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Sunitinib for Patients with Metastatic Non-clear Cell Renal Cell Carcinoma: A Multicenter Retrospective Turkish Oncology Group Trial

IBRAHIM YILDIZ1, MELTEM EKENEL2, TULAY AKMAN3, MUHARREM KOCAR4, MÜKREMIN UYSAL5, METIN KANITEZ6, UMUT VAROL1, IBRAHIM VEDAT BAYOGLU1, DENIZ TURAL7, MEHMET ALI KAPLAN8, NILUFER AVCI9, ZEKI SÜRMELI10, İSA DEDE11, ARIFE ULAŞ12, OZAN YAZICI13 and MERT BASARAN2

Departments of Medical Oncology at: 1Ataturk Training and Research Hospital, Izmir Katip Celebi University, Izmir, Turkey; 2Institute of Oncology, Istanbul University, Istanbul, Turkey; 3Izmir Tepecik Training and Research Hospital, Izmir, Turkey; 4Sanliurfa Education and Research Hospital, Sanliurfa, Turkey; 5Afyon Kocatepe University, Afyonkarahisar, Turkey; 6Marmara University Hospital, Istanbul, Turkey; 7Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey; 8Dicle University, Diyarbakir, Turkey; 9Balikesir State Hospital, Balikesir, Turkey; 10Ege University, Tulay Aktas Oncology Hospital, Izmir, Turkey; 11Ankara University Medical Faculty, Ankara, Turkey; 12Ali Osman Sonmez Oncology Training and Research Hospital, Bursa, Turkey; 13Ankara Numune Education and Research Hospital, Ankara, Turkey

Abstract. Aim: This study aimed to assess the clinical reduction in 27 (42.9%). The objective response rate and efficacy and toxicity of , a targeted-agent, for non- disease control rate were 11.1% and 63.5%, respectively. The clear cell renal cell carcinoma. Patients and Methods: Sixty- median PFS and OS were 7.6 months (95% confidence three patients with complete clinical data from 13 oncology interval (CI)=5.5-9.7 months) and 22.0 months (95% Centers were retrospectively evaluated. Outcomes analyzed CI=13.4-30.6 months), respectively, with 1-year rates of were objective response rate (ORR), progression-free survival 64.7% and 33.7%, respectively. Conclusion: Clinical outcome (PFS), overall survival (OS) and adverse events. Results: The of the metastatic non-clear cell RCC patients with sunitinib median age of all patients, 38 men (60.3%) and 25 women treatment seemed to be worse than the historical data of clear (39.7%), was 63 years (range=25-82 years). Histological cell RCC patients, in terms of PFS, OS and objective response. subtypes included 46 (88%) cases of papillary RCC, 10 of New and more effective targeted-therapies and better chromophobe, and 7 unclassified cases. Median treatment understanding of the underlying molecular processes are duration was seven months (range=2-86 months). At the time necessary to improve survival outcome for these patients. of this analysis, 52 patients had discontinued treatment, 33 of whom had died. Treatment discontinuation was due to disease Renal cell carcinoma (RCC) is distinguished into several progression in 43 patients, and toxicity in nine. Dose distinct subtypes (1), including clear (conventional), papillary interruption was necessary in 22 (34.9%) patients, and dose (types 1 and 2), chromophobe, collecting duct, medullary, and unclassified type (2). These subtypes differ in pathogenetic mechanism, histological appearance, and clinical course. Clear cell RCC is the predominant subtype, accounting for Correspondence to: Ibrahim Yildiz, MD, Department of Medical 75% of all renal epithelial tumors. All other histological Oncology, Ataturk Training and Research Hospital, Izmir Katip subtypes are collectively identified as non-clear cell RCC. Celebi University, Izmir, Turkey. Tel: +90 5057465178, Fax: +90 Except for collecting duct carcinoma, which is sensitive to 2322431530, e-mail: [email protected] platinum-based chemotherapy, metastatic non-clear cell RCC Key Words: Adverse effects, metastatic non-clear cell renal cell is resistant to both immunotherapy and cytotoxic carcinoma, sunitinib. chemotherapy, resulting in poor patient prognosis (3).

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In the past decade, targeted therapies that block angiogenic Baseline evaluation. The pre-treatment assessment included a activity mediated by the vascular endothelial medical history, a physical examination with ECOG PS evaluation, (VEGF) signaling pathway (sunitinib, , , cardiac function testing with electrocardiography and echocardiography, and laboratory examinations such as complete , and ) or by the mammalian target of blood count and serum biochemistry. Computed tomography (CT), rapamycin (mTOR) signaling pathway (temsirolimus and magnetic resonance imaging (MRI), or positron-emission everolimus) have shown profound effects on the clinical tomography was performed when indicated. Each patient was outcome of patients with advanced RCC (4, 5). However, due classified according to the Memorial Sloan-Kettering Cancer Center to the relatively high prevalence of clear cell RCC, clinical risk scoring system (14). trials for targeted-agents have typically focused on this patient Treatment, toxicity, and response evaluation. Sunitinib was population while frequently excluding those with non-clear administered orally at a continuous daily dose of 37.5 mg or an intermittent dose of 50 mg. Treatment cycles of 28 days in duration cell histology. The optimal treatment for patients with non- each were repeated every four weeks on an outpatient basis unless clear cell RCC, including the role of targeted therapy, thus disease progression or severe toxicity was observed. remains uncertain and is under investigation (4). To date, the Hematological and non-hematological toxic effects were graded phase III trial for temsirolimus with non-clear cell RCC according to the Common Terminology Criteria for Adverse Events accounting for 20% of its study cohort, is the largest version 3.0 (15). Toxicity evaluations were conducted on days 1, 14, investigated targeted agents in such patients (6). and 28 of the first treatment cycle and on days 1 and 28 of each Non-clear cell RCC consists of multiple histological subsequent cycle. A dose reduction of sunitinib to 25 mg was allowed depending on the type and severity of the observed adverse event. If subtypes, each with a distinct molecular profile. Although grade 3 hematological toxicity was recorded, treatment was withheld VEGF and mTOR inhibitors are commonly used in the until either recovery to grade 2 or less, or the blood counts returned to management of these patients, a histological diagnosis of non- baseline, after which sunitinib treatment was resumed at the original clear cell type does not appear to be related to the von Hippel- dose. In the case of grade 4 hematological or grade 3 or 4 non- Lindau gene. However, VEGF receptors and their ligands are hematological toxicity, treatment was withheld until recovery to grade overexpressed in papillary RCC and chromophobe RCC (7, 2 or 1, respectively. The sunitinib dose was then reduced from 37.5 to 8). In addition, overexpression of KIT (CD117), a kinase 25 mg daily. When grade 4 hematological or grade 3 or 4 non- hematological toxicity recurred despite such a dose reduction, effectively inhibited by sunitinib, has been observed in treatment was usually discontinued, and the affected patients were chromophobe RCC (9). Furthermore, activating mutations of treated with inhibitors of either or mTOR. mesenchymal-epithelial transition factor (c-MET) have been All patients underwent physical examinations, complete blood observed in RCC of hereditary papillary type 1, whereas cell counts, and serum biochemistry tests on the first day of every inactivating mutations of fumarate hydratase have been treatment cycle. Complete blood cell counts were also performed reported in RCC of hereditary papillary type 2 (5, 10). To date, on day 14 of the first cycle. A CT or MRI was performed at baseline however, the significance of these pathogenetic pathways has and every three treatment cycles to assess clinical response according to the Response Evaluation Criteria in Solid Tumors not been validated in sporadic non-clear cell RCC. version 1.0 (16). Treatment was discontinued in patients with Sunitinib, one of the first tyrosine kinase inhibitors to emerge disease progression and in those experiencing severe toxicity even for the treatment of RCC, is currently standard first-line therapy after sufficient dose reduction. for the disease. Retrospective studies, phase II trials, and expanded access data suggest that sunitinib might also exert Statistical analysis. Quantitative data are presented as means, standard efficacy in patients with non-clear cell RCC (11-13). In the errors, medians, minimums, and maximums as appropriate, whereas present work, we therefore evaluated the efficacy and safety of the results of qualitative analyses are presented as frequencies and sunitinib in Turkish patients with metastatic non-clear cell RCC. percentages. Overall survival (OS) was calculated from the date of the first sunitinib dose to that of death, the final follow-up visit, or Patients and Methods the end of this study as appropriate. Progression-free survival (PFS) was calculated from the date of the first sunitinib dose to that of death Patients. Clinical data of 63 patients from 13 oncology Centers were of any cause or disease progression. Survival curves were estimated retrospectively analyzed. Clinicopathological characteristics such as using the Kaplan–Meier method, and the log-rank test was used for p- age, sex, RCC histological subtype, Eastern Cooperative Oncology their comparison. All statistical tests were two-sided, and values of Group performance status (ECOG PS), prior treatments, metastatic <0.05 were considered statistically significant. The Statistical Package sites, laboratory findings, and patient survival were recorded. The for the Social Sciences (SPSS) version 16.0 (SPSS Inc., Chicago, IL, inclusion criteria were proper bone marrow function (white blood cell USA) was used for all statistical analyses. count ≥3,000/mm3, hemoglobin ≥9 g/dl, and platelet count ≥100,000/mm3) and proper liver function (total bilirubin ≤1.5 mg/dl Results with alanine and aspartate transaminase levels no greater than twice Clinical features. The clinical characteristics of all the upper limit of normal). Patients were included if they were diagnosed with the non-clear cell histological subtype and had received participating patients are listed in Table I. The median age no prior anti-VEGF treatments. However, patients with ECOG PS of 4 was 63 years (range, 25–82 years), and the sample comprised and those with severe concomitant medical illnesses were excluded. of 38 men (60.3%) and 25 women (39.7%). Forty-six (73%)

4330 Yildiz et al: Sunitinib for Patients with Metastatic Non-clear Cell RCC

Table I. Patients’ characteristics. Table II. Objective response, clinical benefit and disease control rates.

Characteristic No. (%) of patients Response No. of patients %

Gender Objective response 7 11.1 Female 25 (39.3) Complete 0 0.0 Male 38 (60.3) Partial 7 11.1 Age (years) Stable disease for ≥3 months 33 52.4 Median 63 Disease control rate 40 63.5 Range 25-82 Histopathological findings Papillary RCC 46 (73.0) Chromophobe RCC 10 (15.9) Undifferentiated 7 (11.1) Adherence to treatment. Twenty-four (38.1%) patients Sarcomatoid received sunitinib as first-line systemic treatment. The Without sarcomatoid 47 (66.1) median treatment duration was seven months (range=2-86 With sarcomatoid 24 (33.9) months), and treatment was on-going for 11 patients (19%). ECOG PS 0 12 (19.0) At the time of this analysis, treatment had been discontinued 1 34 (54.0) in 52 patients, 33 of whom had died. The reasons for ≥2 17 (27.0) treatment withdrawal were disease progression in 43 patients Sites of disease (68.3%) and toxicity in nine (14.3%). Lung 38 (60.3) Liver 15 (23.8) Response rates. Patients were evaluated for their response Bone 23 (36.5) Brain 11 (17.5) to treatment (Table II). Out of the 63 patients with Laboratory findings measurable lesions, seven (11.1%) achieved a confirmed Hemoglobin partial response; 33 (52.4%) had stable disease, and 23

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Figure 1. Progression-free survival in Turkish patients with metastatic Figure 2. Overall survival in Turkish patients with metastatic non-clear non-clear cell renal cell carcinoma. cell renal cell carcinoma.

sunitinib treatment. No grade 3 or 4 hematological or non- The introduction of therapeutic agents targeting the VEGF hematological toxicity occurred during radiotherapy. and mTOR pathways to clinical practice has revolutionized the treatment of metastatic RCC. However, despite recent Discussion advances, there remains a lack of effective systemic options directly applicable to advanced and metastatic non-clear cell In the present analysis, we assessed the efficacy of sunitinib RCC. While targeted-agents mark a major advance in the treatment in patients with advanced non-clear cell RCC. Our treatment of clear cell RCC, nearly every trial in which they results on median PFS (7.6 months), OS (22 months), and were tested excluded other RCC subtypes, providing disease control rate (63.5%) were comparable to those clinicians and their patients little guidance when selecting a previously reported (11-13, 17). However, compared to the systemic treatment for non-clear cell RCC. Fortunately, the findings of previous studies on anti-VEGF-based treatments same methodology of studying the genetic and molecular for clear cell RCC (18, 19), our survival results and objective characteristics of hereditary and sporadic non-clear cell RCC response rates seem inferior. Additionally, when we tumors, which account for approximately 20-25% of all compared our survival results with the outcome of a similar patients with RCC, has identified promising novel pathways study including mostly patients with clear cell RCC, we that are amenable to targeted therapy. found that the benefit of sunitinib was also inferior in Research on the molecular characteristics of RCC has patients with non-clear cell RCC (20). identified different gene expression patterns associated with The histological diversity of non-clear cell RCC presents various histological and macroscopic morphological profiles unique challenges. Except for collecting duct carcinoma, of the many sub-groups of this tumor type, most of which which shows some sensitivity to cisplatin-based cytotoxic are regularly combined under the generic term ‘non-clear cell chemotherapy, non-clear cell RCCs have been considered to RCC’. Given these differences, it would be unreasonable to be resistant to immunotherapy and cytotoxic chemotherapy. assume a similar efficacy and safety profile for clear cell and Patients with metastatic non-clear cell RCC often have a non-clear cell RCC treated with targeted agents. Nonetheless, worse response to immunotherapies than those with clear cell the available data suggest that targeted agents currently RCC (3). Motzer et al. reported a median OS of 9.4 months approved for clear cell RCC are active to a certain degree in in a cohort of patients with non-clear cell RCC treated with non-clear cell RCC. Temsirolimus has demonstrated several types of cytokines (21). therapeutic advantages over interferon-α in patients with

4332 Yildiz et al: Sunitinib for Patients with Metastatic Non-clear Cell RCC

Table III. Hematological and non-hematological toxicity profiles of (13). The median OS was not available, but the 1-year patients treated with sunitinib. survival rate was 65%. These conflicting data suggest that ethnic differences may explain the variable responses to Toxicity Worst toxicity by NCI sunitinib in non-clear cell RCC. Grade 1-2 Grade 3-4 All Most pivotal phase III trials for molecular-targeted agents No. of (%) No. of (%) No. of (%) in patients with metastatic RCC have excluded those with patients patients patients non-clear cell disease. The only exception was a trial for temsirolimus. A subset analysis showed that temsirolimus Hematological Anemia 24 (38.1) 14 (22.2) 38 (60.3) significantly enhanced the OS in patients with non-clear cell Neutropenia 4 (6.3) 0 (0.0) 4 (6.3) RCC (hazard ratio=0.55; 95% CI=0.33-0.90) (6). In addition, Thrombocytopenia 5 (7.9) 2 (3.2) 7 (11.1) the results of a phase II trial for foretinib, a dual inhibitor of Non-hematological c-MET and VEGF, may provide further information and Fatigue 44 (69.8) 8 (12.7) 52 (82.5) open new avenues for papillary RCC treatment (n=74). The Skin discoloration 33 (52.3) 0 (0.0) 33 (52.3) Stomatitis 33 (52.3) 2 (3.2) 35 (55.5) overall response rate was 13.5%, the median PFS was 9.3 Hypertension 25 (39.7) 5 (7.9) 30 (47.6) months, and the median OS was not reached. The presence Anorexia 40 (63.5) 0 (0) 40 (63.5) of a germline MET mutation was highly predictive of a Hypothyroidism 23 (36.5) 4 (6.4) 27 (42.9) response (5/10 vs. 5/57 patients with and without germline Hand–foot syndrome 21 (33.3) 4 (6.4) 25 (39.7) MET mutations, respectively) (17). Nausea 34 (54.0) 1 (1.6) 35 (55.6) Dyspepsia 25 (39.7) 0 (0) 25 (39.7) The toxicity and safety profile of our study was found to Diarrhea 23 (36.5) 2 (3.2) 25 (39.7) be similar to our recent trial including mostly patients with Rash 10 (15.9) 0 (0) 10 (15.9) clear cell RCC in the same population (20). The most Vomiting 15 (23.8) 1 (1.6) 16 (25.4) common grade 3-4 hematological toxicity was anemia, Epistaxis 4 (6.4) 0 (0) 4 (6.4) whereas frequent non-hematological toxicities included Decline in EF 0 (0) 2 (3.2) 2 (3.2) Myocardial infarction 0 (0) 2 (3.2) 4 (3.2) fatigue, hypertension, hypothyroidism, and hand–foot Pulmonary edema 0 (0) 1 (1.6) 1 (1.6) syndrome. In addition, it was possible to perform radiotherapy for bone or brain metastases safely without the NCI: National Cancer Institute; EF: ejection fraction. need to discontinue or interrupt sunitinib treatment in the present study. In summary, non-clear cell histology represents an uncommon and heterogeneous group of RCC for which non-clear cell RCC according to data from a phase III study effective treatments have not yet been established. Sunitinib (6), and expanded-access studies(12) for everolimus, was generally well tolerated in Turkish patients with sunitinib, and sorafenib have all confirmed the activity of metastatic RCC and demonstrated promising activity in those these agents in non-clear cell RCC (10). with non-clear cell RCC. In future trials for novel agents for Furthermore, the expanded access program of sunitinib non-clear cell RCC, in-depth characterization of the in RCC also provided evidence for its potential efficacy in molecular features underlying these subtypes could help non-clear cell RCC. Out of 437 patients with non-clear cell identify rational therapeutic strategies targeting relevant RCC treated with sunitinib, the overall response rate was pathways. 11%, with an additional 57% of the patients having stable disease and a median PFS of 7.8 months (12). A Conflicts of Interest retrospective review of 20 patients with metastatic papillary or chromophobe RCC showed that sunitinib The Authors have no conflicts of interest that are directly relevant to prolonged their PFS (11.9 months), although the response the content of this study. rate was generally low (13%) (11). Data from several prospective phase II studies on sunitinib in advanced non- Funding clear cell RCC have been presented or published. For the most part, there was a low response rate to sunitinib (0- This study received no financial support. 7%), although most patients typically experienced stable disease (52-73%) (22, 23). In contrast, a Korean phase II Acknowledgements study on sunitinib in patients with non-clear cell RCC reported a 36% overall response rate, including eight cases We thank all the patients and their families for participating in this of partial response among 22 patients with papillary RCC, study. We also thank the investigators and their staff from all and a median PFS of 6.4 months (95% CI=4.2-8.6 months) participating sites.

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