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A Report from ECCO 14 Oral Chemotherapy in Colorectal Cancer

A Report from ECCO 14 Oral Chemotherapy in 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 ECCO 14 Oral Chemotherapy in Colorectal Cancer

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  1. A Report from ECCO 14Oral Chemotherapy in 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. Capecitabine in the Treatment of Colorectal Cancer • ECCO 2007 trials of capecitabine in colorectal cancer • Oral vs. IV 5-FU • Adjuvant: X-ACT Trial • First-line metastatic: COFFEE Trial (SICOG) • First-line metastatic CRC • First BEAT Trial • CAIRO2 (CAPOX-B ± cetuximab) • CAIRO (sequential vs. combination chemotherapy) • Novel Approaches (XELOXIRI) • Second-line mCRC • Capecitabine dosing

  3. Capecitabine vs. IV 5-FU

  4. ECCO 14 Abstract 1LB 5-Year Overall Survival Update from the X-ACT Trial of Capecitabine vs. 5-FU/LV as Adjuvant Treatment for Stage III Colon Cancer C. Twelves, W. Scheithauer, J. McKendrick, M. Nowacki, J. Seitz, G. Van Hazel, A. Wong, E. Diaz-Rubio, J. Cassidy

  5. Capecitabine 1250 mg/m2 twice daily, d 1-14, q21d (N = 1004) Chemo-naïve Dukes C, resection ≤ 8 weeks 1° endpoint: disease-free survival (DFS) 24 weeks Bolus 5-FU/LV 5-FU 425 mg/m2 plus LV 20 mg/m2, d 1-5, q28d (N = 983) X-ACT Trial Design Twelves C, et al. ECCO 14. Abstract 1LB.

  6. Standard Eligibility Criteria • Eligible patients • Age 18–75 years • Histologically confirmed Dukes’ C colon cancer • Fully recovered after surgery • ECOG PS: ≤1 • Life expectancy ≥ 5 years • Excluded patients • Metastatic disease • Prior cytotoxic chemotherapy or organ allografts • Clinically significant cardiac disease • Severe renal impairment • Central nervous system disorders • Pregnant or lactating women Twelves C, et al. ECCO 14. Abstract 1LB.

  7. Previously Presented Primary Efficacy (ITT) and Safety Findings At a median follow-up of 3.8 years • DFS in the capecitabine group was at least equivalent to 5-FU/LV • HR = 0.87 (95% CI: 0.75–1.00) • OS in the capecitabine group was at least equivalent to 5-FU/LV • HR = 0.84 (95% CI: 0.69–1.01) • Capecitabine was associated with significantly fewer adverse events than 5-FU/LV (P < 0.001) Twelves C et al. NEJM 2005;352:2696–704.

  8. 5-year Capecitabine (N = 1004) 60.8% 5-FU/LV (N = 983) 56.7% 1.0 0.8 0.6 Estimated Probability 0.4 HR = 0.88 (95% CI: 0.77–1.01) NI margin 1.20 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Months Test of non-inferiority P < 0.0001 Test of superiority P = 0.0682 X-ACT Disease-Free Survival 5-year update – median follow-up 6.8 years (ITT) Twelves C, et al. ECCO 14. Abstract 1LB.

  9. 5-year Capecitabine (N = 1004) 71.4% 5-FU/LV (N = 983) 68.4% 1.0 0.8 0.6 Estimated Probability 0.4 HR = 0.86 (95% CI: 0.74–1.01) NI margin 1.14 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Months Test of non-inferiority P = 0.000116 Test of superiority P = 0.06 X-ACT Overall Survival 5-year update – median follow-up 6.8 years (ITT) Twelves C, et al. ECCO 14. Abstract 1LB.

  10. N Favours Capecitabine Favours 5-FU ITT population Male Female < 40 40–69 years old ≥ 70 pN1 pN2 Baseline CEA < ULN Baseline CEA > ULN 1987 1074 912 76 1513 396 1389 593 1672 155 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Hazard Ratio and 95% CI 5-year Overall Survival Subgroup Analysis Twelves C, et al. ECCO 14. Abstract 1LB.

  11. Multivariate Analysis of Overall Survival Twelves C, et al. ECCO 14. Abstract 1LB.

  12. Treatment Duration and Intensity Twelves C, et al. ECCO 14. Abstract 1LB.

  13. Treatment-related AEs 100 80 60 40 20 0 Capecitabine (N = 993) Bolus 5-FU/LV (N = 974) * * Patients (%) * * * * Diarrhea Stomatitis Hand-foot Neutropenia† Nausea / Alopecia syndrome vomiting *P < 0.001 †Laboratory value Safety Profile of Capecitabine vs. Bolus 5-FU/LV (All Grades) Scheithauer W et al. Ann Oncol 2003;14:1735–43.

  14. Systemic Treatments ( 2%) Given at Relapse Twelves C, et al. ECCO 14. Abstract 1LB.

  15. Locoregional Procedures ( 2%) at Relapse Twelves C, et al. ECCO 14. Abstract 1LB.

  16. Capecitabine (N =1004) X-ACT Bolus 5-FU/LV (N = 983) FOLFOX (N = 672) MOSAIC1 LV5FU2 (N = 675) Twelves C, et al. ECCO 14. Abstract 1LB. 1De Gramont A et al. J Clin Oncol 2007;25(18S):4007. X-ACT and MOSAICOverall Survival in Stage III Patients (ITT) 1.0 0.8 Estimated Probability 0.6 0.4 0 1 2 3 4 5 6 7 8 Years

  17. Stage III Colon Cancer • 5-FU/LV (N = 926) • Mayo Clinic bolus 5-FU/LV • Roswell Park bolus 5-FU/LV XELOX (N = 938) Capecitabine 1000mg/m2 bid d1–14 q3w + Oxaliplatin 130mg/m2 IV d1 q3w NO16968 Study Update • XELOX is feasible and safe • Similar tolerability to bolus 5-FU/LV and FOLFOX4 • Better tolerability than FLOX • Efficacy data are due at end of 2008 Schmoll H-J et al. J Clin Oncol 2007;25:102–9.

  18. X-ACT 5-year Survival UpdateConclusions • Capecitabine is known to be an effective and better tolerated alternative to bolus 5-FU/LV in the adjuvant treatment of stage III colon cancer • Update shows that capecitabine is at least equivalent to bolus 5-FU/LV with a trend to superiority (P = 0.06) in terms of 5-year overall survival • First indication in the adjuvant setting from a cross-trial comparison showing that capecitabine is equivalent to infusional 5-FU Twelves C, et al. ECCO 14. Abstract 1LB.

  19. ECCO 14 Abstract P#3044 Capecitabine or Folinic acid/Fluorouracil IV Bolus Plus Eloxatin Evaluation (COFFE trial) in Metastatic Colorectal Carcinoma (MCRC): Final Results of the Southern Italy Cooperative Oncology Group (SICOG) Phase III Trial 0401 P. Comella, B. Massidda, G. Filippelli, A. Farris, D. Natale, L. Maiorino, G. Condemi, S. Palmeri, S. Leo, A. Gambardella

  20. OXXEL Oxaliplatin 100 mg/m2 d1 + Capecitabine 1,000 mg/m2 twice daily, d 1-11 q 2-weeks (N = 150) mCRC Prior adjuvant therapy (N = 306) to disease progression OXAFAFU Oxaliplatin 85 mg/m2 d1 + Bolus 5-FU/FA 5-FU 850 mg/m2 + FA 250 mg/m2, d 2, q 2-weeks (N = 156) COFFEE Trial Study Design • Primary Endpoint: Response rate (WHO criteria) • Secondary Endpoints: PFS, QoL Comella P, et al. ECCO 14. Abstract P#3044.

  21. COFFEE Trial Baseline Characteristics Comella P, et al. ECCO 14. Abstract P#3044.

  22. COFFEE Trial Treatment Disposition Comella P, et al. ECCO 14. Abstract P#3044.

  23. P < 0.001 27% % of Patients P < 0.043 13% 10% 6% 4% 3% 3% 1% Febrile Neutropenia Anemia Neutropenia Thrombocytopenia COFFEE Trial Hematologic Toxicity Comella P, et al. ECCO 14. Abstract P#3044.

  24. % of Patients HFS Vomiting Diarrhea Stomatitis Fatigue Hepatic Neurological COFFEE Trial Non-Hematologic AEs Comella P, et al. ECCO 14. Abstract P#3044.

  25. COFFEE Trial Efficacy Comella P, et al. ECCO 14. Abstract P#3044.

  26. COFFEE Trial Progression-Free Survival Comella P, et al. ECCO 14. Abstract P#3044.

  27. COFFEE Trial Conclusions • OXXEL regimen produced a similar RR and PFS compared to OXAFAFU • RR: 34% vs. 33% • PFS: 6.2 mos. vs. 6.3 mos. • Occurrence of severe adverse events was significantly lower with OXXEL regimen (32% vs. 43%) • Although more patients went off therapy for toxicity in the OXXEL vs. OXAFAFU arm (14% vs. 6%) • OXXEL regimen resulted in significantly lower incidence of severe neutropenia (10% vs. 27%) and febrile neutropenia (6% vs. 13%), but GI symptoms were significantly more pronounced • These data provide additional support for capecitabine as an effective alternative to IV 5-FU/LV in the treatment of colorectal cancer Comella P, et al. ECCO 14. Abstract P#3044.

  28. Capecitabine in First-Line Metastatic CRC

  29. ECCO 14 Abstract P#3020 Preliminary Efficacy of Bevacizumab with First-Line FOLFOX, XELOX, FOLFIRI and Fluoropyrimidines for mCRC: First BEAT Trial S. Berry, D. Cunningham, M. Michael, A. Kretzschmar, F. Rivera, M. DiBartolomeo, M. Mazier, B. Lutiger, E. Van Cutsem

  30. First BEAT Trial Study Design • 1,965 mCRC patients from 41 countries • Accrued from June 2004 – February 2006 • First-line chemotherapy with bevacizumab until disease progression (physicians choice) • Bevacizumab at 5 mg/kg q2w for 5-FU-based CT • Bevacizumab at 7.5 mg/kg q3w with capecitabine-based CT • Regimens • FOLFOX (28%) • FOLFIRI (26%) • XELOX (18%) • 5-FU/capecitabine (15%) Berry S, et al. ECCO 14. Abstract P#3020.

  31. First BEAT Trial Results • Median TTP 11.1 mos. (1,026 events) • OS data immature; 614 patients died Berry S, et al. ECCO 14. Abstract P#3020.

  32. ECCO 14 Abstract O#3000 Randomised Phase III Study of Capecitabine, Oxaliplatin and Bevacizumab (CAPOXB) with or without Cetuximab in Advanced Colorectal Cancer (ACC), the CAIRO2 Study of the Dutch Colorectal Cancer Group (DCCG). An Interim Safety Analysis J. Tol, M. Koopman, C.J. Rodenburg, A. Cats, G.J. Creemers, C.A.M. de Swart, F.L.G. Erdkamp, L. Mol, N.F. Antonini, C.J.A. Punt

  33. CAPOX-B (N = 195) Advanced CRC No prior therapy (N = 381) CAPOX-B + Cetuximab (N = 186) CAIRO2 Study Design • Target Accrual: 755 patients • Efficacy results pending maturation of data Tol J, et al. ECCO 14. Abstract P#3000.

  34. CAIRO2 Study Interim Safety Analysis Tol J, et al. ECCO 14. Abstract P#3000.

  35. CAIRO2 Study Interim Safety Analysis • Cetuximab associated toxicities (occurring only in the CAPOX-B + Cetuximab arm) • Acneiform skin reaction: • Grade 3: 80% • Grade 4: 20% • Nail Changes • Grade 3: 27% • Grade 4: 4% Tol J, et al. ECCO 14. Abstract P#3000.

  36. CAIRO2 Study Interim Safety Analysis • Conclusions: • Toxicity was acceptable in both arms • Except for skin toxicity, no difference in the incidence of other grade 3/4 toxicities were observed between the two treatment arms • Study is ongoing Tol J, et al. ECCO 14. Abstract P#3000.

  37. Combination vs. Sequential Chemotherapy

  38. ECCO 14 Abstract O#3015 Sequential Compared to Combination Chemotherapy with Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer: A Dutch Colorectal Caner Group (DCCG) Phase III Study M. Koopman, N. F. Antonini, J. Douma, J. Wals, A. H. Honkoop, F. L. G. Erdkamp, R. S. de Jong, C. J. Rodenburg, L. Mol, C. J. A. Punt

  39. CAPIRI (N = 378) CAPOX (N = 213) mCRC No prior therapy (N = 820) Capecitabine (N = 397) Irinotecan (N = 251) CAPOX (N = 143) CAIRO Study Design • Primary Endpoint: Survival • Secondary Endpoints: PFS, RR, Safety, QoL • Sample Size: 1,298 patients in 221 centers Koopman M, et al. ECCO 14. Abstract O#3015.

  40. CAIRO StudyClinical Efficacy Koopman M, et al. ECCO 14. Abstract O#3015.

  41. CAIRO StudyConclusions • Median OS is equivalent between sequential and combination strategies • Highlights the role of effective salvage treatments in mCRC • Sequential therapy is a reasonable treatment option for patients with mCRC • Consider in good risk patients • Role of biologics in improving clinical efficacy and maintaining safety profile Koopman M, et al. ECCO 14. Abstract O#3015.

  42. Novel Chemotherapy Regimens

  43. ECCO 14 Abstract P#3063 Capecitabine (C), in Combination with Irinotecan (I) and Oxaliplatin (O) (XELOXIRI) as First-Line Treatment of Metastatic Colorectal Cancer (MCRC): Results of a Pilot Study by the Gruppo Oncologico Nord-Ovest (G.O.N.O.) S. Bursi, G. Masi, F. Loupakis, A. Antonuzzo, S. Chiara, E. Pfanner, I. Petrini, M. T. Barletta, G.G. Baldi, A. Falcone

  44. XELOXIRI Study Design • Phase I • Dose of C in combination with I and O (q 2wk regimen) • Irinotecan: 165mg/m2 d1 • Oxaliplatin 85 mg/m2 d1 • Capecitabine 2,500 mg/m2/die d1-7; then, increase to 3,000 mg/m2/die or decrease to 2,000 mg/m2/die based on DLT • Recommended dose of C was 2,000 mg/m2 • DLT: diarrhea • Phase II • 36 patients • Endpoints: RR and toxicities Bursi S, et al. ECCO 14. Abstract P#3063.

  45. XELOXIRI Study Patient Characteristics Bursi S, et al. ECCO 14. Abstract P#3063.

  46. XELOXIRI Study Toxicity per Patient Bursi S, et al. ECCO 14. Abstract P#3063.

  47. XELOXIRI Study Toxicity per Cycle Bursi S, et al. ECCO 14. Abstract P#3063.

  48. 71% XELOXIRI Study Efficacy Bursi S, et al. ECCO 14. Abstract P#3063.

  49. XELOXIRI Study Conclusions • XELOXIRI is feasible with grade 3/4 being the DLT • Recommended dose (q 2-weeks): • Capecitabine 2,000 mg/m2/die d1-7 • Irinotecan: 165mg/m2 d1 • Oxaliplatin 85 mg/m2 d1 • At this dose, XELOXIRI is feasible with manageable toxicities but requires administration of a reduced dose intensity of capecitabine compared to XELOX or XELIRI • Preliminary response rate is promising (RR: 71%) • This study is ongoing to better determine activity and safety profile of the combination at the recommended dose Bursi S, et al. ECCO 14. Abstract P#3063.

  50. Capecitabine in Second-Line Metastatic CRC

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