Safety and Efficacy of Cabozantinib for Metastatic Nonclear Renal Cell Carcinoma Real-world Data From an Italian Managed Access Program Michele Prisciandaro, MD,* Raffaele Ratta, MD,* Francesco Massari, MD,† Giuseppe Fornarini, MD,‡ Salvatore Caponnetto, MD,§ Roberto Iacovelli, MD,∥ Ugo De Giorgi, MD,¶ Gaetano Facchini, MD,# Sarah Scagliarini, MD,** Roberto Sabbatini, MD,†† Claudia Caserta, MD,‡‡ Giorgia Peverelli, MD,* Alessia Mennitto, MD,* Elena Verzoni, MD,* and Giuseppe Procopio, MD* Objective: The activity of cabozantinib in nonclear cell histologies has not been evaluated. Materials and Methods: Data were collected across 24 Italian hospi- tals. Patients were aged 18 years and older with advanced nonclear cell renal cell carcinoma (RCC), with an Eastern Cooperative Oncology Group Performance Status 0 to 2, who had relapsed after previous systemic treatments for metastatic disease. Cabozantinib was adminis- tered orally at 60 mg once a day in 28 days cycles. Dose reductions to 40 or 20 mg were made due to toxicity. Adverse events (AEs) were monitored using CTCAE version 4.0. Results: Seventeen patients were enrolled. Three (18%) patients were diagnosed type I papillary RCC, 9 (53%) type II papillary, 3 (18%) chromophobe, and 2 (11%) with Bellini duct carcinoma. In total, 11 patients started with 60 mg. Six patients started a lower dose of 40 mg. Median progression-free survival was 7.83 months (0.4 to 13.4 mo), while median overall survival was not reached but 1-year overall sur- vival was about 60%. Six patients (35%) experienced a partial response to treatment and 6 patients (35%) showed a stable disease. In the remaining 5 (30%), we observed a progressive disease. Grade 3 and 4 AEs were observed in 41% of patients. Among 20 patients, only 1 (6%) discontinued treatment due to AEs. Asthenia (41%), diarrhea (35%), aminotransferase increasing (35%), mucosal inflammation (35%), hand and foot syndrome (24%), and hypothyroidism (24%) were the most frequently AEs. Conclusions: Our data showed that, cabozantinib is a active and feasible treatment in patient with nonclear cell RCC. Key Words: cabozantinib, c-Met, renal cell carcinoma, nonclear cell, targeted therapy (Am J Clin Oncol 2019;42:42–45) R enal cell carcinoma (RCC) represents the seventh most common cancer with 330,000 cases diagnosed and > 140,000 deaths per year worldwide. 1 According to the 2016 World Health Organization (WHO) Classification of Tumours of the Urinary System, RCC can be divided into different subtypes on the basis of cytoplasmic (clear cell and chromo- phobe renal cell carcinomas) or architectural (papillary) features, anatomic site (renal medullary and collecting duct carcinomas), pathognomonic molecular alterations (MiT family translocation carcinomas and succinate dehydrogenase– deficient renal carcinomas), familial predisposition (hereditary leiomyomatosis and RCC–associated RCC) and correlation with other kidney diseases (eg, acquired cystic disease– associated RCCs). Clear cell RCC is the predominant sub- type, accounting for 75% of all renal epithelial tumors. All other histologic subtypes are grouped together as nonclear cell RCC. 2 Except for collecting duct carcinoma, which seems to be sensitive to platinum-based chemotherapy, metastatic nonclear cell RCCs are resistant to cytotoxic chemotherapy, resulting in poor patient prognosis. 3 It is well established that tumor angiogenesis represents a major hallmark in clear cell RCC initiation and progression. Previous studies have demonstrated that the Von Hippel Lindau (VHL) protein is frequently dowregulated, leading to the stabilization of the hypoxia-inducible factors α and β (HIFs) and the upregulation of several genes such as the vascular endothelial growth factor (VEGF), the mesenchymal-epithelial transition factor (MET), and AXL, frequently associated with invasive tumor phenotype and poor prognosis. 4–8 VHL disruption results in highly angiogenic and vascularized tumors providing the rationale for the development of several agents such as tyrosine kinase inhibitors (TKIs) directed against the angiogenic axis, which have demonstrated a significant increase in progression-free survival (PFS) and overall survival (OS) in the advanced disease and have radically revolutionized the From the *Department of Medical Oncology, Genitourinary Cancer Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan; †Division of Oncology, S.Orsola-Malpighi Hospital, Bologna; ‡Medical Oncology Department, IRCCS Azienda Ospedaliera Universitaria San Martino- IST Istituto Nazionale per la Ricerca sul Cancro, Genova; §Department of Medical Oncology B, Policlinico Umberto I “Sapienza” University of Rome, Rome; ∥Medical Oncology Unit, Azienda Ospedaliera Uni- versitaria Integrata (AOUI), University of Verona, Verona; ¶Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola; #Department of Uro- Gynaecological Oncology, Division of Medical Oncology, Istituto Nazionale Tumori Fondazione G. Pascale (IRCCS); **Oncology Unit, Antonio Cardarelli Hospital, Naples; ††Department of Oncology and Haematology and Respiratory Disease, University Hospital, Modena; and ‡‡Oncology Department, Santa Maria Hospital, Terni, Italy. G.P. reports receiving fees for serving on advisory boards from Astellas, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Novartis and Pfizer. R.I. reports receiving fees for serving on advisory boards from Novartis, Pfizer, Bristol-Myers Squibb, and Ipsen. U.D.G. reports receiving fees for serving on advisory boards from Janssen, Astellas, Sanofi, Bristol- Myers Squibb, Pfizer, Novartis and Ipsen. E.V. reports receiving fees for serving on advisory boards from Ipsen, Janssen, Novartis and Pfizer. The remaining authors declare no conflicts of interest. Reprints: Michele Prisciandaro, MD, Department of Medical Oncology, Genitourinary Cancer Unit, Fondazione IRCCS Istituto Nazionale Tumori, Via Giacomo Venezian 1, Milan 20133, Italy. E-mail: michele. prisciandaro@istitutotumori.mi.it. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/19/4201-0042 DOI: 10.1097/COC.0000000000000478 ORIGINAL ARTICLE 42 | www.amjclinicaloncology.com American Journal of Clinical Oncology  Volume 42, Number 1, January 2019 Copyright r 2018 Wolters Kluwer Health, Inc. All rights reserved.