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A Report from ASCO 2007 Adjuvant Colorectal Cancer

A Report from ASCO 2007 Adjuvant Colorectal Cancer. John L. Marshall, MD Chief, Division of Hematology/Oncology Associate Director of Clinical Research Director, Developmental Therapeutics and GI Oncology Lombardi Comprehensive Cancer Center Georgetown University Medical Center

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A Report from ASCO 2007 Adjuvant Colorectal Cancer

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  1. A Report from ASCO 2007Adjuvant Colorectal Cancer John L. Marshall, MD Chief, Division of Hematology/Oncology Associate Director of Clinical Research Director, Developmental Therapeutics and GI Oncology Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC

  2. Abstract 4007 Oxaliplatin/5-FU/LV in Adjuvant Colon Cancer: Updated Efficacy Results of the Mosaic Trial, Including Survival, with a Median Follow-up of 6-Years Aimery de Gramont, Corrado Boni, Matilde Navarro, Josep Tabernero, Tamas Hickish, Clare Topham, Andrea Bonetti, Philip Clingan, Christelle Lorenzato, Thierry André, and MOSAIC investigators

  3. Primary end-point: disease-free survival Secondary end-points: safety, overall survival • N = 2246 • Enrollment: Oct 1998–Jan 2001 • (146 centres; 20 countries) • Completely resected colon cancer • Stage II, 40%; Stage III, 60% • Age 18–75 years • KPS ≥60 • No prior chemotherapy FOLFOX4 (LV5FU2+ oxaliplatin 85 mg/m²) (N = 1,123) R LV5FU2 (N = 1,123) MOSAIC: Study Design LV5FU2: Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 days FOLFOX4: LV5FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1

  4. MOSAIC: Cut-off Dates for Efficacy Analyses André, et al. N Engl J Med 2004;350:2343–2351.

  5. Primary End-Point: Disease-Free Survival • DFS allows for a quicker determination regarding the efficacy of a new treatment • Clinical trials can be completed more quickly • Drug development time can be shortened • Better therapy can be made available to patients more quickly • DFS can be considered as an endpoint of its own merit in decreasing the high cost, quality-of life impact, and debilitating consequence of recurrent disease Sargent, et al. J Clin Oncol 2005;23:8664–8670.

  6. 0.8 0.75 r = 0.88 0.7 3-Year DFS 0.65 0.6 0.55 0.5 0.5 0.55 0.6 0.65 0.7 0.75 0.8 5-Year OS 3-Year DFS vs. 5-Year OS Sargent, et al. J Clin Oncol 2005;23:8664–8670.

  7. MOSAIC: Disease-Free Survival Events = Relapse + Second Primary Colon Cancer + Death by any cause Andre, et al. N Engl J Med 2004;350:2343–2351.

  8. 1.0 0.9 P = 0.003 0.8 5.9% 0.7 0.6 0.5 Probability Events FOLFOX4 304/1123 (27.1%) LV5FU2 360/1123 (32.1%) HR [95% CI]: 0.80 [0.68–0.93] 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 Disease-Free Survival (months) MOSIAC: Disease-Free Survival (ITT) Data cut-off: June 2006

  9. 1.0 P = 0.258 3.8% 0.9 0.8 P = 0.005 0.7 7.5% 0.6 Probability 0.5 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III 0.4 0.3 HR [95% CI] P-value Stage II 0.84 [0.62–1.14] 0.258 Stage III 0.78 [0.65–0.93] 0.005 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months MOSIAC: Disease-Free SurvivalStage II and Stage III Patients Data cut-off: June 2006

  10. 1.0 7.2% 0.9 0.8 0.7 FOLFOX4 (N = 286) LV5FU2 (N = 290) 0.6 • High-Risk Stage II – defined as at least one of the following: • T4 • Tumor perforation • Bowel obstruction • Poorly differentiated tumor • Venous invasion • <10 lymph nodes examined 0.5 Probability 3-year 5-year FOLFOX4 85.4% 82.1% LV5FU2 80.4% 74.9% HR [95% CI]: 0.74 [0.52–1.06] 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Disease-Free Survival (months) MOSIAC: Disease-Free SurvivalHigh-Risk Stage II Patients Exploratory analysis Data cut-off: June 2006

  11. MOSIAC: Long-Term Safety Peripheral Sensory Neuropathy Second Cancer De Gramont A, et al. ASCO 2007. Abstract #4007. Data cut-off: January 2007

  12. 1.0 P = 0.057 0.9 0.8 2.6% 0.7 0.6 0.5 Probability 0.4 Events FOLFOX4 243/1123 (21.6%) LV5FU2 279/1123 (24.8%) HR [95% CI]: 0.85 [0.72–1.01] 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Overall Survival (months) MOSIAC: Overall Survival(ITT) Data cut-off: January 2007 De Gramont A, et al. ASCO 2007. Abstract #4007.

  13. 1.0 P = 0.996 0.1% 0.9 P = 0.029 0.8 0.7 4.4% 0.6 0.5 Probability FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III 0.4 HR [95% CI] Stage II 1.00 [0.71–1.42] Stage III 0.80 [0.66–0.98] 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Overall Survival (months) MOSIAC: Overall SurvivalStage II and Stage III Data cut-off: January 2007 De Gramont A, et al. ASCO 2007. Abstract #4007.

  14. MOSIAC: Conclusions For FOLFOX4 vs. LV5FU2: • The DFS benefit at 3-years was maintained at 5-years • Trend showing improved DFS in “high-risk” stage II patients • Significant OS benefit in stage III patients • No increase in the rate of secondary cancers • Continued recovery from sensory neuropathy De Gramont A, et al. ASCO 2007. Abstract #4007.

  15. Abstract 4022 Tissue Biomarkers (BIOM) in Colon Cancer (COC): The Translational Study on the Randomized Phase III Trial Comparing Infused Irinotecan/5-fluorouracil (5-FU)/Folinic Acid (FA) to 5-FU/FA in Stage II-III COC Patients (Pts) (PETACC 3 - EORTC 40993 -SAKK 60-00) A.D. Roth1, S. Tejpar2, P. Yan3, R. Fiocca4, D. Dietrich5, G. Bodoky6, R. Labianca7, D. Cunningham8, E. Van Cutsem2, F. Bosman3 1Oncosurgery, Geneva University Hospital, Geneva, Switzerland, 2Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium, 3Dpt of Pathology, Lausanne University, Lausanne, Switzerland, 4Dpt of Surgical and Morphological Sciences, University of Genova, Genova, Italy, 5Swiss Group of Clinical Cancer Research, Bern, Switzerland, 6Oncology, St Lazlo Hospital, Budapest, Hungary, 7Unit of Medical Oncology, Ospedali Riuniti, Bergamo, Italy, 8Medical Oncology, The Royal Marsden Hospital, Sutton, United Kingdom.

  16. Methods (1) • FFPE tissue blocks prospectively collected and cut in 5-20µ sections • Immunohistochemistry (IHC) • P53: mouse mAb clone D07, ABC Basic DAB Detection (Ventana medical system) • SMAD4: mouse mAb clone B8 (IgG1, Santa Cruz Biotechnology). Novocastra polymer detection kit • Thymidylate Synthetase (TS): Monoclonal antibody TS 106/4H4B1 (IgG1, Zymed). DAKO EnVision detection system • Telomerase (HTERT): Monoclonal antibody NCL-hTERT (IgG2, Novocastra). DAKO EnVision detection system Roth AD, et al. ASCO 2007. Abstract #4022.

  17. Methods (2) • DNA was extracted with phenol/chloroformfrom normal (Nor) and tumoral (Tu) tissues after microdissection of FFPE sections • Molecular analysis: • Microsatellite Instability (MSI): assessed on 10 markers • (BAT-25, BAT-26, D5S346, D2S123, D17S250, BAT-40, TGF-ß RII, D18S58, D18S69, D17S787) • 18q and 8p LOH: multiple SNPs typing by pyrosequencing on Nor/Tu DNA • KRAS exon 2 and BRAF exon 15: Allele specific real time PCR on Tu DNA • UGT1A1 7/7 genotype: PCR and fragment sizing on Nor DNA Roth AD, et al. ASCO 2007. Abstract #4022.

  18. Analysis Success Rate • 1,530 patient slides analyzed by IHC • DNA successfully extracted from 1,201 patient slides (91.2%) Roth AD, et al. ASCO 2007. Abstract #4022.

  19. Biomarker Alteration Observed (Mutation, Expression, or Deletion) * Intense expression, More than 45% cells positive ** Any loss *** Positive = more than 25% cell positive Roth AD, et al. ASCO 2007. Abstract #4022.

  20. 1.0 / 0.9 / / 0.8 / / / / / / / / / / / / / / / 0.7 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / Proportion Disease-Free / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / 0.6 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / 0.5 / / / / / / / / / / / / No Expression Expression Present 0.4 Day 0 500 1500 1000 At Risk: 145 95 57 2 817 663 449 38 SMAD4: Preliminary Results (Stage III) Roth AD, et al. ASCO 2007. Abstract #4022.

  21. 1.0 / / / 0.9 / / 0.8 / / / / / / / / / / / / / / / / Proportion Disease-Free / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / 0.7 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / 0.6 Stable/Low High Day 0.5 1500 0 500 1000 At Risk: 753 595 396 33 104 89 61 3 MSI: Preliminary Results(Stage III) Roth AD, et al. ASCO 2007. Abstract #4022.

  22. Abstract 4008 Time-dependent Patterns of Failure and Treatment Benefit from Adjuvant Therapy for Resectable Colon Cancer: Lessons from the 20,800 Patient ACCENT Dataset D Sargent, for the Adjuvant Colon Cancer Endpoints (ACCENT) Group

  23. No Treatment Control Active Control Trial N Trial N N784852 247 NSABP C03 1,081 INT 0035 926 NSABP C04 2,151 N874651 408 NSABP C05 2,176 Siena 239 N894651 915 NCIC 359 N914653 878 FFCD 259 SWOG 9415 1,078 NSABP C01 773 INT 0089 3,547 NSABP C02 718 GERCOR 905 GIVIO 867 QUASAR 3,517 ACCENT Dataset Trials Included Total: 18 trials; 20,898 pts Sargent D, et al. ASCO 2007. Abstract #4008.

  24. Three Questions Facing Adjuvant Colon Cancer Trialists • Nature and duration of treatment benefit on overall survival (OS), disease-free survival (DFS) • Long-term recurrence rates • Adequacy of statistical assumptions, using DFS endpoint Sargent D, et al. ASCO 2007. Abstract #4008.

  25. Overall Survival Disease-Free Survival Surgery Alone Arms Surgery Alone Arms 0.0006 0.0006 5-FU Based Rx Arms 5-FU Based Rx Arms 0.0004 0.0004 Hazard Rate Hazard Rate 0.0002 0.0002 0.0 0.0 0 2 4 6 8 0 2 4 6 8 Follow-up Time (Years) Follow-up Time (Years) Hazard Rates for OS and DFS Sargent D, et al. ASCO 2007. Abstract #4008.

  26. Recurrence Rate by Time from Randomization(All Patients) • After 5 years, recurrence rates < 1.5% / year • After 8 years, recurrence rates < 0.5% / year Sargent D, et al. ASCO 2007. Abstract #4008.

  27. Adequacy of Statistical ModelsConclusions • Similar exercises demonstrated < 2% power loss due to non-constant risk of event • Real world impact of DFS endpoint on trial design, for range of treatment effects observed in ACCENT, is minimal • Continued use of standard approaches for sample size determination remains appropriate Sargent D, et al. ASCO 2007. Abstract #4008.

  28. Abstract 4009 Survival Following Recurrence in Patients with Adjuvant Colon Cancer: Findings from the ACCENT Dataset MJ O’Connell, for the ACCENT Collaborative Group

  29. No Treatment Control Active Control Trial N Trial N N784852 247 NSABP C03 1,081 INT 0035 926 NSABP C04 2,151 N874651 408 NSABP C05 2,176 Siena 239 N894651 915 NCIC 359 N914653 878 FFCD 259 SWOG 9415 1,078 NSABP C01 773 INT 0089 3,547 NSABP C02 718 GERCOR 905 GIVIO 867 QUASAR 3,517 ACCENT Dataset Trials Included Total: 17 trials; 17,381 pts O’Connell M, et al. ASCO 2007. Abstract #4009.

  30. Prognostic Factors Examined • Time from randomization on surgical adjuvant protocol to tumor recurrence (<1, 1-2, 2-3, 3-4, >4 years) • Initial stage of colon cancer (II, III) • 5-FU-based adjuvant therapy vs. surgery alone • Era patient entered onto surgical adjuvant protocol (1978-1985, 1986-1992, 1993-1999) O’Connell M, et al. ASCO 2007. Abstract #4009.

  31. 100 Year 0- 1 (N = 1,846) Year 1-2 (N = 1,854) Year 2-3 (N = 924) Year 3-4 (N = 516) Year 4+ (N = 582) Total (N = 5,722) 80 60 % Alive 40 P < 0.0001 20 0 0 1 2 3 4 5 6 7 8 Time (Years) Time from Recurrence to Deathby Year of Recurrence O’Connell M, et al. ASCO 2007. Abstract #4009.

  32. 100 Year 0-1 (N = 311) Year 1-2 (N = 351) Year 2-3 (N = 198) Year 3-4 (N = 118) Year 4+ (N = 175) Total (N = 1,153) 80 60 % Alive 40 P = 0.1368 20 0 0 1 2 3 4 5 6 7 8 Time (Year) Time from Recurrence to Death byYear of Recurrence for Stage II Patients O’Connell M, et al. ASCO 2007. Abstract #4009.

  33. 100 Year 0-1 (N = 1,533) Year 1-2 (N = 1,499) Year 2-3 (N = 724) Year 3-4 (N = 394) Year 4+ (N = 400) Total (N = 4,550) 80 60 % Alive 40 P < 0.0001 20 0 0 1 2 3 4 5 6 7 8 Time (Year) Time from Recurrence to Death byYear of Recurrence for Stage III Patients O’Connell M, et al. ASCO 2007. Abstract #4009.

  34. 100 Stage II (N = 1,153) Stage III (N = 4,550) Total (N = 5,703) 80 60 % Alive 40 P < 0.0001 20 0 0 1 2 3 4 5 6 7 8 Time (Years) Time from Recurrence to Death by Stage O’Connell M, et al. ASCO 2007. Abstract #4009.

  35. 100 1978-1985 (N = 628) 1986-1992 (N = 3,904) 80 1993-1999 (N = 1,190) Total (N = 5,722) 60 % Alive 40 P < 0.0001 20 0 0 1 2 3 4 5 6 7 8 Time (Years) Time from Recurrence to Death by Era O’Connell M, et al. ASCO 2007. Abstract #4009.

  36. 100 Surgery Alone (N = 916) Adjuvant Treatment (N = 754) Total (N = 1,670) 80 60 % Alive 40 P < 0.0005 20 0 0 1 2 3 4 5 6 7 8 Time (Years) Time from Recurrence to Death byAdjuvant Treatment vs. Surgery Alone O’Connell M, et al. ASCO 2007. Abstract #4009.

  37. Conclusions • Time from initial surgery and stage of the primary colon cancer were important prognostic variables in patients with recurrent colon cancer • Patients who have recurrent tumor following 5-FU-based adjuvant therapy had worse prognosis than those without adjuvant chemotherapy • Survival following recurrence improved from 1978-1999 O’Connell M, et al. ASCO 2007. Abstract #4009.

  38. Abstract 4019 The Impact of Dietary Patterns on Cancer Recurrence and Survival in Patients with Stage III Colon Cancer: Findings from CALGB 89803 Jeffrey A. Meyerhardt1, Donna Niedzwiecki2, Donna Hollis2, Leonard B. Saltz3, Walter Willett4, Robert J. Mayer1, Charles S. Fuchs1 1Dana-Farber Cancer Institute, Boston, MA; 2CALGB Statistical Center, Durham, NC; 3Memorial Sloan-Kettering Cancer Center, New York, NY; 4 Harvard School of Public Health, Boston, MA

  39. Pearson Correlation Coefficients for the Relationship Between Food Intake and Factors Representing Dietary Patterns *values < 0.15 are not shown (---). † Vegetables other than yellow, cruciferous, or leafy-green vegetables. ‡ Potato, corn chips, crackers, or popcorn. Meyerhardt J, et al. ASCO 2007. Abstract #4019.

  40. Impact of Western Pattern Diet on Colon Cancer Recurrence and Mortality Meyerhardt J, et al. ASCO 2007. Abstract #4019.

  41. Impact of Prudent Pattern Diet on Colon Cancer Recurrence and Mortality Meyerhardt J, et al. ASCO 2007. Abstract #4019.

  42. Adjuvant Colorectal CancerClosing Comments John L. Marshall, MD

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