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Whom to treat and how long to treat after resection of GIST

Whom to treat and how long to treat after resection of GIST. Professor John R Zalcberg Chief Medical Officer & Director, Division of Cancer Medicine Peter MacCallum Cancer Centre Chair, Australasian Gastro-Intestinal Trials Group. Disclosures. Novartis Pfizer Bayer Amgen BMS.

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Whom to treat and how long to treat after resection of GIST

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  1. Whom to treat and how long to treat after resection of GIST Professor John R Zalcberg Chief Medical Officer & Director, Division of Cancer Medicine Peter MacCallum Cancer Centre Chair,Australasian Gastro-Intestinal Trials Group

  2. Disclosures Novartis Pfizer Bayer Amgen BMS • Research / Travel Support / Advisory Board

  3. Risk of Recurrence After Resection of Primary GIST Approximately 40% of patients who undergo complete resection of primary GIST have a recurrence within 5 years DeMatteo RP et al. Cancer. 2008;112:608-615.

  4. Risk Assessment Accurate assessment of risk of aggressive malignant behaviour in GIST poses a challenge1 Morphologic features most predictive of outcome1,2 - Mitotic index - Tumour size Tumour site and rupture also affect risk of recurrence and progression2,3 Mutational status is useful in predicting treatment response in the metastatic setting4,5 ?applicable in the adjuvant setting 1. Fletcher CD et al. Hum Pathol. 2002;33:459-465. 2. Demetri GD et al. J Natl Compr Cancer Netw. 2007;5(suppl 2):S1-S29. 3. Miettinen M, Lasota J. Arch Pathol Lab Med. 2006;130:1466-1478. 4. Debiec-Rychter M et al. Eur J Cancer. 2006;42:1093-1103. 5. Heinrich MC et al. J Clin Oncol. 2003;21:4342-4349.

  5. Primary GIST:Risk Factors for Recurrence After Surgery Rates of RFS were independently predicted by mitotic index, tumour size, and tumour location Adapted with permission from DeMatteo RP et al. Cancer.2008;112:608-615.

  6. Overall Survival by Risk Group Cumulative Survival AFIP, Armed Forces Institute of Pathology. Adapted with permission from Goh BKP et al. Ann Surg Oncol. 2008;15:2153-2163.

  7. Specific KIT Mutations Have Prognostic Importance RFS in 127 patients with completely resected localized GIST based on mutation type 1.0 KIT exon 11 PM/INS (n=32) Other KIT exon 11 deletion (n=17) 0.8 PDGFRA mutation (n=8) No mutation (n=29) 0.6 Proportion Recurrence-Free KIT exon 11 DEL557/8 (n=35) 0.4 0.2 KIT exon 9 mutation (n=4) P<0.001 0.0 0 1 2 3 4 5 6 7 8 9 10 Years After Resection DeMatteo RP et al. Cancer. 2008;112:608-615.

  8. Risk Stratification of Primary GIST: Miettinen (AFIP) Data are based on long-term follow-up of 1055 gastric, 629 smallintestinal, 144 duodenal, and 111 rectal GISTs. † Denotes smallnumbers of cases. ≈ Tumour size categories combined for bothduodenal and rectal GISTs because of small numbers. ∂ No tumours of such category were included in this study. Original source: Miettinen M, Lasota J. Semin Diagn Pathol. 2006;23:70-83.

  9. Nomogram to Predict RFS Following Complete Surgical Resection of Primary GIST Gold JS et al. Lancet Oncol. 10; 1045-1052, 2009

  10. Risk Classification – Room for Refinement Additional factors: - Mutational status1 - Rupture2 - Necrosis3 1. Wardelmann E et al. Virchoves Arch. 2007;451:743-749. 2. Joensuu H. Hum Path. 2008;39:1411-1419. 3. Dei Tos AP et al. J Clin Oncol. 2009;27(suppl). Abstract 10555.

  11. Joensuu H et al. Lancet Oncol, 13; 265-274, 2012

  12. Adjuvant Studies of Imatinib 1. DeMatteo RP et al. ASCO GI Cancers Symposium; 2004. Abstract 8. 2. DeMatteo RP et al. J Clin Oncol. 2005;23:818s. Abstract 9009. 3. Nilsson B et al. Br J Cancer. 2007;96:1656-1658. 4. Li J et al. J Clin Oncol. 2009;27(suppl).Abstract 10556.5. Kang Y et al. J Clin Oncol. 2009;27(suppl). Abstract e21515.6. ClinicalTrials.gov. Accessed August 26, 2009.

  13. 713 patients randomised 97 discontinued treatment early 87 discontinued treatment early 30 events 5 GIST-unrelated deaths ACOSOG Z9001: Trial Schema Imatinib (359 randomised) (337 treated) IM 400 mg/day or placebo for 1 yr (Phase III) 778 patients 70 events 5 GIST-related deaths 3 GIST-unrelated deaths Placebo (354 randomised) (345 treated) • Phase III, randomised, double-blind, placebo-controlled multi-centre trial DeMatteo RP et al. Lancet. 2009; 373: 1097-1104

  14. ACOSOG Z9001: Study Design/Methods Key Eligibility Criteria: • Patients ≥18 years with localised and primary GIST • KIT-positive tumours ≥3 cm • Complete surgical resection • Endpoints: • Primary: Recurrence-free Survival (RFS) • Secondary: Overall Survival (OS) and safety Other Key Elements: • Dose modifications upon grade 3 or 4 events • PD patients unblinded: - If placebo  IM 400 mg/day or - If IM 400 mg/day  IM 800 mg/day

  15. Patient characteristics (continued) R0 – negative microscopic margins; R1 – positive microscopic margins

  16. Recurrence-free Survival (RFS)* Median follow-up: 19.7 months Estimated 1-year RFS (95% CI): Imatinib: 98% (96-100) Placebo: 83% (78-88) HR = 0.35 (0.22-0.53) p < 0.0001 CI, confidence interval; HR, hazard ratio Events experienced: Imatinib: 8.0% (30) Placebo: 20.0% (70) *All randomised patients were included in the analysis; recurrence-free survival was defined as the time from patient registration to the development of tumour recurrence or death from any cause. Intention-to-treat analyses were done for recurrence-free survival (ie, analysed patients by randomised group).

  17. Recurrence-free Survival (Tumour size) size >6cm and <10cm size >3 and <6 cm • Imatinib adjuvant therapy results in significantly longer RFS in each of the tumour size categories compared to placebo size >10cm

  18. Overall Survival (OS)* • No difference in OS between imatinib and placebo adjuvant therapies *All randomised patients were included in the analysis; Overall survival was defined as the time from patient registration to death from any cause. Intention-to-treat analyses were done for overall survival (ie, analysed patients by randomised group).

  19. Imatinib at 400 mg/day is safe and well tolerated when administered as adjuvant therapy after complete resection of primary GIST Adjuvant imatinib resulted in an improvement in RFS in patients with all tumour sizes - Especially relevant for high-risk patients (e.g. tumour size ≥10 cm or high mitotic rate) since this patient population has a 50% higher chance of recurrence at 2 years without adjuvant therapy OS between imatinib and placebo groups comparable at this time A longer follow-up period is likely required to observe differences Ongoing trials in the adjuvant setting are under way to determine appropriate treatment duration of imatinib and impact on OS SSGXVIII/AIO EORTC 62024 Summary

  20. Adjuvant Imatinib: Beyond 1 Year of Treatment

  21. SSGXVIII: Study design An open-label Phase III study Imatinib 400mg/d for 12 months Follow-up Random assignment 1:1 Stratification: 1) R0 resection, no tumor rupture 2) R1 resection or tumor rupture Imatinib 400mg/d for 36 months Follow-up

  22. SSGXVIII: Objectives Primary: RFS Time from randomization to GIST recurrence or death Secondary objectives included: Safety Overall survival

  23. SSGXIII: Key inclusion criteria Histologically confirmed GIST, KIT-positive High risk of recurrence according to the modified Consensus Criteria*: Tumor diameter>10 cmor Tumor mitosis count >10/50 HPF** or Size >5 cm and mitosis count >5/50 HPFsor Tumor rupture spontaneously or at surgery *Fletcher CD et al. Hum Pathol 2002; 33:459-65 **HPF, High Power Field of the microscope

  24. Patient disposition Category 12 Months 36 Months No. (%) No. (%) Randomized (Feb 2004 to Sep 2009) 200 200 Included in ITT Population*199 198 - No GIST at pathology review 5 (3) 10 (5) - GIST metastases at study entry 13 (7) 11 (6) Included in Efficacy Population181 177 Included in Safety Population 194 198 - On treatment at data collection cut-off 0 (0) 19 (10) Discontinued assigned treatment29 (15) 63 (32) - GIST recurred during treatment 4 (2) 12 (6) - Adverse event 15 (8) 27 (14) - Other reason 10 (5) 24 (12) *3 patients who withdrew consent excluded

  25. Baseline characteristics (ITT) Characteristic 12-Mo group 36-Mo group 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 - /50 HPFs 10 (0-250) 8 (0-165) Tumor rupture - (%) 18 22 GIST gene mutation site - (%)* - KIT exon 9 6 7 - KIT exon 11 69 71 - KIT exon 13 2 1 - PDGFRA (D842V) 13 (10) 12 (8) - wild type 10 8 *Available for 366 (92%) out of the 397 tumors

  26. SSGXVIII: Recurrence-free survival (ITT) 100 % 86.6% 36 Months 80 12 Months 65.6% 60 60.1% 47.9% 40 Hazard ratio 0.46 (95% CI, 0.32-0.65) P <.0001 Median follow-up time 54 months 20 0 Years 0 1 2 3 4 5 6 7 No. at risk (n=397) 36 Months of imatinib 198 184 173 133 82 39 8 0 12 Months of imatinib 199 177 137 88 49 27 10 0

  27. Subgroup No. of patients Hazard ratio (95% CI), RFS P value 36 mo better 12 mo better Age ≤65 256 0.47 (0.30-0.74) .001 >65 141 0.49 (0.28-0.85) .01 Sex Male 201 0.46 (0.28-0.76) .002 Female 196 0.46 (0.28-0.76) .002 Tumor site Stomach 202 0.42 (0.23-0.78) .005 Other 193 0.47 (0.31-0.73) <.001 Tumor size ≤ 10 cm 219 0.40 (0.23-0.69) <.001 >10 cm 176 0.47 (0.29-0.76) .002 Mitoses/50 HPF (local) ≤ 10 mitoses 209 0.76 (0.43-1.32) .33 > 10 mitoses 154 0.29 (0.17-0.49) <.001 Mitoses/50 HPF (central) ≤ 10 mitoses 256 0.58 (0.34-0.99) .04 > 10 mitoses 137 0.37 (0.23-0.61) <.001 Tumor rupture No 318 0.43 (0.28-0.66) <.001 Yes 79 0.47 (0.25-0.89) .02 Tumor mutation site KIT exon 9 26 0.61 (0.22-1.68) .34 KIT exon 11 256 0.35 (0.22-0.56) <.001 Wild type 33 0.41 (0.11-1.51) .16 Other 51 0.78 (0.22-2.78) .70 0.1 1.0 10 0.1 1.0 10

  28. Clinical Risk Factors and Risk-Reduction with 3 Years of Adjuvant Imatinib

  29. SSGXVIII: Overall survival (ITT) 96.3% 92.0% 100 % 94.0% 80 81.7% 60 36 Months Hazard ratio 0.45(95% CI, 0.22-0.89) P = .019 12 Months 40 20 0 Years 0 1 2 3 4 5 6 7 No. at risk (n=397) 36 Months of imatinib 198 192 184 152 100 56 13 0 12 Months of imatinib 199 188 176 140 87 46 20 0

  30. Treatment safety *Lung injury

  31. Most frequent adverse events

  32. Conclusions Compared to 1 year of adjuvant imatinib, 3 years of imatinib improves - RFS - Overall survival as treatment of GIST patients who have a high estimated risk of recurrence after surgery. Adjuvant imatinib is relatively well tolerated; severe adverse events are infrequent.

  33. Phase 3 Adjuvant Trial (EORTC 62024): Overview Inclusion criteria • Intermediate- or high-risk GIST • Completely resected • KIT-positive GIST Objectives Treatment • Primary • Time to secondary resistance • Secondary • Overall survival • Relapse-free survival • Relapse-free interval • Drug safety • Imatinib • 400 mg/day for 2 years EORTC. http://clinicaltrials.gov/ct/show/NCT00103168.

  34. Phase 3 Adjuvant Trial (EORTC 62024): Design Observation (for 2 years) Follow for 5 years after treatment to evaluate TTSR, PFS, and OS Complete resection of primary GIST Imatinib (400 mg/day for 2 years) Discontinued treatmenta • aDue to progression or unacceptable toxicity. • TTSR, time to secondary resistance; PFS, progression-free survival; OS, overall survival EORTC. http://clinicaltrials.gov/ct/show/NCT00103168.

  35. Post-Resection Evaluation of Recurrence-Free Survival for Gastro-Intestinal Stromal Tumors Treated with Adjuvant Imatinib: PERSIST-5 Resected GIST >2 cm and mitotic rate >5 or Non-gastric primary >5 cm Imatinib 400 mg/d x 5 years Register Phase II N = 85 patients Primary objective: Recurrence-free survival Adapted DeMatteo

  36. Conclusions from SSGXVIII * In GIST, 3 years of adjuvant imatinib are better than one in terms of recurrence-free and overall survival Three years of post-operative imatinib treatment represent the new gold standard for patients with resected “high-risk” GISTs The overall risk at which adjuvant imatinib should be commenced requires further clarification * Adapted from discussion by Charles Blanke, ASCO 2011

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