Oncologiche e Chirurgiche, Università degli Studi di Padova, via Giustiniani, Padua, Italy. Tel ; Fax: address: vincenzo.ficarra@unipd.it (V. Ficarra) /$ see front matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 european urology supplements 7 (2008) Introduction Sunitinib malate (Sutent) is an oral, multitargeted receptor tyrosine kinase inhibitor targeting the major subtypes of the vascular endothelial growth factor receptor (VEGFR1, 2, and 3), platelet-derived growth factor receptor (PDGFR-a and -b), stem cell factor receptor (c-kit), colony stimulating factor receptor type 1 (CSF-1R), FMS-like tyrosine kinase-3 receptor (FLT3), and the glial cell-line derived neurotrophic factor receptor (RET) [1 5]. Sunitinib has demonstrated clinical activity in metastatic renal cell carcinoma (mrcc), including in patients with spinal cord compression resulting from mrcc [6], and is the reference standard of care for the first-line treatment of mrcc [7]. Sunitinib is approved multinationally for the treatment of advanced renal cell carcinoma (RCC) and/or mrcc [7]. The development of several targeted agents demonstrating clinical efficacy for the treatment of mrcc highlights the importance selecting the appropriate treatments for individual patients. Prognostic factors that affect treatment outcome allow patients with mrcc to be stratified into risk groups. Several prognostic algorithms can be used to estimate the cancer-specific survival or diseasefree survival in RCC [8,9]. TheStageSizeGradeand Necrosis (SSIGN) score is able to accurately stratify patients with localized clear-cell RCC according to different possible outcomes and to assess the risk of developing metastatic disease [10,11]. The Memorial Sloan-Kettering Cancer Center (MSKCC) [12] model can also be used to stratify patients into favorable, intermediate, and poor risk groups. This stratification model is used for patients with metastatic disease. Treatment can then be optimized according to the patient s risk. Sunitinib is recommended as first-line therapy for patients with mrcc who are considered to be at favorable or intermediate risk [13]. For patients with poor prognosis, temsirolimus is recommended based on the results of a phase 3 trial [11], and sunitinib may also be considered [14]. In this paper, we describe the use of sunitinib in two patients with mrcc. The first patient, stratified into the intermediate MSKCC risk category, was treated with sunitinib following the occurrence of multiple soft-tissue and lung metastases. The second patient was considered at poor prognostic risk, had synchronous multiple liver metastases, and was treated successfully with sunitinib in the first-line setting. 2. Case report 1 The subject was a 57-yr-old woman without significant comorbidities, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, and hematuria (S2). She presented with a renal mass on the right kidney on a chest and abdominal computed tomography (CT) scan. The renal mass was 10 cm in size and without adrenal or lymph node involvement. No distant metastases were detected, and the contralateral kidney presented as normal. Open radical nephrectomy was successfully performed. Histologic examination revealed clearcell RCC with perirenal fat and adrenal gland invasion (pt3a N0 M0), Fuhrman nuclear grade IV, and coagulative necrosis. Based on a SSIGN score of 9, the patient was deemed to be at high risk of developing metastases. In accordance with the current guidelines, no adjuvant systemic therapy was administered and the patient was monitored at 6-mo intervals with abdominal CT scans and chest x-rays. At the 24-mo postnephrectomy follow-up, the patient presented with multiple soft-tissue and lung metastases. Analysis of risk factors by MSKCC risk stratification revealed corrected serum calcium levels of 12 mg/dl, hemoglobin of 10 g/dl, lactate dehydrogenase (LDH) levels of 180 U/l, and a Karnofsky performance status (PS) of In addition, the time from diagnosis to systemic treatment was longer than 12 mo. Based on these factors, the patient was stratified into the intermediate prognostic risk category and started on sunitinib at 50 mg per day on schedule 4/2 (6-wk cycles of 4 wk on treatment followed by 2 wk off treatment). After eight cycles of sunitinib treatment, tumors in both the soft tissue and the lungs remained unchanged in size; however, the contrast enhancement was lower for both sites (Fig. 1). The patient experienced an improvement in disease-related symptoms, and her anemia resolved. During treatment, grade 1 leukopenia, diarrhea, and petechial bleeding occurred. No sunitinib dose reductions were required, however, and the diarrhea symptoms were managed by using antidiarrheal medication. Increased hypertension was controlled using antihypertensive treatment (an angiotensin-converting enzyme [ACE] inhibitor and b-blocker) during the sunitinib dosing cycles. Initial treatment with b-blockers was unable to effectively manage increased blood pressure, and the patient was switched to treatment with ACE inhibitors. This treatment, combined with antihypertensive treat-

3 612 european urology supplements 7 (2008) Fig. 1 Chest x-ray and computed tomography (CT) scan of metastases in (a) the lungs and (b) soft tissue at initial diagnosis and at 12-mo follow-up. ment during sunitinib treatment cycles, was able to effectively control hypertension and allow the patient to remain on sunitinib therapy. At the next 12-mo follow-up, the patient had stable metastases but contrast enhancement of the tumors was lower; therefore, it was difficult to determine whether the patient achieved a partial response or stable disease as defined by both Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) criteria. Response to therapy is evaluated in most clinical studies using the RECIST criteria developed in the era of cytokine therapy. Other criteria also used in clinical studies to evaluate response include the WHO criteria. Because targeted therapies are antiangiogenic agents that do not act in a cytotoxic capacity, these criteria may not be the most suitable for assessing response to treatment with targeted agents. Our conclusion was that the patient achieved a partial response. The response observed in this case confirms clinical efficacy of sunitinib in the treatment of patients stratified into the intermediate risk category. In addition, the adverse events experienced by the patient were mild to moderate in intensity and easily managed. This case highlights the need for alternative tools for assessing response to targeted therapy. 3. Case report 2 A 63-yr-old male patient presented with symptoms of fever and weight loss (S3), hypertension (Charlson score 1), and ECOG PS of 0. Chest and abdominal CT scans revealed a right renal mass, 7 cm in size, with renal vein involvement. No lymph nodes were involved, and the contralateral kidney was normal. The patient also had synchronous multiple liver metastases. Following open cytoreductive radical nephrectomy, the tumor was identified as clear-cell RCC with sarcomatoid differentiation. The primary tumor extended to the perirenal fat and the renal vein. One of the 20 lymph nodes removed during extended paracaval and interaortocaval lymphadenectomy was also positive for metastatic disease (ct3b N1 M1). The Fuhrman nuclear grade was IV, and coagulative necrosis was present. The patient achieved a SSIGN score of 15, suggesting a poor prognosis in terms of cancer-specific survival. MSKCC risk factor analysis revealed corrected serum calcium levels of 9.3 mg/dl, hemoglobin 9.5 g/dl, LDH 180 U/l and Karnofsky PS of 70 80, with a time from diagnosis to systemic treatment of <12 mo, suggesting that the patient could be stratified into the poor risk category.

4 european urology supplements 7 (2008) (from 10 cm to 6 cm). Further regression of metastases (from 6 cm to 2.5 cm) occurred after a total of 10 mo of treatment with sunitinib (Fig. 2). The patient experienced grade 1 leucopenia, diarrhea, and petechial bleeding. Grade 1/2 hand foot syndrome was also observed, but no sunitinib dose reductions were required. The hand foot syndrome was managed through effective pedicures and local painkillers as well as the use of moisturizing lotion, cotton socks, and soft shoes. Despite unfavorable histology (sarcomatoid differentiation) and poor prognosis, this patient achieved a partial response. The patient has been receiving sunitinib for 13 mo with minimal toxicity. The patient s quality of life, evaluated by means of the Short Form-36 (SF-36) health survey questionnaire at the start of treatment, remains similar to that recorded at treatment initiation in both the emotional and the physical domains. 4. Conclusions Sunitinib has demonstrated clinical efficacy in the treatment of patients with mrcc and is generally well tolerated with most adverse events being grade 1 or 2 in intensity. The case studies reported in this paper confirm the effectiveness of sunitinib for the treatment of mrcc with manageable adverse events such that no dose reduction or interruptions were required. In addition, the cases reported in this paper demonstrate that sunitinib may be used in patients with differing prognostic-risk-factor profiles, including those stratified into the MSKCC poor risk group. The new targeted therapies appear to act differently on tumors compared to chemotherapy or cytokines. As a result, there is a need for new definitions for tumor responses for the new targeted therapies, as highlighted in case report 1. Conflicts of interest Fig. 2 Regression of liver metastases following treatment with sunitinib at 50 mg per day in a patient stratified into the Memorial Sloan-Kettering Cancer Center category for poor risk. The patient was considered to be a suitable candidate for first-line systemic therapy, and sunitinib 50 mg per day (schedule 4/2) was initiated. After 3 mo of treatment with sunitinib, there was significant regression of liver metastases Vincenzo Ficarra has received honoraria from Pfizer Inc. Manfred Johannsen has received honoraria from Bayer Pharmaceuticals, Pfizer Inc, and Sanofi-Aventis. No conflicts of interest were declared by Antonio Galfano and Marco Cosentino. Funding support Pfizer Inc. provided funding for editorial assistance.

5 614 european urology supplements 7 (2008) Acknowledgements The authors acknowledge ACUMED (Tytherington, UK) for providing editorial assistance for this paper. References [1] Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2003;2: [2] Kim DW, Jo YS, Jung HS, et al. An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab 2006;91: [3] Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;9: [4] Murray LJ, Abrams TJ, Long KR, et al. SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 2003;20: [5] O Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003;101: [6] Trinh Q-D, Cardinal E, Gallina A, Perrotte P, Saad F, Karakiewicz PI. Sunitinib relieves renal cell carcinoma spinal cord compression. Eur Urol 2007;51: [7] Sutent, summary of product characteristics. New York, NY: Pfizer Inc; [8] Ficarra V, Galfano A, Novara G, et al. Risk stratification and prognostication of renal cell carcinoma. World J Urol 2008;26: [9] Karakiewicz PI, Trinh Q-D, Bhojani N, et al. Renal cell carcinoma with nodal metastases in the absence of distant metastatic disease: prognostic indicators of diseasespecific survival. Eur Urol 2007;51: [10] Frank I, Blute ML, Cheville JC, et al. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol 2002; 168: [11] Leibovich BC, Blute ML, Cheville JC, et al. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 2003;97: [12] Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20: [13] Ljungberg B, Hanbury DC, Kuczyk MA, et al. Renal cell carcinoma guideline. Eur Urol 2007;51: [14] Gore M. Sunitinib in metastatic renal cell carcinoma (mrcc): preliminary assessment of toxicity in an expanded open access trial with subpopulation analysis. J Clin Oncol 2007;25:237S.