11 One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal Tumor A Randomized Trial Joensuu H, Eriksson M, Sundby Hall K, et al. JAMA. 2012;307(12):1265–1272

2 Imatinib for 12 months An open-label Phase III study Imatinib for 36 months Follow-up Random Assignment 1:1 Stratification: 1) R0 resection, no tumor rupture 2) R1 resection or tumor rupture Joensuu H et al. JAMA 2012;307(12):1265–1272 N=400 SSGXVIII/AIO: Design

3 SSGXVIII/AIO: Methods HPF, high-power field of the microscope. 1.Joensuu H et al. JAMA 2012;307(12):1265– Fletcher CD et al. Hum Pathol 2002;33:459–465 3.Joensuu H. Hum Pathol 2008;39:1411−1419. Endpoints 1 Primary RFS Secondary Treatment safety OS GIST-specific survival Treatment 1 Imatinib 400 mg/d (12 vs 36 months) Key inclusion criteria 1 Histologically confirmed GIST, KIT-positive High risk of recurrence according to the modified consensus criteria 2,3  Tumor size >10 cm or  Tumor mitosis count >10/50 HPF or  Size >5 cm and mitosis count >5/50 HPF or  Tumor rupture before surgery or at surgery

4 SSGXVIII/AIO: Patient Disposition *Three patients who withdrew consent were excluded Joensuu H et al. JAMA 2012;307(12):1265–1272 Category12 Months n (%) 36 Months n (%) Randomized (Feb 2004 to Sep 2008)200 Included in ITT population* − No GIST at pathology review5 (3)10 (5) − GIST metastases at study entry13 (7)11 (6) Included in efficacy population Included in safety population (SP) Discontinued assigned treatment (SP)29 (15)63 (32) − GIST recurred during treatment4 (2)12 (6) − Adverse event15 (8)27 (14) − Patient preference0 (0)11 (6) − Tumor histology not GIST6 (3) − Other reason4 (2)7 (4)

5 SSGXVIII/AIO: Baseline Characteristics (ITT Population) *Per 50 high power fields **Available for 366 (92%) out of the 397 tumors Joensuu H et al. JAMA 2012;307(12):1265–1272 Characteristic 12-Month (n=199) 36-Month (n=198) Median age (range), years 62 (23–84) 60 (22–81) Male, %52 49 ECOG performance status 0, %85 86 Gastric primary tumor, %49 53 Median tumor size (range), cm 9 (2–35) 10 (2–40) Median mitosis count (central)*10 (0−250) 8 (0−165) Tumor rupture, %18 22 GIST gene mutation site, %** – KIT exon – KIT exon – PDGFRA exon 1221 – PDGFRA exon – PDGFRA exon 18 mutation D842V97 – Wild type10 7

6 SSGXVIII/AIO: Baseline Characteristics (ITT Population) Characteristic 12-Month (n=199) 36-Month (n=198) Modified Consensus Classification Risk Group. % – High8991 – Intermediate84 – Low risk12 – Very low risk00 – Not available23 Joensuu H et al. JAMA 2012;307(12):1265–1272

7 SSGXVIII/AIO: RFS Events and Deaths (ITT Population) Event12-Month (n=199) No. (%) 36-Month (n=198) No. (%) RFS events (recurrences or deaths) 84 (42) 50 (25) Deaths 25 (13)12 (6) – From GIST14 (7) 7 (4) – Another cause11 (6) 5 (3) Median follow-up time: 54 months (from the date of randomization to the date of data cut-off, Dec 31, 2010) Joensuu H et al. JAMA 2012;307(12):1265–1272

8 SSGXVIII/AIO: Recurrence-Free Survival (ITT Population) Joensuu H et al. JAMA 2012;307(12):1265– year survival : 36 months, 86.6% 12 months, 60.1% 5-year survival : 36 months, 65.6% 12 months, 47.9% Percentage Time Since Randomisation, y 36 Months of imatinib Months of imatinib HR, 0.46 (95% CI, ) Log-rank P<.001 No. of patients 36 Months of imatinib 12 Months of imatinib

9 Excluded: consent withdrawn, no GIST at pathology review, or overt metastases at study entry SSGXVIII/AIO: RFS in Efficacy Population 3-year survival : 36 months, 88.1% 12 months, 62.1% 5-year survival : 36 months, 67.4% 12 months, 50.3% Joensuu H et al. JAMA 2012;307(12):1265–1272 HR, 0.46 (95% CI, ) Log-rank P< Months of imatinib 12 Months of imatinib Percentage Time Since Randomisation, y 36 Months of imatinib Months of imatinib No. of patients

10 Joensuu H et al. JAMA 2012;307(12):1265–1272 No. of PatientsNo. of EventsHR 12-mo Group 36-mo Group 12-mo Group 36-mo Group (95% CI) Age, y ≤ ( ) > ( ) Tumor site Stomach ( ) Other ( ) Tumor size, cm ≤ ( ) > ( ) Mitotic count/50 HPF Local ≤ ( ) > ( ) Central ≤ ( ) > ( ) Tumor rupture No ( ) Yes ( ) Completeness of surgery R ( ) R ( ) Tumor mutation site KIT exon ( ) KIT exon ( ) Wild type ( ) Other ( ) P Value < < < < < < SSGXVIII/AIO: RFS in Subgroups Favors 36 mo of Imatinib Favors 12 mo of Imatinib HR (95% CI)

11 Joensuu H et al. JAMA 2012;307(12):1265– year survival : 36 months, 96.3% 12 months, 94.0% 5-year survival : 36 months, 92.0% 12 months, 81.7% HR, 0.45 (95% CI, ) Log-rank P =.02 Percentage Time Since Randomisation, y 36 Months of imatinib 12 Months of imatinib SSGXVIII/AIO: Overall Survival (ITT Population) 36 Months of imatinib Months of imatinib No. of patients

12 SSGXVIII/AIO: Treatment Safety  Cardiac AEs and second malignancies were low and comparable in both treatment arms Joensuu H et al. JAMA 2012;307(12):1265–1272 No. (%) All GradesGrade 3 or 4 Events 12-mo Group (n = 194) 36-mo Group (n = 198) P Value a 12-mo Group (n = 194) 36-mo Group (n = 198) P Value a Any event 192 (99.0) 198 (100.0) (20.1) 65 (32.8).006 Hematological Anemia Leukopenia 140 (72.2) 67 (34.5) 159 (80.3) 93 (47.0) (0.5) 4 (2.1) 1 (0.5) 6 (3.0) > Nonhematological Periorbital edema Fatigue Nausea Diarrhea Muscle cramps Leg edema 115 (59.3) 94 (48.5) 87 (44.8) 85 (43.8) 60 (30.9) 64 (33.0) 147 (74.2) 96 (48.5) 101 (51.0) 107 (54.0) 97 (49.0) 81 (40.9).002 > < (0.5) 2 (1.0) 3 (1.5) 1 (0.5) 2 (1.0) 1 (0.5) 4 (2.0) 2 (1.0) > >.99 Biochemical Elevated blood lactate dehydrogenase Elevated serum creatinine 84 (43.3) 59 (30.4) 119 (60.1) 88 (44.4) a Fisher exact test

13 SSGXVIII/AIO: Conclusions Compared with 1 year of treatment, 3 years of adjuvant imatinib significantly improves RFS and OS for patients with GIST who are at a high risk of recurrence after surgery Adjuvant imatinib is relatively well tolerated; severe adverse events are infrequent This trial has established 3 years of 400 mg imatinib as the new standard of care for adjuvant treatment of patients with high-risk GIST  Both the US Food and Drug Administration and European commission approved label updates that include 3-year duration for adjuvant treatment of KIT+ GIST patients  The National Comprehensive Cancer Network updated recommendations to include 3 years of adjuvant imatinib therapy as the new standard of care for KIT+ GIST patients Joensuu H et al. JAMA 2012;307(12):1265–1272