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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. Rationale • Optimal duration of treatment of mCRC is still under debate • While some physicians maintain treatment until unacceptable toxicity and/or progression occurs, some others stop all or part of the drugs after patients have been treated for around 4-6 months • Bevacizumab has a good long-term safety profile and cross-study comparisons suggest that its maximum benefit may be observed when it is maintained until disease progression • This study was aimed to demonstrate that maintenance treatment with single agent bevacizumab after 6 cycles of induction chemotherapy plus bevacizumab could be a reasonable option, thus avoiding cumulative toxicity without reducing the efficacy of treatment

  3. Study Design 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

  4. Statistical design • Sample Size: • Non-inferiority design, 10 months as median PFS • Non-inferiority limit (NIL) of 7.6 m and HR = 1.32 • Alpha error = 0.025, one side • Power = 80% • Randomization 1:1 • 470 patients; 235 per arm • 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 mCRC 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 • Oxaliplatin: 130 mg/m2, iv, d1 q3wk • Capecitabine: 1000 mg/m2 oral bid, d1-14 q3wk • Bevacizumab (BEV): 7.5 mg/kg, iv, d1 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. Progression Free Survival Patients at risk Follow-up 21.1 (0-40)20.4 (0-38) median (range), months

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

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

  13. Summary of efficacy *Odds Ratio

  14. PFS Non-inferiorityresults interpretation Non-inferiority limit HR Protocol PFS HR Macro PFS 0.89 1.11 1.37 1 1.32 s/a BEV better XELOX-BEV better

  15. 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 (%) G 3-4 AEs SAEs AEs leading to death Death within 60 days

  16. G 3-4 Treatment-related AEs* *According to NCI-CTCAE v3.0 Includes grade 5

  17. Treatment compliance

  18. Oxaliplatin exposure % Cycles Reduced or Suspended Median Cumulative Dose (mg/m2) Xelox-Bev(N = 238) s/a Bev(N = 238) Xelox-Bev(Cycles = 1807) s/a Bev(Cycles = 1229)

  19. Oxaliplatin exposure (mg/m2) Cumulative dose (mg/m2) + + XELOX-BEV s/a BEV Treatment

  20. Xelox-Bev(N = 238) s/a Bev(N = 238) Bevacizumab exposure % Cycles Reduced or Suspended Median Cumulative Dose (mg/Kg) Xelox-Bev(Cycles = 2521) s/a Bev(Cycles = 2730)

  21. Xelox-Bev(N = 238) s/a Bev(N = 238) Xelox-Bev(Cycles = 2521) s/a Bev(Cycles = 2730) Capecitabine exposure % Cycles Reduced or Suspended Median Cumulative Dose (mg/m2)

  22. Surgery

  23. Patients % Treatment upon progression

  24. Conclusions • This data indicate that a priori specified non-inferiority cannot still be confirmed, but we can reliably exclude a detriment of larger than 3 weeks in median PFS • This study suggests that maintenance therapy with single agent bevacizumab may be an appropriate treatment option following induction XELOX-bevacizumab in patients with mCRC • Other studies evaluating maintenance treatment with bevacizumab after standard chemotherapy in mCRC are under recruitment/evaluation (DREAM, CAIRO-3, AIO-ML21768)

  25. E. Aranda (H. Reina Sofía) B. Massutí (H. General Universitario de Alicante) J. Sastre (H. Universitario Clínico San Carlos) A. Abad (ICO. H. Germans Trias i Pujol ) M. Valladares (C. H. Universitario) F. Rivera (H. Marqués de Valdecilla) Mª J. Safont (H. General Universitario de Valencia) P. Martínez de Prado (H. de Basurto) M. Gallén (H. del Mar) E. González (H. Virgen de las Nieves) M. Benavides (H. Universitario Carlos Haya) E. Marcuello (H. Santa Creu i Sant Pau) C. Fernández-Martos(Instituto Valenciano de Oncología) F. Losa (H. General de L'Hospitalet) P. Escudero (H. C. Universitario Lozano Blesa) A. Cervantes (H. Clínico de Valencia) A. Arrivi (F. H. Son Llatzer) R. Dueñas (H. Ciudad de Jaén) A. Lacasta (H. de Donostia) M. Llanos (H. Universitario de Canarias) A. López-Ladrón (H. Nuestra Señora de Valme) A. Anton (H. Miguel Servet) J. Tabernero (H. Universitari Vall d’Hebrón) J. Remón (H. de Mataró) C. Martín (H. del Espíritu Santo) J. Mª. Vicent (H. de Sagunto) H. Manzano (H. Son Dureta) J. Alfaro (C. Sanitari de Terrasa) Mª. J. Gómez (H. Puerta del Mar) T. García (H. Morales Meseguer) A. Velasco (H. Universitario de la Princesa) J. L. García López (H. Ramón y Cajal) D. Almenar (H. Dr. Peset) R. Vera (H. de Navarra) E. Jiménez (H. Jerez de la Frontera) A. Carrato (H. General Universitario de Elche) J. L. García Puche (H. Clínico San Cecilio) J. García-Foncillas (C. Universitaria de Navarra) V. Alberola (H. Arnau de Vilanova) M. Constenla (Complejo Hospitalario) A. Etxeberría (Instituto Oncológico) P. Bueso (H. de Barbastro) T. Checa (I. de Oncología Corachán) L. del Río (H. Virgen de los Lirios) A. Ruiz (H. de Fuenlabrada) C. Alonso (H. General de Albacete) Acknowledgments The physicians listed below cared for the patients in this study. The authors thank them for their cooperation and support: TTD Data Center: I Ruiz de Mena and S. Rodríguez Statistics and Data Management: Pivotal (N. Martin and J.J. García) Monitoring: Dynamic Solutions: A. Ríos and A. Sotés Sponsors: Roche: B. Bendahmane and G. Garcia Sanofi Aventis:O. Diez and X. Marfà

  26. BACK-UP

  27. 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)

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

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

  30. Treatment Cycles Patients %

  31. + + XELOX-BEV s/a BEV Bevacizumab

  32. + + Capecitabine + + +

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