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J. Tabernero E. Aranda, A. Gomez, B. Massutí, J. Sastre, A. Abad,

Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC) the MACRO trial. J. Tabernero E. Aranda, A. Gomez, B. Massutí, J. Sastre, A. Abad,

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J. Tabernero E. Aranda, A. Gomez, B. Massutí, J. Sastre, A. Abad,

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  1. Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC) the MACRO trial J. Tabernero E. Aranda, A. Gomez, B. Massutí, J. Sastre, A. Abad, M. Valladares, F. Rivera, Mª J. Safont, E. Diaz-Rubio On behalf of the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD)

  2. Disclosures for J. Tabernero • Advisory Board member and lecturer for: • Sanofi-Aventis and Roche; • Merck-Serono; Amgen; Imclone; MSD; Bayer; Onyx; BMS; Boehringer; Celgene; Johnson & Johnson; Novartis; Pfizer

  3. Capecitabine Oxaliplatin Bevacizumab x6 cycles q3w Capecitabine Oxaliplatin Bevacizumab until progression N=239 R Progression Capecitabine Oxaliplatin Bevacizumab x6 cycles q3w Bevacizumab until progression N=480 N=241 Study Design

  4. Statistical analysis • Sample Size: 470 patients; 235 per arm • Non-inferiority design • Assuming 10 months as median PFS • Non-inferiority limit of 7.6 m (HR=1.32) • Alpha error = 0.025, one side • Power = 80% • Randomization 1:1 • Efficacy analysis populations: • ITT population: All randomized patients • Safety population: All patients with, at least, one dose of treatment • Statistical Analysis: • Kaplan-Meier curves • Cox model hazard ratio (if proportional assumptions are met)

  5. Study Objectives • Primary endpoint • Progression free survival* (PFS) • Secondary endpoints • Overall survival (OS) • Objective tumor response by RECIST • Time to response (TTR) • Response duration • Number of treatment cycles • Safety * Time from randomization to progression or death

  6. Inclusion Criteria • Age ≥ 18 years • Histologically confirmed metastatic colorectal adenocarcinoma • Measurable disease (RECIST) • ECOG ≤ 2 • No previous exposure to bevacizumab • No previous chemotherapy for metastatic or advanced colorectal cancer • No adjuvant chemotherapy within 6 months before randomization • No clinically significant cardiovascular disease

  7. Treatment • XELOX-BEV • Bevacizumab (BEV): 7.5 mg/kg, iv, d1 q3wk • Oxaliplatin: 130 mg/m2, iv, d1 q3wk • Capecitabine: 1000 mg/m2 oral bid, d1-14 q3wk • Administered until progression of disease, severe toxicity or consent withdrawal • s/a BEV • 6 cycles XELOX-BEV q3wk • BEV 7.5 mg/kg, iv, d1 q3wk until progression of disease, severe toxicity or consent withdrawal

  8. Pt Selected N=483 • 3 Incl / Excl criteria Pt Randomized N=480 XELOX-BEV N=239 s/a BEV N=241 ITT • 1 Incl / Excl criteria • 2 Incl / Excl criteria • 1 Other XELOX-BEV N=238 s/a BEV N=238 Safety CONSORT

  9. Patient characteristics

  10. LNI: 1.32 Patients at risk Follow-up median months (range) 21.1 (0-40)20.4 (0-38) Progression Free Survival ITT

  11. Patients at risk Follow-up median months (range) 21.1 (0-40)20.4 (0-38) Overall Survival ITT

  12. Patients % Odds ratio (95% CI)= 0.89 (0.62-1.27) 49 % 46 % Xelox-Bev(N=239) s/a Bev(N=241) Confirmed Objective Best Tumor Response (RECIST)

  13. Summary of efficacy *Odds Ratio

  14. Surgery

  15. Patients % Chemotherapy: 2nd lines

  16. Safety Treatment-related AEs XELOX-Bev(N=238) 128 (53.8) 34 (14.2) 4 (1.7) 4 (1.7) s/a Bev (N=238) 114 (47.9) 48 (19.0) 8 (3.4) 6 (2.5) n (%) AEs G3-4 SAEs AEs leading to death Death 60 days

  17. Safety: Treatment-related NCI Grade 3-4* AEs * Include grade 5

  18. Treatment compliance

  19. Conclusions • This data indicate that a priori specified non-inferiority cannot be still confirmed, but we can reliably exclude a detriment of larger than 3 weeks in PFS. • This study suggests that maintenance therapy with single agent BEV may be an appropriate option following induction XELOX-BEV in pts with mCRC. • Further studies evaluating single agent BEV after standard chemotherapy in mCRC are warranted.

  20. BACK-UP

  21. LNI HR Protocol PFS HR Macro PFS 0.89 1.11 1,37 1 1,32 s/a BEV better XELOX-BEV better PFS Non-inferiorityresults interpretation

  22. Odds ratio (95% CI)= 1.15 (0.80-1.67) Patients % 62.3 58.9 Odds ratio (95% CI)= 0.89 (0.62-1.27) 49.0 46.0 Objective Best Tumor Response (RECIST)

  23. Patients % Total (Confirmed) 56.9 (42.7) 54.4 (44.4) 27.4 25.9 5.4 (3.3) 4.6 (4.6) 7.5 5.4 Complete Partial Progression Stable Not confirmed Not confirmed Objective Best Tumor Response (RECIST)

  24. Safety: NCI Grade 3-4* AEs * Include grade 5

  25. Safety: NCI Grade 3-4 AEs * Include grade 5

  26. Safety: Treatment-related NCI Grade 3-4 AEs * Include grade 5

  27. Treatment-related AEs leading to death * Seven deaths cycles 1-6; one death cycle 42

  28. Treatment Cycles Patients %

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