Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC Clinical Focus: Optimal Management of Gastrointestinal Stromal Tumors With Targeted Therapy This program is supported by an educational grant from Image: Gastrolab/Copyright©2012 Photo Researchers, Inc. All Rights Reserved

Faculty Faculty Disclosure Margaret von Mehren, MD Professor, Medical Oncology Director, Sarcoma Oncology Fox Chase Cancer Center Philadelphia, Pennsylvania Faculty Disclosure Margaret von Mehren, MD, has disclosed that she has received consulting fees from GlaxoSmithKline, Pfizer, and Novartis and grants for research support from Merck.

GIST Thought to Arise From the Interstitial Cells of Cajal Interstitial cells of Cajal are the likely progenitor cells of GIST ICCs represent a complex cellular network of heterogeneous, fibroblastlike or musclelike cells within the gut muscle wall that serve as pacemaker cells for peristalsis Express KIT receptor (CD117) GIST, gastrointestinal stromal tumor; ICC, interstitial cells of Cajal. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the intestinal tract. However, GIST only represents approximately 1% of gastrointestinal malignancies.[1] First described by Mazur and Clark,[2] GIST has features of both smooth muscle and nerve. These tumors are thought to arise from the interstitial cells of Cajal, or their precursors.[3,4] References Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw. 2010;8(suppl 2):S1-S41. Mazur MT, Clark HB. Gastric stromal tumors. Reappraisal of histogenesis. Am J Surg Pathol. 1983;7:507-519. Lee HT, Hennig GW, Fleming NW, et al. The mechanism and spread of pacemaker activity through myenteric interstitial cells of Cajal in human small intestine. Gastroenterology. 2007;132:1852-1865. Min KW, Leabu M. Interstitial cells of Cajal (ICC) and gastrointestinal stromal tumor (GIST): facts, speculations, and myths. J Cell Mol Med. 2006;10:995-1013. In this image, myenteric ICCs form a complex matted pacemaker network. Bundles of ICCs run parallel to the circular (top to bottom) and the longitudinal muscles (left to right). These are joined by obliquely running bundles or strands.  3. Lee HT, et al. Gastroenterology. 2007;132:1852-1865.

Typical Primary Gastric GIST GIST Epidemiology Incidence: 1.45-0.65/ 100,000 people Median age of onset: 63-69 yrs Locations Stomach (common) Small bowel (common) Rectum/pelvis (rare) Typical Primary Gastric GIST GIST, gastrointestinal stromal tumor. Epidemiologic studies from Europe and the United States report an incidence of 1.45-0.65 per 100,000 people.[5-11] The median age of onset in these studies is 63-69 years, with most studies finding no difference in incidence between men and women. The most common tumor location is the stomach accounting for 50.0% to 62.9% of cases, followed by small bowel (23.4% to 45.3%), rectum/pelvis (2.2% to 12.0%) and other sites including omentum, esophagus, mesentery, anus, and peritoneum (1.0% to 7.5%). The annual incidence of GIST in children younger than 14 years of age has been reported to be 0.02 per million.[12] Estimates of the percentage of GIST diagnosed at 18 years of age or younger have ranged from 0.5% to 2.7%. Unlike adults, GIST in children is most commonly seen in females (70%). References Tryggvason G, Gislason HG, Magnusson MK, Tonasson JG. Gastrointestinal stromal tumors in Iceland, 1990-2003: the Icelandic GIST study, a population-based incidence and risk stratification study. Int J Cancer. 2005;117:289-293. Nillson B, Bumming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: The incidence, prevalence, clinical course and prognostication in the pre-imatinib mesylate era: A population-based study in Western Sweden. Cancer .2005;103:821-829. Tran T, Devila JA, El-Serag HB. The epidemiology of gastrointestinal stromal tumors: An analysis of 1,458 cases from 1992-2000. Am J Gastroenterol. 2005;100:132-168. Cassier PA, Ducimetiere F, Lurkin A, et al. A prospective epidemiological study of new incident GISTs during two consecutive years in Rhone Alps region: incidence and molecular distribution of GIST in a European region. Br J Cancer. 2010;103:165-170. Steigen SE, Eide TJ, Wasag B, Lasota J, Miettinen M. Mutations in gastrointestinal stromal tumors: a population-based study from Northern Norway. APMIS. 2007;115:289-298. Mucciarini C, Rossi G, Bertolini F, et al. Incidence and clinicopathologic features of gastrointestinal stromal tumors: a population-based study. BMC Cancer. 2007;7:230. Rubio J, Marcos-Gragera R, Ortiz MR, et al. Population-based Incidence and survival of gastrointestinal stromal tumors (GIST) in Girona, Spain. Eur J Cancer. 2007;43:144-148. Benesch M, Wardelmann E, Ferrari A, et al. Gastrointestinal stromal tumors (GIST) in children and adolescents: a comprehensive review of the current literature. Pediatr Blood Cancer. 2009;93:1171-1179. 5. Tryggvason G, et al. Int J Cancer. 2005;117:289-293. 6. Nillson B, et al. Cancer. 2005;103:821-829. 7. Tran T. Am J Gastroenterol. 2005;100:132-168. 8. Cassier PA, et al. Br J Cancer. 2010;103:165-170. 9. Steigen SE, et al. APMIS. 2007;115:289-298. 10. Muccarini C, et al. BMC Cancer. 2010;103:165-170. 11. Rubio J, et al. Eur J Cancer. 2007;43:144-148.

Primary GIST: Risk Stratification by Mitotic Index, Size, and Site Tumor Parameters Risk of PD,* % Mitotic index ≤ 5 per 50 HPF Size, cm Gastric[16] Duodenum[17] Jejunum/Ileum[18] Rectum[19] ≤ 2 None (0) > 2 to ≤ 5 Very low (1.9) Low (8.3) Low (4.3) > 5 to ≤ 10 Low (3.5) High (34) Moderate (24) High (57) > 10 Moderate (12) High (52) Mitotic index > 5 per 50 HPF None† (Insuff. data) High† High (54) Moderate (16) High (50) High (73) High (86) High (85) High (82) High (90) GIST, gastrointestinal stromal tumor; HPF, high-power fields.   Life expectancy in patients with GIST has changed during the past decade. Prior to the use of targeted therapy, prognosis for patients with unresectable or metastatic disease was poor, at approximately 5-12 months.[13,14] Prognosis following initial resection varies based on the site of tumor origin, size, and number of mitoses per 50 high-powered fields (HPF). Tumors originating in the stomach have the best prognosis. Tumors larger than 5 cm or with more than 5 mitoses per 50 HPF have poorer outcomes. Lastly, evidence of tumor rupture always portends an increased risk for recurrence. Risk determination has been quantified by several groups; the modified Miettinen criteria[15-19] and the Memorial Sloan-Kettering Cancer Center nomogram[20] are the most commonly used. For example, using the modified Miettinen criteria a patient with a mitotic index of at least 5 per HPF and tumor size of 2-5 cm has a high risk of recurrence in the jejunum/ileum. References Clary BM, DeMatteo RP, Lewis JJ, Leung D, Brennan MF. Gastrointestinal stromal tumors and leiomyosarcoma of the abdomen and retroperitoneum: a clinical comparison. Ann Surg Oncol. 2001;8:290-299. DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231:51-58. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006;23:70-83. Miettinen M, Sobin LH, Lasota J. Am J Surg Pathol. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. 2005;29:52-68. Miettinen M, Kopczynski J, Makjhlouf HR, et al. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical, and molecular genetic study of 167 cases. Am J Surg Pathol. 2003;27:625-641. Miettinen M, Makhlouf H, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up. Am J Surg Pathol. 2006;30:477-489. Miettinen M, Furlong M, Sarlomo-Rikala M, et al. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: a clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases. Am J Surg Pathol. 2001;25:1121-1133. Gold JS, Gonen M, Gutierrez A, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol. 2009;10:1045-1052. Data based on long-term follow-up of 1074 gastric, 629 small intestinal, 140 duodenal, and 111 rectal GISTs. *Defined as alive with evidence of PD at follow-up or tumor-related death. †Denotes small numbers of cases. 16. Miettinen M, et al. Am J Surg Pathol. 2005;29:52-68. 17. Miettinen M, et al. Am J Surg Pathol. 2003;27:625-641. 18. Miettinen M, et al. Am J Surg Pathol. 2006;30:477-489. 19. Miettinen M, et al. Am J Surg Pathol. 2001;25:1121-1133.

New Nonlinear Predictive Tool to Determine Risk of Recurrence in GIST Novel prognostic contour maps generated using nonlinear modeling of tumor size and mitotic count, as well as primary site and presence or absence of rupture Nonlinear model accurately predicted risk of recurrence within 10 yrs (AUC: 0.88; 95% CI: 0.86-0.90) AUC, area under the curve; CI, confidence interval; GIST, gastrointestinal stromal tumor. The newest predictive tool uses all of the known risk factors but is able to quantify risk using the variables such as size and mitotic count as continuous variables rather than dichotomous variables.[21] It is also the only tool that incorporates the presence of absence of perforation in determining the risk of recurrence. Reference 21. Joensuu H, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol. 2012;13:265-274. 21. Joensuu H, et al. Lancet Oncol. 2012;13:265-274.

GIST: Symptoms Clinical presentation of patients with GIST varies depending on anatomic location of the tumor and tumor size and aggressiveness Most common presentation of GIST is gastrointestinal bleeding, which may be acute (melena or hematemesis) or chronic, and results in anemia Patients may also present with Acute abdomen due to tumor rupture Gastrointestinal obstruction Appendicitislike pain GIST, gastrointestinal stromal tumor. A large fraction of patients diagnosed with GIST is asymptomatic. However, patients do present with a wide variety of signs and symptoms dependent on the location of the primary tumor[22]: palpable mass, obstructive symptoms, and bleeding, especially in tumors that arise in the small or large intestine. Other symptoms include pain, nausea, vomiting, early satiety, and fever. Reference 22. National Cancer Institute. General information about gastrointestinal stromal tumors. Available at http://www.cancer.gov/cancertopics/pdq/treatment/gist. Accessed September 24, 2012. Fatigue Dysphagia Satiety 22. NCI Gastrointestinal Stromal Tumors Treatment (PDQ®).

GIST Diagnosis: Endoscopic Imaging Gastric submucosal tumors are found in ~ 0.36% of routine upper gastrointestinal endoscopies Endoscopic ultrasound can differentiate intramural tumors from extraluminal compressions, and can show the layer of origin Endoscopic Ultrasound of Submucosal Gastric Lesion Endoscopy of Submucosal Gastric Lesion GIST, gastrointestinal stromal tumor. Tumors are diagnosed most commonly by endoscopy or computed tomography imaging, where a submucosal mass arising along the intestinal tract is identified.[23] Lesions in the stomach can be biopsied using endoscopic ultrasound, but areas that are not accessible should not be biopsied prior to resection unless preoperative therapy is being contemplated.   Endoscopic criteria for malignant process (independent factors associated with malignancy)[24]: Tumor size greater than 4 cm Irregular extraluminal border, Echogenic foci Cystic spaces References 23. Papanikolaou IS, Triantafyllou K, Kourikou A, Rosch T. Endoscopic ultrasonography for gastric submucosal lesions. World J Gastrointest Endosc. 2011;3:86-94. 24. Davila RE, Faigel DO. GI stromal tumors. Gastrointest Endosc. 2003;58:80-88. 23. Papanikolaou IS, et al. World J Gastrointest Endosc. 2011;3:86-94.

KIT and PDGFRA Mutations GIST Pathophysiology KIT and PDGFRA Mutations Spindle Cell Epithelioid GIST, gastrointestinal stromal tumor. GIST are malignant tumors characterized by the expression of the growth factor tyrosine kinase receptor kinase KIT (also known as CD117) in approximately 95% of cases.[25] An additional 5% of tumors have a mutation in PDGFRA gene.[26,27] A minority of tumors has been identified with BRAF mutations.[28] These mutations lead to constitutive activation of the kinase and result in cell growth and proliferation.[29] References Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 2002;33:459-465. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708-710. Hirota S, Ohashi A, Nishida T, et al. Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology. 2003;125:660-667. Agaram NP, Wong GC, Guo T, et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2008;47:853-859. Pierotti MA, Tamborini E, Negri T, et al. Targeted therapy in GIST: in silico modeling for prediction of resistance. Nat Rev Clin Oncol. 2011;8:161-170. 29. Pierotti MA, et al. Nat Rev Clin Oncol. 2011;8:161-170.

SDH Mutations in Patients With Wild-Type GIST Patients with GIST and wild-type KIT and/or wild-type PDGFR can have germline mutations in succinate dehydrogenase SDH–ubiquinone complex II catalyses oxidation of succinate to fumarate in the Krebs cycle (ie, part of the respiratory chain) SDH mutations result in loss of SDH expression (Carney-Stratakis syndrome) and can lead to GIST and increased risk of paraganglioma Pathogenic SDH mutations and lack of complex II activity may be a central oncogenic mechanism in wild-type GIST GIST, gastrointestinal stromal tumor; SDH, succinate dehydrogenase. Of those cases without a tyrosine kinase receptor mutation, often referred to as wild-type GIST, the majority overexpresses IGF-1R and has loss of expression of succinate dehydrogenase B (SDH).[30] Recent data have identified mutations in members of the SDH family, Krebs cycle enzymes.[31] Some of these mutations are not only present in the tumor but also in the germline and are associated with a risk for paragangliomas; patients with paragangliomas and GIST who have SDH gene mutations have Carney-Stratakis syndrome; Carney triad patients have GIST, paragangliomas, and pulmonary chondromas but do not have mutations in SDH genes. References 30. Janeway KA, Kim SY, Lodish M, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 2011;108:314-318. 31. Kim SY, Lodish M, Raygada M, et al. Clinical results from the NIH GIST clinic and identification of SHD mutations. Program and abstracts of the Connective Tissue Oncology Society (CTOS) 15th annual meeting; November 5-7, 2009; Miami, Florida. Abstract 39284. 31. Kim SY, et al. CTOS 2009. Abstract 39284. 30. Janeway KA, et al. Proc Natl Acad Sci U S A. 2011;108:314-318.

Imatinib: Selective TKI Targeting KIT, PDGFRA, and Abl Mechanism of action: Imatinib binds to the same site as ATP, thereby preventing phosphorylation of downstream substrates and inhibiting KIT or PDGFRA signaling[32] A B Approved for treatment of unresectable, advanced KIT-positive GIST[33,34] and as adjuvant therapy for resectable GIST[35] P P P ADP ADP P Y Substrate IMAT IMAT Y Substrate P P P P GIST, gastrointestinal stromal tumor; PDGFR, platelet-derived growth factor receptor; TKI, tyrosine kinase inhibitor.   GIST has been a model disease to demonstrate the benefits of targeted therapies because tumor growth and survival depend on constitutively activated mutant KIT and PDGFRA receptors. Imatinib, and then sunitinib, demonstrated efficacy in control of advanced GIST.[33-35] Imatinib is an inhibitor of both KIT and PDGFRA via competing for ATP-binding sites.[32] Its efficacy varies depending on the site of mutation, with the greatest benefit for progression-free survival seen in patients with tumors containing exon 11 mutations.[36] Typical adverse effects of imatinib (≥ 30% frequency) in GIST include edema, nausea, diarrhea, abdominal pain, myalgia, muscle cramps, anemia, fatigue, and skin rash, but the majority tends to be mild (grade 1 or 2 using the National Cancer Institute common toxicity criteria). References Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal tumour. Lancet. 2007;369:1731-1741. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472-480. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26:626-632. DeMatteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:1097-1104. Judson IR. Prognosis, imatinib dose, and benefit of sunitinib in GIST: knowing the genotype. J Clin Oncol. 2008;26:5322-5325. P ADP ADP P P P Imatinib Mesylate P ADP P Y Substrate H N H N N P N N N O CH3So3H KIT-activated signal transduction resulting in GIST proliferation and survival Inhibition of KIT activated signal transduction, causing reduced GIST proliferation or induction of apoptosis N 32. Rubin BP, et al. Lancet. 2007;369:1731-1741. 33. Demetri GD, et al. N Engl J Med. 2002;347:472-480. 34. Blanke CD, et al. J Clin Oncol. 2008;26:626-632. 35. DeMatteo RP, et al. Lancet. 2009;373:1097-1104.

Sunitinib in GIST: Selective Targeting of VEGFR and KIT Mechanism of action: Sunitinib binds to the same site as ATP, thereby preventing phosphorylation of downstream substrates and inhibiting VEGFR, PDGFR, KIT, CSF-1R, and FLT signaling Approved for treatment of GIST after disease progression on or with intolerance to imatinib CSF R (FMS) VEGFR (FLT) VEGFR2 (FLK) VEGFR3 (KDR/FLT4) PDGFRA PDGFRB KIT FLT3 GIST, gastrointestinal stromal tumor; mTOR, mammalian target of rapamycin. Sunitinib is approved for second-line therapy of patients with advanced GIST. It has been shown to significantly prolong progression-free and overall survival compared with placebo in phase III testing.[37-39] In patients pretreated with imatinib, progression-free survival is greatest in those with exon 9 KIT mutations or wild-type tumors.[40] With progression, many tumors with exon 11 mutations will be found to have additional mutations; of those, secondary mutations located in exons 13 or 14 are sensitive to sunitinib, whereas those located in the more distal regions of the KIT molecule are not.[41] Limited numbers of PDGFRA tumors make a similar analysis unfeasible. References Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329-1338. Wolter P, Schoffski P. Targeted therapies in the treatment of GIST: Adverse events and maximising the benefits of sunitinib through proactive therapy management. Acta Oncol. 2010;49:13-23. Faivre S, Demetri G, Sargent W, et al. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov. 2007;6:734-745. Heinrich MC, Maki RG, Corless CL, et al. Sunitinib (SU) response in imatinib-resistant (IM-R) GIST correlates with KIT and PDGFRA mutation status. Program and abstracts of the 42nd annual meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Georgia. Abstract 9502. Corless C. GIST: What exons are predictive and prognostic? Program and abstracts of the 2011 Gastrointestinal Cancers Symposium; January 20-22, 2011; San Francisco, California. 38. Wolter P, et al. Acta Oncol. 2010;49:13-23. 39. Faivre S, et al. Nat Rev Drug Discov. 2007;6:734-745.

GIST Progression: Secondary Mutations Tumors that progress on imatinib often are found to have secondary mutations as the underlying cause for resistance to imatinib Case no. No. samples Primary KIT mutation site Primary KIT mutation type Secondary KIT mutation site Secondary KIT mutation type No. mutated samples 1 2 Wild-type — None 7 Exon 11 K558N, V559_V560del Exon 17 Y823D 3 Exon 9 A504_Y505ins 4 5 N567_P573del Exon 14 S709F T670I 6 Q556H, W557T, K558_V559del 8 9 D579del Exon 13 Exon 17 V654A D820G 1 1 10 D816E D820E D820Y N822K 1 1 1 1 GIST, gastrointestinal stromal tumor; TKI, tyrosine kinase inhibitor. GIST progress due to inherent resistance to targeted therapies or because of the outgrowth of resistant clones.[42] Examples of inherent (ie, primary) resistance include mutations in KIT exon 9 and Pdgfra exon 18 mutation D842V.   Often progression is seen early in these patients, within the first 6 months of therapy. Secondary resistance, most commonly because of the outgrowth of a resistant clone, is associated with the presence of a secondary mutation making imatinib ineffective. Reference 42. Wardelmann M, Merkelbach-Bruse S, et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res. 2006;12:1743-1749. 42. Wardelmann M, et al. Clin Cancer Res. 2006;12:1743-1749.

Newly Developed Nodules Within Responding Tumor Mass Subtle Disease Progression in Patients With Apparent Long-term Disease Control Despite apparent long-term disease control on imatinib, patients with GIST may nevertheless be experiencing progression Solid regions can develop within a responding nodule New nodules often have acquired a second mutation in addition to the primary mutation found in the primary tumor Newly Developed Nodules Within Responding Tumor Mass GIST, gastrointestinal stromal tumor. Patients maintained on imatinib can have long-term disease control; however, progression can be observed at a median of 2 years. This can be subtle with more solid regions developing within a responding nodule. At the molecular level, secondary tumors often carry the original mutation(s) from the primary tumor. Images courtesy of M. von Mehren

Phase II Study (RTOG 0132): Imatinib as Neoadjuvant Tx or Preop Cytoreduction Resection + Imatinib 600 mg/day for 2 yrs Patients with primary, locally advanced GIST or operable recurrent/metastatic GIST (N = 53) 2 yrs’ imatinib maintenance SD or PR Imatinib 600 mg/day for 8-12 wks PD Off protocol Further treatment at physician’s discretion Outcome Primary Locally Advanced GIST (≥ 5 cm; n = 31) Resectable Metastatic/ Recurrent GIST (≥ 2 cm; n = 22) 5-yr PFS, % 57 30 5-yr OS, % 77 68 Median TTP, yrs Not reached 4.4 Disease progression* 7/11 > 2 yrs from registration 10/13 > 2 yrs from registration Although this approach is feasible, a high percentage of patients experienced progression Consider longer treatment in patients with int- to high-risk GIST GIST, gastrointestinal stromal tumor; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TTP, time to progression; Tx, treatment. Patients with tumors that are borderline resectable or would result in significant morbidity should receive neoadjuvant therapy. This has been evaluated in a phase II RTOG trial demonstrating that this approach is feasible without excess surgical morbidity.[43] In retrospective series, the time to maximum tumor response was approximately 6 months.[44,45] References 43. Wang D, Zhang Q, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132. Ann Surg Oncol. 2012;19:1074-1080. 44. Fiore M, Palassini E, Fumagalli E, et al. Preoperative imatinib mesylate for unresectable or locally advanced primary gastrointestinal stromal tumors (GIST). Eur J Surg Oncol. 2009;35:739-745. 45. Andtbacka RH, Ng CS, Scaife CL, et al. Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Ann Surg Oncol. 2007;14:14-24. *6 pts in each group had stopped imatinib prior to progression. 43. Wang D, et al. Ann Surg Oncol. 2012;19:1074-1080.

Adjuvant Therapy With Imatinib in High-Risk GIST: 12 vs 36 Mos (Phase III Study) Patients with KIT-positive GIST and high risk of recurrence* after surgery (N = 400) Imatinib PO 400 mg/day for 12 mos (n = 200) Imatinib PO 400 mg/day for 36 mos (n = 200) *At least 1 of: longest tumor diameter > 10 cm, mitotic count > 10 mitoses per 50 HPF, tumor diameter > 5 cm and mitotic count > 5 mitoses per 50 HPF, or tumor rupture before or at surgery. GIST, gastrointestinal stromal tumor; HPF, high-power fields; OS, overall survival; PO, orally. Adjuvant therapy with imatinib has been evaluated in a series of trials. A recent study, SSGXVII/AIO, tested the benefit of 12 months vs 36 months of therapy in patients with high-risk tumors (> 50% risk of recurrence or with evidence of tumor perforation at the time of surgical resection).[46] Reference 46. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307:1265-1272. Primary endpoint: relapse-free survival Secondary endpoints: safety, OS, GIST-specific survival 46. Joensuu H, et al. JAMA. 2012;307:1265-1272.

12 vs 36 Mos of Adjuvant Imatinib in High-Risk GIST: Results (ITT Population) Compared with 12 months of adjuvant imatinib, 36 months of imatinib improved RFS and OS in patients with resected GIST and a high risk of recurrence 5-Yr RFS: 47.9% for 12 mos vs 65.6% for 36 mos 5-yr OS: 81.7% for 12 mos vs 92.0% for 36 mos 100 100 36 mos of imatinib 36 mos of imatinib 80 80 12 mos of imatinib 60 Patients Remaining Alive (%) 60 Patients Without Recurrence (%) GIST, gastrointestinal stromal tumor; ITT, intent to treat; OS, overall survival; RFS, relapse-free survival. The phase III SSGXVII/AIO trial demonstrated improved progression-free and overall survival for patients receiving 36 months of adjuvant imatinib vs 12 months.[47] At 5 years, the recurrence-free survival rate in those receiving 12 months of imatinib was 47.9% compared with 65.6% for 36 months. The overall survival rate was 81.7% vs 92.0%, respectively. It is important to note that patient selection for adjuvant therapy is important as those patients whose tumors are at low risk of recurrence receive no benefit from adjuvant therapy. Although the SSGXVII/AIO trial did not evaluate patients with intermediate risk of recurrence, the phase III ACOSOG Intergroup Z9001 study of 1 year of adjuvant imatinib vs placebo[48] did suggest a recurrence-free survival benefit in that group of patients based on an unplanned retrospective analysis.[49] References 47. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307:1265-1272. 48. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:1097-1104. 49. Blackstein ME, Corless CL, Ballman KV, et al. Risk assessment for tumor recurrence after surgical resection of localized primary gastrointestinal stromal tumor (GIST): North American Intergroup phase III trial ACOSOG Z9001. Program and abstracts of the 2010 Gastrointestinal Cancers Symposium; January 22-24, 2010; Orlando, Florida. Abstract 6. 12 mos of imatinib 40 40 20 HR: 0.46 (95% CI: 0.32-0.65; log-rank P < .001) 20 HR: 0.45 (95% CI: 0.22-0.89; log-rank P = .02) 1 2 3 4 5 6 1 2 3 4 5 6 Yrs Since Randomization Yrs Since Randomization Pts at Risk, n 36 mos of imatinib 12 mos of imatinib Pts at Risk, n 36 mos of imatinib 12 mos of imatinib 198 199 184 177 173 137 133 88 82 49 39 27 8 10 198 199 192 188 184 176 152 140 100 87 56 46 13 20 47. Joensuu H, et al. JAMA. 2012;307:1265-1272.

Follow-up and Risk Assessment After Surgery in Patients With GIST Follow-up recommendations NCCN: H&P with abdominal/pelvic CT every 3-6 mos[50] ESMO: no routine follow-up recommended, choose follow-up based on mitotic count, tumor size, and tumor site; low-risk patients may not need routine follow-up[51] High-risk patients generally relapse within 2-3 yrs, whereas low-risk patients relapse later and less frequently[51] NCCN guidelines discuss use of a nomogram to predict 2- and 5-yr RFS[52] 10 20 30 40 50 60 70 80 90 100 Points Size (cm) 5 10 15 25 35 45 Mitotic index ≥ 5/50 HPF <5/50 HPF CT , computed tomography; ESMO, European Society of Medical Oncology; GIST, gastrointestinal stromal tumor; H&P, history and physical; HPF, high-power fields; NCCN, National Comprehensive Cancer Network; RFS, relapse-free survival. Treatment of GIST in the adjuvant setting requires appropriate patient selection. The primary prognostic factors for risk of recurrence include tumor size, tumor location, number of mitoses per 50 HPF, as well as evidence of tumor perforation at the time of surgery.[50-52] According to the National Comprehensive Cancer Network, patients should be monitored for recurrence initially every 3-6 months for 2 years and then every 6 months for up to 5 years. Longer follow-up should be individualized based on risk of recurrence. References 50. National Comprehensive Cancer Network. Clinical practice guidelines: soft tissue sarcoma. v.2.2012. Available at: http://www.nccn.org. Accessed September 24, 2012. 51. Casali PG, Blay JY. Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(suppl 5):v98-v102. 52. Gold JS, Gonen M, Gutierrez A, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol. 2009;10:1045-1052. Colon/rectum Site Stomach/other Small intestine Total points 20 40 60 80 100 120 140 160 180 200 Probability of 2-yr RFS 90 80 70 60 50 40 30 20 10 Probability of 5-yr RFS 90 80 70 60 50 40 30 20 10 50. NCCN. Clinical practice guidelines in oncology: soft tissue sarcoma. 51. Casali PG, et al. Ann Oncol. 2010;21(suppl 5):v96-v102. 52. Gold JS, et al. Lancet Oncol. 2009;10:1045-1052.

TKIs in GIST: Adverse Events Grade 3/4 Toxicity, % Imatinib[53] Sunitinib[54] Anemia 14 4 Neutropenia 10 Nausea/diarrhea 6 Hypertension -- 3 Rash Cause of dose reduction or delay 1 Hand-foot syndrome Renal dysfunction Hypothyroidism 4% (all grades) GIST, gastrointestinal stromal tumor; TKI, tyrosine kinase inhibitor. Initiation of treatment with imatinib or sunitinib requires appropriate monitoring and disease reassessment. Patients receiving imatinib and sunitinib should be monitored for effects on white blood cell counts, hemoglobin, and platelet counts.[53,54] Liver function tests should also be monitored for evidence of transaminitis. Renal dysfunction is observed, although infrequently. Thyroid function should be monitored in patients receiving imatinib and thyroid hormone supplementation, as some will require an increase in their dose. Sunitinib can lead to hypothyroidism, and therefore, monitoring should be ongoing.   Unlike imatinib, sunitinib can cause hypertension because it not only targets KIT and PDGFRA but also VEGFRs. Of note, sunitinib has been occasionally associated with cardiac dysfunction, and assessment of cardiac function at baseline should be performed. The risk of cardiac dysfunction is rare in patients receiving imatinib. Dermatologic adverse effects can be seen with both agents. On imatinib, many patients can develop a self-limited rash that should be treated symptomatically. Sunitinib is associated with a risk for hand–foot syndrome, which can be painful. Patients should be counseled to monitor for tenderness and erythema and use emollient lotions as well as strategies to decrease friction to the palms and soles. References 53. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26:626-632. 54. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329-1338. 53. Blanke CD, et al. J Clin Oncol. 2008;26:626-632. 54. Demetri GD, et al. Lancet. 2006;368:1329-1338.

Treatment Interruption Mos From Randomization BFR14: Effect of Discontinuing Imatinib in Advanced GIST (Phase III Study) Interrupting therapy in responding patients resulted in rapid disease progression and significantly shorter PFS at all time points measured 1.0 Continuation group Interruption group Time Point Treatment Interruption Continued Treatment 1 yr PD: 81% Median PFS: 7 mos PD: 31% Median PFS: 29 mos 2 yrs PFS: 16% PFS: 80% 3 yrs Median PFS: 9 mos Not reached 5 yrs Median PFS: 13 mos 0.8 Continuation Group 1-yr PFS: 92% (95% CI: 72-98) 2-yr PFS: 80% (95% CI: 58-91) 0.6 Survival Probability 0.4 Interruption Group 1-yr PFS: 32% (95% CI: 15-50) 2-yr PFS: 16% (95% CI: 5-33) CI, confidence interval; GIST, gastrointestinal stromal tumor; PD, progressive disease; PFS, progression-free survival. In patients with metastatic GIST that is unresectable, ongoing therapy with a tyrosine kinase inhibitor without interruptions is the standard of care. The BFR14 study evaluated the effect of discontinuing imatinib therapy in patients with advanced GIST, including those in whom surgical resection had left them with no evidence of disease.[55] Discontinuing imatinib at 1, 3, and 5 years was associated with an increased risk of progression within 6-9 months. Most patients were salvaged by the reinitiation of imatinib. Ongoing continuous kinase inhibitor therapy should be considered standard of care for patients with metastatic disease, even in the setting of lack of radiographic evidence of disease. Reference 55. Blay JY, Perol D, Le Cesne A. Imatinib rechallenge in patients with advanced gastrointestinal stromal tumors. Ann Oncol. 2012;23:1659-1665. 0.2 6 12 18 24 30 36 42 48 54 Mos From Randomization Patients at Risk, n Continuation group Interruption group 25 25 23 8 20 3 10 2 55. Blay JY, et al. Ann Oncol. 2012;23:1659-1665.

Surgical Resection for Patients With GIST and Limited Disease Progression Patients with advanced GIST and SD or limited progression on TKI therapy have longer PFS and OS after resection vs those with generalized disease progression PFS OS 1.0 1.0 SD 0.8 0.8 P = .22 Limited disease progression SD 0.6 0.6 Probability Probability GIST, gastrointestinal stromal tumor; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor. Patients receiving tyrosine kinase therapy can demonstrate progression in a limited, or more diffuse, manner.[56,57] Patients with limited progression should be considered for surgical resection. Other local modalities such as radiofrequency ablation or tumor embolization can be considered for lesions that are not amenable to surgery. References 56. Raut CP, Posner M, Desai J, et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol. 2006;24:2325-2331. 57. Gronchi A, Fiore M, Miselli F, et al. Surgery of residual disease following molecular targeted therapy with imatinib mesylate in advanced/metastatic GIST. Ann Surg. 2007;245:341-346. P = .002 0.4 0.4 Limited disease progression P < .0001 0.2 P < .0001 0.2 Generalized disease progression Generalized disease progression 5 10 15 20 25 30 35 40 5 10 15 20 25 30 35 40 Mos Mos 56. Raut CP, et al. J Clin Oncol. 2006;24:2325-2331.

Managing Progression in GIST Therapeutic options for patients with progression include Increasing imatinib from 400 mg/day to 800 mg/day Sunitinib: sole approved agent for patients with imatinib resistance Standard sunitinib dosing in GIST: continuous daily dosing (not FDA approved) Dose reduction for management of toxicities preferred over discontinuation, if feasible GIST, gastrointestinal stromal tumor. Patients with GIST and multifocal progression require a change to systemic therapy.[58-69] Patients receiving imatinib 400 mg can consider increasing to 800 mg/day; approximately 30% of patients will have disease stabilization.[61] Once imatinib is no longer a therapeutic option, sunitinib should be started. Although initially studied at a starting dose of 50 mg/day for 4 weeks, followed by 2 weeks off, some patients will experience recurrent disease related symptoms and evidence of increased metabolic activity by FDG-PET imaging. Daily therapy starting with sunitinib 37.5 mg has been shown to be safe and effective and is the preferred dosing regimen for GIST.[62] References Blay JY. Pharmacological management of gastrointestinal stromal tumours: an update on the role of sunitinib. Ann Oncol. 2010;21:208-215. Wolter P, Beuselinck B, Pans S, Schoffski P. Flare-up: an often unreported phenomenon nevertheless familiar to oncologists prescribing tyrosine kinase inhibitors. Acta Oncol. 2009;48:621-624. George S, Blay JY, Casali PG, et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer. 2009;45:1959-1968. Patel S, Zalcberg JR. Optimizing the dose of imatinib for treatment of gastrointestinal stromal tumours: lessons from the phase 3 trials. Eur J Cancer. 2008;44:501-519. Li J, Gao J, Hong J, Shen L. Efficacy and safety of sunitinib in Chinese patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors. Future Oncol. 2012;8:617-624. 58. Blay JY. Ann Oncol. 2010;21:208-215. 59. Wolter P, et al. Acta Oncol. 2009;48:621-624. 60. George S, et al. Eur J Cancer. 2009;45:1959-1968.

Regorafenib: Novel Multitargeted TKI Regorafenib has a wide spectrum of target inhibition: KIT; PDGFR; VEGFR-1, -2, -3; TIE2; RET, fibroblast growth factor receptor 1; RAF; and p38 MAPK[63] Phase II study (N = 33) in metastatic GIST: 4 PRs, 22 SD ≥ 22 wks, median PFS: 10 mos[63] Phase III GRID study[64] Significant PFS improvement vs placebo in 199 pts with metastatic or unresectable GIST and progression on imatinib and sunitinib Most common grade 3/4 events: hand-foot skin reaction, hypertension, diarrhea Regorafenib (n = 133) Placebo (n = 66) Median PFS, mos (95% CI) 4.8 (4.1-5.8) 0.9 (0.9-1.1) Events, n (%) 81 (60.9) 63 (95.5) 1.00 HR: 0.27 (95% CI: 0.19-0.39) 1-sided P < .0001 0.75 Placebo Regorafenib CI, confidence interval; GIST, gastrointestinal stromal tumor; PFS, progression-free survival; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor. Regorafenib is a multitargeted tyrosine kinase inhibitor[63] currently under review by the US Food and Drug Administration and the European Medicines Agency for treatment of patients with advanced GIST that have progressed on standard therapy. In a phase III trial, regorafenib, compared with placebo, was associated with significant progression-free survival improvements in patients with metastatic or unresectable GIST who had progressed on imatinib and sunitinib.[64] References 63. George S, Wang Q, Heinrich MC, et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol. 2012;30:2401-2407. 64. Demetri G, Reichardt P, Kang YK, et al. Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial. Program and abstracts of the 2012 Annual Meeting of the American Society of Clinical Oncology; June 1–5, 2012; Chicago, Illinois. Abstract LBA10008. Proportion Without Progression 0.50 0.25 50 100 150 200 250 300 Days From Randomization 63. George S, et al. J Clin Oncol. 2012;30:2401-2407. 64. Demetri G, et al. ASCO 2012. Abstract LBA10008.

GIST: What Comes Next? Study Phase Planned N Agent(s) Setting II 20 Crenolanib[65] GIST with D852-related PDGFR mutations or deletions 80 Pazopanib[66] Metastatic/unresectable GIST resistant to imatinib and sunitinib 34 AUY922 (HSP90 inhibitor)[67] Metastatic/unresectable GIST with progression on or intolerance of imatinib and sunitinib 36 AT13387 (HSP90 inhibitor) ± imatinib[68] Metastatic/unresectable GIST with progression on 1-3 TKIs 21 IMC-3G3 (anti-PDGFRA antibody)[69] Metastatic/unresectable GIST with or without PDGFRA mutations 30 Masitinib[70] Inoperable locally advanced or metastatic GIST 55 Ganetespib[71] Metastatic/unresectable GIST resistant/refractory to prior systemic treatment including imatinib and sunitinib 40 Linsitinib[72] Pediatric and adult wild-type GIST GIST, gastrointestinal stromal tumor; TKI, tyrosine kinase inhibitor. Future therapy for advanced disease likely will focus on combination therapies. In vivo data suggest that with disease progression, downstream signaling molecules may no longer be inhibited. This is particularly true for AKT. Studies have evaluated mammalian target of rapamycin inhibitors as well as ongoing studies evaluating combination therapies with AKT and/or MEK inhibitors. Another approach that is very successful in the laboratory, which is now being studied in clinical trials, is the use of HSP90 inhibitors. As single agents, there has been limited benefit demonstrated to date, but ongoing trials are looking at combination therapies.   Another approach being taken is to choose therapies based on the specific mutation in the GIST. Although imatinib and sunitinib are particularly effective for patients with KIT mutations, they have less benefit for those without kinase mutations and some patients with PDGFRA mutations. As discussed, it appears that the majority of GIST with normal KIT and PDGFRA has overexpression of IGF-1R and mutations in SDH complex genes. Thus, studies are testing the IGF-1R inhibitor linsitinib. Patients with PDGFRA D842V mutations are refractory to imatinib and sunitinib. Ongoing studies are evaluating crenolanib and IMC-3G3, an anti-PDGFR antibody. In summary, patients with GIST should be started on imatinib as adjuvant therapy or as first-line treatment for metastatic disease. Upon progression, patients should be switched to sunitinib. Promising research directions include phase III results with regorafenib and phase II results from a variety of other agents. References ClinicalTrials.gov. Phase II study of crenolanib (CP-868,596), a selective and potent inhibitor of PDGFR, for the Treatment of patients with advanced gastrointestinal stromal tumors with the D842-related mutations and deletions, including the D842V Mutation, in the PDGFRA gene. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01243346. Accessed October 8, 2012. ClinicalTrials.gov. A phase ii randomized multicentre study evaluating the efficacy of pazopanib+best supportive care (BSC) versus BSC alone in metastatic and/or locally advanced unresectable GIST, resistant to imatinib and sunitinib. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01323400. Accessed October 8, 2012. ClinicalTrials.gov. A phase II randomized multicentre study evaluating the efficacy of pazopanib+best supportive care (BSC) versus BSC alone in metastatic and/or locally advanced unresectable GIST, resistant to imatinib and sunitinib. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01404650. Accessed October 8, 2012. ClinicalTrials.gov. An open-label, randomised, multi-centre, phase II study to investigate the safety and efficacy of AT13387, either as monotherapy or in combination with imatinib, in patients with unresectable and/or metastatic malignant GIST whose tumour has progressed following treatment with a maximum of three tyrosine kinase inhibitors. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01294202. Accessed October 8, 2012. ClinicalTrials.gov. A phase 2 study of a human anti-PDGFRα monoclonal antibody (IMC-3G3) in previously treated patients with unresectable and/or metastatic gastrointestinal stromal tumors (GIST). Available at: http://www.clinicaltrials.gov/ct2/show/NCT01316263. Accessed October 8, 2012. ClinicalTrials.gov. Phase 2 study of oral AB1010 in non pre-treated, inoperable patients with locally advanced/metastatic gastro-intestinal stromal tumour (GIST). Available at: http://www.clinicaltrials.gov/ct2/show/NCT00998751. Accessed October 8, 2012. ClinicalTrials.gov. A non-randomized, open label, multi-center phase 2 study evaluating the efficacy and safety of STA-9090 in patients with metastatic and/or unresectable GIST resistant or refractory to prior systemic treatments including imatinib and sunitinib. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01039519. Accessed October 8, 2012. ClinicalTrials.gov. A phase 2 study of OSI-906 in patients with pediatric and adult wild type gastrointestinal stromal tumors. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01560260. Accessed October 8, 2012. 65. ClinicalTrials.gov. NCT01243346. 66. ClinicalTrials.gov. NCT01323400. 67. ClinicalTrials.gov. NCT01404650. 68. ClinicalTrials.gov. NCT01294202. 69. ClinicalTrials.gov. NCT01316263. 70. ClinicalTrials.gov. NCT00998751. 71. ClinicalTrials.gov. NCT01039519. 72. ClinicalTrials.gov. NCT01560260.