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ASCO 2009 – GI Highlights

ASCO 2009 – GI Highlights. Eileen M. O’Reilly, M.D. Associate Member Memorial Sloan-Kettering Cancer Center Associate Professor Weill Medical College of Cornell University. CONKO-004.

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ASCO 2009 – GI Highlights

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  1. ASCO 2009 – GI Highlights Eileen M. O’Reilly, M.D. Associate Member Memorial Sloan-Kettering Cancer Center Associate Professor Weill Medical College of Cornell University

  2. CONKO-004

  3. A Randomized Prospective Trial of Chemotherapy +/- LMWH, Enoxaparin, in Patients with Advanced Pancreas Adenocarcinoma (LBA #4506) H. Riess, U. Pelzer. G. Deutschinoff, B. Opitz, M. Stauch, P. Rietzig, S. Hahnfeld, A. Hilbig, J. Stieler, H. Oettle

  4. Cancer, PC & Thromboses • VTE in malignancy related to poor prognosis • 12% vs 36% I-yr OS for VTE vs no VTE in Ca pts • Data suggest improved outcome in PC with the addition of anticoagulation to systemic tx • Retrospective review in metastatic PC • Addition of LMWH to chemotherapy improved survival from 3.8 → 6.6 mths (p= 0.006) Sorensen, et al. NEJM, 2000. Chew, et al. Arch Int Med, 2006. Von Delius, et al. Thromb Haemost, 2007

  5. Study Endpoints • Primary endpoint • Symptomatic venous thromboembolism (VTE) within the first 3 months of chemotherapy • Secondary endpoints • VTE in the first 6, 9 and 12 mths • Major bleeding within 3, 6, 9 and 12 mths • PFS, OS, RR • Toxicity Riess, et al. ASCO, 2009 (LBA #4506)

  6. Systemic Therapy + Enoxaparin* R A N D O M I Z E Systemic Therapy CONKO-004 (LBA #4506) Stratify N= 540 (planned) • Locally advanced vs M1 • Primary vs Relapsed • PS 80- 100% vs 60- 70% • Creatinine level ≤/ > ULN *Enoxaparin 1 mg/kg/day for 3 mths → 40 mg/day until POD Riess, et al. ASCO, 2009 (LBA #4506)

  7. Study Treatment • Treatment allocation based on PS + creatinine • For pts with PS ≥ 80% and creat ≤ ULN • Gemcitabine, 5FU/LV, Cisplatin (GFFC); d 1,8,22 • For pts with PS of 60 - < 80% or creat > ULN • Gemcitabine (G); d 1,8, 5, q 28 • Experimental arm • Enoxaparin 1 mg/kg for 12 weeks → 40 mg SQ El Rayes, et al. J Clin Oncol, 2003. Araneo, et al. Can Invest, 2003. Riess et al. ASCO, 2009 (LBA #4506)

  8. Eligibility • Histologically proven PC • Measurable disease • No prior systemic therapy • KPS ≥ 60% • Adequate hematologic, hepatic function • No VTE within previous 2 years • No major haemorrhage, no aspirin > 500mg • Calculated creatinine clearance > 30 ml/min • No indication for anticoagulation Riess, et al. ASCO, 2009 (LBA #4506)

  9. Biostatistics • Hypothesis: Significant decrease in symptomatic VTE from 10% → 3% with LMWH • Sample size: N= 540, 1: 1 ratio,15% dropout or 24 pts with VTE • Stratify: KPS 60- 70% vs 80- 100%; M0 vs M1; Primary vs Recurrent; Creat ≤ / > ULN Riess, et al. ASCO, 2009 (LBA #4506)

  10. Study Conduct • Open-label, randomized phase II • Recruitment 4/04- 1/09, 33 centers • Date of analysis 4/09 Riess, et al. ASCO, 2009 (LBA #4506)

  11. Demographics (N= 312) Recruitment ceased 1/09 (24 VTE episodes) Riess, et al. ASCO, 2009 (LBA #4506)

  12. Gemcitabine (N= 57) PS 60-70% or creat > ULN Gemcitabine, Cis, 5-FU (N= 255) PS ≥ 80% and creat ≤ ULN CONKO-004 (N= 312) Gemcitabine (N= 27) Gemcitabine + Enoxaparin (N= 30) Gem, Cis, 5-FU, LV (N= 125) Gem, Cis, 5-FU + Enoxaparin (N= 130) Riess, et al. ASCO, 2009 (LBA #4506)

  13. VTE in the first 3 Months 1 pt had DVT + PE. 18 events in 17 pts Riess, et al. ASCO, 2009 (LBA #4506)

  14. VTE in the first 3 Months • Observation 9.9% vs 1.3% in enoxaparin arm • p< 0.01 • Difference of 8.6% between two arms • Relative risk reduction of 87% • VTE according to chemotherapy • Gemcitabine 12.4% vs 6.6% Gem,Cis,5FU,LV • Poor PS pts – more VTE Riess, et al. ASCO, 2009 (LBA #4506)

  15. Major Bleeding Events (3 months) 9 non-fatal, *1 fatal upper GI haemorrhage (observation arm) Riess, et al. ASCO, 2009 (LBA #4506)

  16. Overall Results (Med f/up 34 wks) 3 fatal haemorrhages: *2 tumor-related lethal GI bleeds in two GFFC pts (12.4, 13.4 wks) #1 lethal GI haemorrage in a gemcitabine-treated pt (16.7 wks) Riess, et al. ASCO, 2009 (LBA #4506)

  17. CONKO-004 Conclusions • Advanced PC high risk of symptomatic VTE • PS may be more powerful predictor of VTE risk over treatment intensity • Enoxaparin 1mg/kg/day significant reduces clinically relevant VTE • No undue safety concerns observed • Impacts of enoxaparin prophylaxis on RR, PFS, OS immature

  18. Interpretation CONKO-004 • Early data reassuring regarding safety • Need maturity to assess impact on PFS, OS • Low dose of enoxaparin? • No change in standard practice for advanced disease for now

  19. Neuroendocrine

  20. Placebo-Controlled, Double-Blind, Prospective Randomized Study of the Effect of Octreotide LAR in the control of tumor growth in patients with Metastatic Neuroendocrine Midgut Tumors:A Report from the PROMID Study Group Rudolf Arnold for the PROMID Study Group Department of Internal Medicine, Philipps University, Marburg, Germany

  21. Octreotide LAR • Binds somatostatin receptors 2, 5 • FDA-approved for functional tumors for symptomatic relief • Indicated for progressive metastatic non-functioning NET’s • Anti-proliferative value not well established • No well-designed phase III trials to answer question in midgut NET’s

  22. Promid Study (Abst #4508) Octreotide LAR 30mg IM q 4 wks (N= 42) R A N D O M I Z E Midgut NET‘s N= 85 Placebo IM q 4 wks (N= 43) Randomized phase III, placebo-controlled, double-blind Midgut NET’s: Jejunem, ileum, appendix, right colon Primary Endpoint: TTP Secondary Endpoints: RR (WHO), OS Arnold, et al. ASCO, 2009 (Abst #4508)

  23. PROMID Study 18 centers in Germany from 2001 to 2008 85 patients treated from a planned 162 accrued Planned Interim Analysis Based on 67 POD and 16 observed deaths Log-rank test, planned group sequential analysis at level of 0.0122 ASCO 2009: updated results

  24. Patient Population • Untreated, metastatic, well-diff midgut NET’s • Histologic confirmation • Functional or non-functional • Primary tumor located in the mid-gut • No curable therapeutic intervention feasible • Measurable disease by CT or MRI Arnold, et al. ASCO, 2009 (Abst #4508)

  25. Study Endpoints • Primary endpoint • Time-to-tumor progression • Secondary endpoints • Survival • Objective responses (WHO) • Biochemical response • Symptom control • Quality of life • Safety

  26. Patient Demographics

  27. 1 0.75 0.5 0.25 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Octreotide LAR 30mg Significantly Increases Time to Tumor Progression Octreotide LAR vs placebo P=0.000017 HR= 0.33 [95% CI: 0.19–0.55] Octreotide LAR: 42 patients / 27 events Median 15.6 months [95% CI: 11.0–29.4] Placebo: 43 patients / 41 events Median 5.9 months [95% CI: 5.5–9.1] Proportion without progression Time (months) Based on Intention to treat analysis

  28. PROMID: TTP Arnold,et al. ASCO, 2009 (Abst #4508)

  29. PROMID: Response Rates Arnold, et al. ASCO, 2009 (Abst #4508)

  30. Is the Treatment Effect Homogenous across Subgroups? • Benefit of octreotide LAR versus placebo seen irrespective of • Functioning or non-functioning NETs • Elevated or non-elevated CgA • Most favorable outcome in patients with • Hepatic tumor load ≤10%: HR= 0.21 • Resected primary: HR= 0.16

  31. 1 1 0.75 0.75 0.5 0.5 0.25 0.25 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Octreotide LAR Lengthens TTP in Patients with Functioning and Non-Functioning Midgut NETs Patients with functioning tumors Patients with non-functioning tumors Octreotide LAR: 17 patients / 11 events Median TTP 10.35 months Placebo: 16 patients / 14 events Median TTP 5.45 months Octreotide LAR: 25 patients / 9 events Median TTP 27.14 months Placebo: 27 patients / 24 events Median TTP 7.21 months Proportion without progression Proportion without progression Time (months) Time (months) P= 0.0008; HR= 0.27 [95% CI: 0.12–0.61] P= 0.0007; HR= 0.23 [95% CI: 0.09–0.57] Based on the per protocol analysis

  32. Safety Consistent with Established Octreotide LAR Profile • No treatment-related deaths • Treatment was discontinued because of AE’s in 5 of 42 octreotide LAR recipients and no placebo recipients • Most frequent serious AEs affected • GI tract (octreotide LAR n= 6; placebo n= 8) • Hematopoietic system (octreotide LAR n= 5; placebo n=1 ) • General health status, e.g. fatigue, fever (octreotide LAR n= 8; placebo n= 2) • Serious AE’s in 11 octreotide LAR and 10 placebo pts

  33. Summary • Octreotide LAR 30mg significantly improves TTP in metastatic well-differentiated midgut NETs • 67% reduction in POD for octreotide LAR pts • Regardless of functional status • Overall survival – difficult to assess given cross-over from placebo to octreotide LAR at progression • Observed safety findings similar to those seen in previous studies of octreotide LAR in NETs

  34. Interpretation • Strengths – placebo-controlled, double-blinded, central radiology review, homogenous NET’s • Limitations – small numbers, cross-over, not powered for survival, imbalance in time prior to enrollment • An option to initiate octreotide LAR for newly diagnosed NET’s

  35. RADIANT 2 Trial R A N D O M I Z E Octreotide LAR + Everolimus Advanced Carcinoid (progressive) N= 390 Octreotide LAR + Placebo Primary Endpoint: PFS Accrual completed – Results awaited Yao, et al (PI)

  36. SWOG 0518 R A N D O M I Z E Octreotide LAR + Bevacizumab Advanced Poor Prognosis Carcinoid N= 287 Octreotide LAR + IFN α-2b Primary Endpoint: PFS Ongoing recruitment Yao, et al (PI)

  37. ESPAC-3

  38. ESPAC-3(v2) A Multicentre, International, Open-label, Randomised Controlled Phase III Trial of Adjuvant 5-Fluorouracil/Folinic acid (5-FU/FA) vs Gemcitabine (GEM) in Patients with Resected Pancreatic Ductal Adenocarcinoma European Study Group for Pancreatic Cancer CR-UK Liverpool Cancer Trials Unit

  39. Background ESPAC-1 compared chemotherapy [5FU/FA ] with chemoradiation Using a 2x2 factorial design Observation Chemotherapy (CT) Chemoradiotherapy (CRT) CRT CT

  40. ESPAC-1 Lancet, 2001 No benefit for Chemoradiation – Potential benefit for Chemotherapy Lancet, 2001;358(9293):1576-85

  41. ESPAC-3(v1) Trial Design Patients with ductal adenocarcinoma undergoing ‘curative’ resection Target N=990 RANDOMISE 5FU/ FA 5-FU 425mg/m2 & FA 20mg/m2 for 5 days every 28 days for 6 cycles Target N=330 GEMCITABINE 1000mg/m2 once a week for 3 of 4 weeks for 6 cycles Target N=330 OBSERVATION Target N=330 330 per arm to detect 10% difference in 2y survival rate (= 5%, 1-b= 80%) Trial opened July 2000

  42. Eligibility Complete macroscopic resection for pancreatic ductal adenocarcinoma (WHO Classification) R0 or R1 resection No: ascites, liver or peritoneal metastasis, or any other distant abdominal or extra-abdominal organ spread No previous or concurrent malignancy diagnoses WHO performance status < 2 Life-expectancy of more than 3 months Fully informed written consent

  43. ESPAC-1 ESPAC-1 NEJM 2004: No benefit for Chemoradiation confirmed Survival rates 2-year 5-year No CRT: 41.4% 19.6% CRT: 28.5% 10.0% HR=1.28 (0.99, 1.66), p=0.053 NEJM 2004; 350:1200-10

  44. ESPAC-1 ESPAC-1 NEJM 2004: Benefit for Chemotherapy confirmed Survival rates 2-year 5-year No CT: 30.0% 8.4% CT: 39.7% 21.1% HR=0.71 (0.55, 0.92), p=0.009 NEJM 2004; 350:1200-10

  45. Impact • OBSERVATION arm closed on DMC advice June 2003 (n=61) • Target recruitment updated to detect 10% difference in survival at 2-years with 90% power, DMC July 2005 • Updated Target: 515 pancreatic ductal adenocarcinoma patients (275 events) per chemotherapy group

  46. ESPAC-3(v2) Trial Design Patients with ductal adenocarcinoma undergoing ‘curative’ resection Target N=1030* RANDOMISE 5FU/ FA Target N=515 Actual=551 GEMCITABINE Target N=515 Actual N=537 3-monthly follow-up to death 515 per arm to detect 10% difference in 2y survival rate ( = 5%, 1-b = 90%) *Actual N=1088

  47. Patient Demographics 5FU/FA GEM TOTAL n=551 n=537 n=1088 Age (years)63 (34-85)63 (31-81) 63 (31-85) Sex Male 301 (55%)297 (55%) 598 (55%) Female 250 (45%)240 (45%) 490 (45%) Baseline PS † 0 200 (36%)167 (31%) 367 (34%) 1 286 (52%)303 (57%) 589 (54%) 2 64 (12%)64 (12%) 128 (12%) Smoking †Never207 (43%)189 (40%) 396 (41%) Past 192 (39%)207 (44%) 399 (42%) Present 87 (18%)78 (16%) 165 (17%) Surgery to Rand (days) 45 (4-114)45 (5-98) 45 (4-114) † Significant prognostic variable

  48. Tumor Pathology 5FU/FA GEM TOTAL n=551 n=537 n=1088 Stratification factor: R Status † R0 356 (65%)348 (65%) 704 (65%) R1 195 (35%)189 (35%) 384 (35%) Max Tumour Size (mm) † 30 (2-350)30 (2-105) 30 (2-350) Grade † Well 81 (15%)66 (13%) 147 (14%) Mod 327 (60%)336 (63%) 663 (62%) Poor 135 (25%)125 (24%) 260 (24%) Undiff2 (0%)2 (0%) 4 (0%) Nodes † Neg161 (29%) 144 (27%) 305 (28%) Pos 387 (71%)391 (73%) 778 (72%) † Significant prognostic variable

  49. On-Study Data 5FU/FA GEM TOTAL n=551 n=537 n=1088 Diabetic No 388 (75%)375 (75%)763 (75%) Non-insulin dep54 (11%)51 (10%)105 (10%) Insulin dep72 (14%) 73 (15%)145 (14%) Surgery Whipples286 (56%) 295 (59%)581 (58%) Pylorus Pres 158 (31%) 147 (30%)305 (30%) Total Panc27 (5%)14 (3%) 41 (4%) Distal Panc40 (8%)39 (8%) 79 (8%) Local Invasion †No 297 (58%) 284 (57%)581 (58%) Yes 213 (42%) 215 (43%)428 (42%) Post-op Comps No 396 (78%) 364 (74%)760 (76%) Yes 112 (22%) 130 (26%)242 (24%)

  50. χ2LR = 31.8, p<0.001 χ2LR = 24.2, p<0.001 χ2LR = 52.7, p<0.001 χ2LR = 16.3, p<0.001

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