Gastrointestinal Stromal Tumor Life Fest 2006 Jon Trent

Gastrointestinal Stromal Tumor Life Fest 2006 Jon Trent, MD, Ph. D Assistant Professor Dept. of Sarcoma Medical Oncology The University of Texas, M. D. Anderson Cancer Center jtrent@mdanderson. org www. ctos. org

Background

GIST Overview n n Most common GI sarcoma n 0. 2% of all GI tumors, but 80% of GI sarcomas Distinct clinical and histopathologic entity n Highest incidence in the 40 -60 year age group n Similar male/female incidence n Many misclassified as leiomyosarcoma GIST have an incidence of 14. 5 per million annually and a prevalence of 129 per million Clinical presentation is variable n pain, hemorrhage, anemia, anorexia, nausea, perforation

Median Overall Survival in Metastatic GIST

Chemotherapy Trials Advanced GIST Regimen DOX + DTIC +/– IF IF + VP-16 Paclitaxel Gemcitabine Liposomal DOX DOX or docetaxel High-dose IF EPI + IF Various DTIC/MMC/DOX/ CDDP/GM–CSF Temozolamide TOTAL Number of Patients 43 60 10 15 17 15 12 9 26 13 40 21 19 280 Partial Response n (%) 3 (7%) 10 (15%) 0 (0%) 1 (7%) 0 (0%) 0 (0%) 4 (10%) 1 (5%) 0 (0%) 19 (6. 8%)

GIST Overview n GIST share several characteristics with ICC n Neuromuscular pacemaker cell of the GI tract n Found in myenteric plexus throughout GI tract n Expression of CD 34 in ~80% of cases n Expression of KIT (CD 117) in ~95% of cases ICC = interstitial cells of Cajal. Corless et al. J Clin Oncol. 2004; 22: 3813. Sircar et al. Am J Surg Pathol. 1999; 23: 377.

Kit Receptor Structure Extracellular Domain (exon 9, 10. 2%) Juxtamembrane Domain (exon 11, 66. 1%) ATP Tyrosine Kinase Domain I (exon 13/14, 1. 2%) Tyrosine Kinase Domain II (exon 17, 0. 6%) = common mutation site

Kit Receptor Phenotype ADP ATP + P Proliferation Survival Adhesion Invasion Metastasis Angiogenesis

Imatinib Mesylate Formula: MW: n Rational drug design n n 2 -phenylamino pyrimidine Based on structure of ATP binding site Highly water soluble Oral bioavailability C 30 H 35 N 7 SO 4 589. 7 Inhibitor of selective tyrosine kinases bcr-abl Potent (IC 50 0. 1 M) PDGF-R c-kit

Kit Receptor Phenotype ATP Im ati nib Proliferation Survival Adhesion Invasion Metastasis Angiogenesis = imanitib contact point

The First GIST Patient: Histology H&E (at diagnosis) H&E Ki 67 CD 117 Pretreatment Joensuu H et al. N Engl J Med. 2001; 344: 1052 -1056. One month of therapy

What is the chance of imatinib helping me?

Clinical Trials of Imatinib in GIST Study Phase OS TTP N OR CR PR SD PD (2 yr) (median) PFS van Oosterom, 2001 I 36 53% 0% 53% 36% 11% - - - von Mehren, 2002 II 147 63% 0% 63% 19% 12% - 72 wks - Verweij, 2003 II 27 71% 4% 67% 18% 11% - - 73% (1 yr) Rankin, 2004 III 746 -400 mg daily 48% 3% 45% - - 78% - 50% (2 yr) -800 mg daily 48% 3% 45% - - 73% - 53% (2 yr) -400 mg daily 50% 5% 45% 32% 13% 69% - 44% (2 yr) -800 mg daily 54% 6% 48% 32% 9% 74% - 52% (2 yr) Verweij, 2004 III 946 Courtesy Dejka Steinert, M. D.

Phase III dose-randomized study of Imatinib mesylate (Gleevec, STI 571) for GIST: NA Intergroup S 0033 early results. Robert S. Benjamin, UT MD Anderson Cancer Center and SWOG, Houston, TX, Cathryn Rankin, SWOG, Christopher Fletcher, Dana Farber Cancer Institute, Charles Blanke, SWOG, Margaret von Mehren, ECOG, Robert Maki, CALGB, Vivien Bramwell, NCIC, Laurence Baker, SWOG, Ernest Borden, SWOG, George D. Demetri, Dana Farber Cancer Institute, CALGB, as the North American Sarcoma Intergroup Benjamin et al, ASCO 2003

North American Sarcoma Intergroup Schema R A N D O M I Z A T I O N Low Dose Imatinib 400 mg/d High Dose Imatinib 800 mg/d Progression C R O S S O V E R Progression High Dose Imatinib Progression Off Protocol Treatment

EORTC Phase III Imatinib for Advanced GIST Survival Benefit Verweij, et al 2004

How long do I take imatinib?

The First GIST Patient: Histology H&E (at diagnosis) H&E Ki 67 CD 117 Pretreatment Joensuu H et al. N Engl J Med. 2001; 344: 1052 -1056. One month of therapy

Phase III Trial: US Intergroup S 0033: Time to Progression on Crossover

Estimated TTP probability (%) Time to Tumor Progression 100 Sunitinib (N=207) Placebo (N=105) 90 Hazard ratio = 0. 335 P<0. 00001 80 70 60 Median (95% CI) 6. 3 (3. 7, 7. 6) 1. 5 (1. 0, 2. 3) 50 40 30 20 10 0 0 3 6 Time (Months) 9 12

Discontinuation of Imatinib Increases the Risk of Progression (BFR 14) % of patients 100 80 n P=0. 0001 60 40 Stop therapy (n=25) Median PFS: 6 months 20 0 n Continuous therapy (n=23) 0 2 4 6 8 10 12 14 16 Months after randomization Patients who achieved clinical benefit after 12 months were randomized to continue or to stop imatinib mesylate therapy Randomization has been suspended Blay et al. Proc Am Soc Clin Oncol. 2004; 23: 815. Abstract 9006.

What dose of imatinib should I take?

EORTC Phase III Imatinib for Advanced GIST Progression-free Survival Benefit Verweij, et al 2004

Progression-free Survival By Imatinib Dose Kit Exon 11 Mutation

Progression-free Survival By Imatinib Dose Kit Exon 9 Mutation

Kit Mutation in GIST Benefit from 800 mg Imatinib Exon 11 (n=211) Exon 9 (n=25) Wild-type (n=33) Odds Ratio P-value 1. 0 0. 96 8. 0 0. 03 1. 5 0. 62 Heinrich et al, ASCO 2050

Tell me about the side effects…. .

Side effects: 400 vs. 800 mg Toxic Event Adjusted p-Value Edema <0. 001 Anemia Rash <0. 001 Fatigue Nausea Hemorrhage Diarrhea Dyspnea Pleuritic Pain <0. 001 0. 0026 0. 036 0. 053 Verweij et al, 2004

Interruptions and Reductions of Therapy 400 mg 800 mg Treatment Interruption 40% 64% -Hematologic 6% 7% -Non-Heme 23% 43% Dose Reduction 16% 60% -Hematologic 2% 4% -Non-heme 10% 42%

North American Intergroup Phase III Study of Imatinib in Advanced GIST Dose Reduction 400 mg (376 pts) 800 mg (370 pts) 800 mg X-Over 1 10% 44% 16% 2 7% 26% 5% 3 2% 11% 0% 4 1% 4% 0% Dileo et al, ASCO 2005

How do I know if imatinib is working?

Confirmed Overall Responses with Gleevec

Best Response (B 222) 400 mg N=73 n (%) 600 mg N=74 n (%) All Patients N=147 n (%) Complete Response Partial Response 0 2 (2. 7) 2 (1. 4) 50 (68. 5) 48(64. 9) 98 (66. 7) Stable Disease 10 (13. 7) 13 (17. 6) 23 (15. 6) Progression 11 (15. 1) 6 (8. 1) 17 (11. 6) 2 (2. 7) 5 (6. 8) 7 (4. 8) Not evaluable

Time to PR by RECIST Cumulative incidence of CT responses 2 Months 1 0. 9 0. 8 3 Months 0. 7 CI 0. 6 6 Months 0. 5 0. 4 0. 3 400 mg 800 mg 0. 2 0. 1 0 0 0. 5 1 1. 5 2 Years Verweij et al, ASCO 2003

CT Scan Results Jun 27, 2000 Before Imatinib Oct 4, 2000 After Imatinib

Background (cont) Decrease in GIST intravenous contrast uptake after patient is treated for 8 weeks with imatinib mesylate

Overall Survival by Best Response (B 222, Kaplan Meier Estimate) 1. 0 0. 9 SD (n=23): Median n/a 0. 8 0. 7 PD (n=17): Median 36 wks 0. 6 0. 5 PR (n=98): Median 248 wks 0. 4 0. 3 0. 2 Best Response CR PR SD PD UNK 0. 1 0. 0 Wks: 0 0 12 24 2 98 23 17 7 36 48 60 72 Number at Risk 40 80 2 97 22 7 5 84 Median Duration 95% CI LL UL N/A 248 Wks N/A 36 Wks 144 Wks 2 92 20 4 4 96 108 172 226 149 15 18 120 N/A N/A 56 223 132 144 156 168 180 192 204 216 228 240 252 264 Weeks Post First Dose [CR (n=2; median OS n/a) and unknown/NE (n=7; median OS 144 wks) not included]

Effects of Imatinib on GIST: CT and PET findings 1/18 3/23 1/26 10/8 3/22

Pseudoprogression Early During Treatment With Imatinib Mesylate CT 18 FDG-PET Pre-imatinib mesylate Choi et al. AJR Am J Roentgenol. 2004; 183: 1619. 2 months imatinib mesylate

Effects of Imatinib on GIST: CT findings 1/12 3/30 5/24

Modified RECIST for GIST CT Size + Density (Choi) n Tumor size decrease of >10% or tumor density decrease of >15% were highly correlated with decrease in SUV by >70% to a value <2. 5 on PET. n RECIST criteria substantially underestimate, at least initially, the value of therapy with imatinib for GIST.

What is “genotyping? ”

Kit Receptor Structure Extracellular Domain (exon 9, 10. 2%) Juxtamembrane Domain (exon 11, 66. 1%) ATP Tyrosine Kinase Domain I (exon 13/14, 1. 2%) Tyrosine Kinase Domain II (exon 17, 0. 6%) = common mutation site

Kit Mutation in GIST Response to Imatinib (n=332)

Overall Survival by Genotype (B 222, Kaplan Meier Estimate) Median Survival Exon 11 Not reached Exon 9 1347 days (192 wks) No mut 250 days (36 wks) Exon 11 Exon 9 No Mutation

Kit-Negative GIST PFS (2 year) OS (2 year) Kit-negative GIST 43% 57% Kit-expressing GIST 49% 77% NS 0. 01 IHC Result P-value Blackstein et al, ASCO 2005

How will you know whether my GIST comes back?

Type of Progression Limited progression Nodular progression Stable disease Stable lesion Progressing lesion Widespread progression

Limited Progression

Resistance to Imatinib Mesylate: Recognition of Clonal Evolution Courtesy of Dr. G. D. Demetri.

Secondary Mutation Heinrich et al, JCO 2006

What do I do if my GIST is resistant to imatinib?

Therapy by Type of Progression n Limited or Nodular Progression Hepatic Artery Embolization n Hepatic Radio-frequency Catheter Ablation n Surgical Resection n n Widespread progression Increase Imatinib to 800 mg daily n Sunitinib n Clinical Trial n

Hepatic Artery Embolization Preembolization Postembolization Courtesy of Dr. R. De. Matteo.

Metastatic GIST Trials n Phase II studies in advanced GIST n n n n AMN 107: Kit and Abl inhibitor AMG 706: High affinity Kit inhibitor and VEGFR inhibitor Dasatinib: High affinity Kit, Abl and Src inhibitor (+other targets) Sorafinib: High affinity Kit inhibitor Perifosine (AKT/Map. K/p 21 inhibitor)+Imatinib: inhibit PI 3 K activation of AKT G 3139 (antisense bcl-2) + Imatinib : restore apoptosis RAD 0001 (m. TOR inhibitor)+Imatinib Phase I studies in GISTs and other solid tumors n n IGF-1 R inhibitor TRAIL

SU 11248 in Advanced GIST Sunitinib Malate, Sutent Stop imatinib 4 weeks PD on imatinib R A N D O M I Z E SU 11248 (207) 6 weeks Placebo (105) PD Off PD

SU 11248 in Advanced GIST Objective Response Rates Sunitinib Placebo Imatinib 800 mg* PR 7% 0% 6% SD 58% 50% 32% SD> 6 mo 19% 0% ND PD 20% 39% 48% NE 14% 11% 13% *Escalation of imatinib from 400 mg to 800 mg daily.

Estimated TTP probability (%) Time to Tumor Progression 100 Sunitinib (N=207) Placebo (N=105) 90 Hazard ratio = 0. 335 P<0. 00001 80 70 60 Median (95% CI) 6. 3 (3. 7, 7. 6) 1. 5 (1. 0, 2. 3) 50 40 30 20 10 0 0 3 6 Time (Months) 9 12

Should I take imatinib after my GIST was removed?

Survival of GIST Patients by Primary Tumor Size De. Matteo et al, 2000

Post-operative Imatinib Trials n n Z 9000: ACOSOG Study of Adjuvant Imatinib in GIST Z 9001: ACOSOG Randomized Study of Adjuvant Imatinib Versus Placebo in GIST n n Primary Objective is survival Secondary objective to obtain tumor before Imatinib and at recurrence n n n Resected < 10 weeks prior to Imatinib High risk for local or distant failure (> 3 cm primary, intraperitoneal hemorrhage, tumor rupture) Z 9002: Adjuvant Duration?

Preoperative Imatinib Trials n MDACC ID 03 -0023: Preop/Postop Imatinib in Patients with Resectable GIST n n n Laboratory correlations Clinical endpoints of DFS, OS RTOG S-0132: Preoperative Imatinib in Patients with Potentially Resectable GIST n n n Laboratory correlations Clinical endpoints of DFS, OS Imatinib to maximum response

Patient Characteristics n=13 Characteristic Value Age (median) 52 (range 38 -67) Gender (M/F) 7/6 Primary Site of Tumor - Stomach 6 - Small Intestine 5 - Colon 2 Duration of Imatinib - 3 days 4 - 5 days 5 - 7 days 4

Preoperative Imatinib Toxicity Grade 3/4 Toxicity Number of Patients (n=13) Nausea/emesis 2 Abdominal pain 1 GI Hemorrhage 1 Hypovolemia 1 None 11 Patients able to finish 1 year of therapy: 7/9 Patients with recurrence: 1

PET Response at Day 5 Pre-imatinib Post-imatinib (Day 5)

PET Response Data n=12 Responders 3 Days 3 5 Days 2 7 Days 3 Total 8 Non-responder 1 2 1 4 PET-CT imaging Courtesy Homer Macapinlac, M. D.

Apoptosis After Imatinib 5 days post-imatinib

Effect of Imatinib on Apoptosis Pre-Imatinib Post-Imatinib (3 days of therapy) Immunofluorescent TUNEL Assay

Will my kids get GIST?

Familial GIST I II III IV III II V VII VI I II VIII IV

Gastrointestinal Stromal Tumors A Paradigm of Targeted Anti-Tumor Therapy Jon Trent, MD, Ph. D jtrent@mdanderson. org Dept. of Sarcoma Medical Oncology The University of Texas, M. D. Anderson Cancer Center