Pediatr Blood Cancer 2009;52:767–771 Sunitinib Treatment in Pediatric Patients With Advanced GIST Following Failure of Imatinib Katherine A. Janeway, MD, 1 Karen H. Albritton, MD, 1 Annick D. Van Den Abbeele, MD, 2 Gina Z. D’Amato, MD, 3 Paolo Pedrazzoli, MD, 4 Salvatore Siena, MD, 4 Joel Picus, MD, 5 James E. Butrynski, MD, 6,7,8,9 Marcus Schlemmer, MD, 10 Michael C. Heinrich, MD, 11 and George D. Demetri, MD 6,7,8 * INTRODUCTION Gastrointestinal stromal tumor (GIST) is a tumor of mesen- chymal origin occurring in the gastrointestinal tract. Approximately 85% of GISTs in adults harbor gain-of-function mutations in either the KIT or platelet-derived growth factor receptor alpha (PDGFRA) proto-oncogenes [1 – 3]. GIST is poorly responsive to treatment with standard chemotherapy, and median survival was 20 months prior to the advent of targeted therapies [4]. Treatment with small-molecule inhibitors of KIT and PDGFRA has prolonged survival in adult patients with GIST [5,6]. There have been no systematic studies and few published reports addressing the use of small-molecule inhibitors of KIT and PDGFRA in pediatric patients with GIST. Pediatric GIST appears to have a different biology and clinical behavior than adult GIST. In contrast to GISTs in adults, >85% of GISTs in children are wild-type (WT), with no detectable mutations in KIT or PDGFRA [7]. Further evidence supporting a distinct biology are recently published reports of differing gene-expression profiles [8] and genetic progression mechanisms [7] in pediatric versus adult GIST. Clinical features also suggest that pediatric GIST is a distinct entity. In pediatric patients, GIST is more common in females, whereas gender distribution is equal in adults. Pediatric GIST more often has an epithelioid morphology whereas adult GIST most often has a spindle morphology [9]. These differences raise the question of whether therapies that are effective for adult GIST will be equally efficacious in pediatric patients. Sunitinib malate is a potent small-molecule inhibitor of several members of the split-kinase-domain family of receptor tyrosine kinases (RTKs). In vitro and in vivo studies have shown that sunitinib inhibits KIT, PDGFRA, PDGFRB, vascular endothelial growth factor receptors (VEGFRs), as well as several other RTKs [10–15] (Pfizer Inc., New York, NY, data on file). Sunitinib is 10 times more potent than imatinib with regard to inhibition of WT KIT [8]. In adult patients with advanced imatinib-resistant GIST, sunitinib significantly prolongs time to tumor progression (TTP) and survival [5]. Sunitinib is approved multi-nationally for the treatment of GIST after disease progression on imatinib and is recommended for this purpose in current clinical practice guidelines [16]. Patients with WT GIST are among those achieving the greatest clinical benefit on sunitinib [17]. While pediatric GISTs lack KIT mutations, KIT is expressed and activated, suggesting that inhibition of WT KIT may have clinical efficacy in these tumors [7]. We hypothesized that sunitinib may be effective in pediatric patients with advanced imatinib-resistant GIST; however, a pros- pective trial limited to children was determined to lack feasibility. In order to describe the response and toxicity profiles of sunitinib in pediatric GIST, we reviewed the experience of pediatric GIST patients treated with sunitinib on a treatment-use protocol. Background. Sunitinib inhibits KIT and other members of the split-kinase-domain family of receptor tyrosine kinases. Sunitinib prolongs survival in adult patients with imatinib-resistant gastro- intestinal stromal tumor (GIST). We report the experience with sunitinib in pediatric patients with advanced GIST following failure of imatinib. Procedure. Sunitinib therapy was provided through a treatment-use protocol. Patients were 10–17 years old at enrollment. All patients had GIST resistant to imatinib therapy. Sunitinib was administered daily for 4 weeks in 6-week treatment cycles. KIT and platelet-derived growth factor receptor alpha (PDGFRA) genotyping of tumor tissue were performed. Results. One patient achieved a partial response, five patients had stable disease and one patient had progressive disease on sunitinib. The duration of disease stabilization was between 7 and 21þ months, with a mean of 15 months. Time to tumor progression was longer on sunitinib than on prior imatinib treatment for five of six patients. Two patients experienced grade 3 adverse events. All other adverse events were grade 1–2. None of the five patients tested had mutations in KIT or PDGFRA. Conclusion. Sunitinib treatment was associated with substantial initial antitumor activity and acceptable tolerability in this group of pediatric patients with imatinib-resistant GIST. Pediatr Blood Cancer 2009;52:767–771. ß 2009 Wiley-Liss, Inc. Key words: clinical trials; drug resistance; new agents; pediatric oncology; soft tissue sarcoma ß 2009 Wiley-Liss, Inc. DOI 10.1002/pbc.21909 Published online 00 Month 2009 in Wiley InterScience (www.interscience.wiley.com) —————— 1 Pediatric Oncology, Dana-Farber Cancer Institute and Department of Medicine, Children’s Hospital Boston, Boston, Massachusetts; 2 Department of Radiology, Dana-Farber Cancer Institute, Boston, Massachusetts; 3 H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; 4 Divisione Oncologia Medica Falck, Ospedale Niguarda Ca’ Granda, Milan, Italy; 5 Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri; 6 Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; 7 Ludwig Center at Dana-Farber/ Harvard Cancer Center, Boston, Massachusetts; 8 Harvard Medical School, Boston, Massachusetts; 9 University of Washington and Seattle Cancer Care Alliance, Seattle, Washington; 10 Department of Internal Medicine III, Klinikum Grosshadern Medical Center, Munich, Germany; 11 Portland VA Medical Center and Knight Cancer Institute at Oregon Health & Science University, Portland, Oregon Grant sponsor: Pfizer Inc., The Virginia and Daniel K. Ludwig Trust for Cancer Research, The Quick Family Fund for Cancer Research, Leslie’s Links, Veterans Affairs Merit Review Grant, Life Raft Group, GIST Cancer Research Fund, National Institutes of Health (Grant 5T32HL007574.25), the Clinical Investigator Training Program, Oncologia Ca’ Granda Onlus Fondazione, and Associazione Italiana per la Ricerca sul Cancro (AIRC). *Correspondence to: George D. Demetri, Ludwig Center at Dana- Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, D1212, 44 Binney St., Boston, MA 02115. E-mail: gdemetri@partners.org Received 7 October 2008; Accepted 19 November 2008