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.

Presentación del tema: "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."— Transcripción de la presentación:

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 Progression R Capecitabine Oxaliplatin Bevacizumab x6 cycles q3w Bevacizumab until progression N=480 N=239 N=241 Capecitabine Oxaliplatin Bevacizumab x6 cycles q3w Capecitabine Oxaliplatin Bevacizumab until progression

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/m 2, iv, d1 q3wk –Capecitabine: 1000 mg/m 2 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 CONSORT Pt Selected N=483 Pt Randomized N=480 XELOX-BEV N=239 s/a BEV N=241 XELOX-BEV N=238 s/a BEV N=238 ITT Safety 2 Incl / Excl criteria 1 Other 1 Incl / Excl criteria 3 Incl / Excl criteria

9 Patient characteristics XELOX-BEV (N=239) s/a BEV (N=241) Age median (range), years63 (30-80)64 (33-82) Sex: Male/Female, %64/36 ECOG PS 0/1/2 %49/49/259/39/2 Primary tumor rectum/colon/both % 31/57/1223/67/10 Metastases confined to liver %3935 Previous Adjuvant CT / RDT %13/817/8 Nº of organs affected2 (1-5)3 (1-12) Surgery of primary tumor %6975

10 Progression Free Survival Follow-up 21.1 (0-40) 20.4 (0-38) median (range), months Patients at risk

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

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

13 Summary of efficacy XELOX-BEV (N=239) s/a BEV (N=241) HR (95% CI) PFS median Events % 10.4 (9.3-11.9) 67% 9.7 (8.5-10.6) 72% 1.11 (0.89–1.37) OS median Events % 23.4 (20.0-26.0) 55% 21.7 (18.3-25.1) 54% 1.04 (0.81–1.32) Confirmed OR % 46%49%0.89 (0.62-1.27)* *Odds Ratio

14 PFS Non-inferiority results interpretation 1 0.891.111.37 1.32 HR Protocol PFS HR Macro PFS XELOX-BEV better s/a BEV better Non-inferiority limit

15 Safety XELOX-Bev (N=238) 128 (53.8) 34 (14.2) 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 Treatment-related AEs

16 G 3-4 Treatment-related AEs* XELOX-BEV N=238 s/a BEV N=238 N%N% Paresthesia 5924.8187.6 Diarrhea 2610.93313.9 Hand-foot syndrome 2912.2166.7 Fatigue 2410.5104.2 Hypertension 93.8177.1 Protenuria 10.441.7 Thrombosis 20.831.3 GI perforation 20.810.4 Bleeding 10.41 *According to NCI-CTCAE v3.0 Includes grade 5

17 Treatment compliance XELOX-BEV (N=238) s/a BEV (N=238) Total cycles administered induction + maintenance phases, median (range) 9 (1-37) 10 (1-53) Induction phase cycles, median (range) 6 (1-6) 6 (1-6) Maintenance phase cycles, median (range) 3 (0-31) 4 (0-47)

18 Oxaliplatin exposure Xelox-Bev (Cycles = 1807) s/a Bev (Cycles = 1229) % Cycles Reduced or Suspended Xelox-Bev (N = 238) s/a Bev (N = 238) Median Cumulative Dose (mg/m 2 )

19 XELOX-BEV s/a BEV + + (mg/m 2 ) Oxaliplatin exposure Mean (CI 95%) Median XELOX-BEV 893 (833 - 951) 800 s/a BEV 649 (621 - 678) 770 Treatment Cumulative dose (mg/m 2 )

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

21 Capecitabine exposure Xelox-Bev (Cycles = 2521) s/a Bev (Cycles = 2730) Xelox-Bev (N = 238) s/a Bev (N = 238) % Cycles Reduced or Suspended Median Cumulative Dose (mg/m 2 )

22 Surgery XELOX-BEV (N=239) s/a BEV (N=241) Salvage surgery N (%)28 (11.7)23 (9.5) R0 surgery N (%)21 (8.8)14 (5.8) Site: Liver N (%) Lung N (%) Other N (%) 25 (10.5) 2 (0.8) 1 (0.4) 18 (7.5) 2 (0.8) 3 (1.2) Time to surgery median (range), months 6.8 (3.5-30-0) 8.7 (3.8-17.6)

23 Treatment upon progression Patients %

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 Acknowledgments 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) 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

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27 Objective Best Tumor Response (RECIST) Not confirmed CompletePartial Stable Progression Patients % Total (Confirmed) 5.4 (3.3) 4.6 (4.6) 56.9 (42.7) 54.4 (44.4) 25.9 27.4 7.5 5.4 XELOX-BEV N=239 s/a BEV N=241 N (%) N (%) Odds Ratio (CI95%) OR Total 149 (62.3%) 142 (58.9%) 1.15 (0.80 - 1.67) OR Confirmed 110 (4.0%) 118 (49.0%) 0.89 (0.62 - 1.27)

28 Safety: NCI Grade 3-4 AEs XELOX-BEV N=238s/a BEV N238 NCI Grade 3NCI Grade 4*NCI Grade 3NCI Grade 4* N%N%N%N% NEUROPATHY SENSORY 5924.8..187.6.. DIARRHEA 2610.9..3414.310.4 HAND FOOT SKIN REACTION 2912.2..166.7.. FATIGUE 3012.610.4125.0.. HYPERTENSION 114.6..187.6.. OBSTRUCTION/GI 72.920.883.452.1 THROMBOSIS 10.41 41.7.. PERFORATION, GI 20.82..2 PROTEINURIA 10.4..41.7.. BLEEDING 20.810.420.8.. CARDIAC ISCHEMIA 20.8..10.4.. * Include grade 5

29 Safety: Treatment-related NCI Grade 3-4 AEs XELOX-BEV N=238s/a BEV N=238 NCI Grade 3NCI Grade 4NCI Grade 3NCI Grade 4 N%N% N%N% NEUROPATHY SENSORY 5924.8..187.6.. DIARRHEA 2610.9..3213.510.4 HAND FOOT SKIN REACTION 2912.2..166.7.. FATIGUE 239.710.4104.2.. HYPERTENSION 93.8..177.1.. PROTEINURIA 10.4..41.7.. THROMBOSIS 10.41 31.3.. PERFORATION, GI..20.8..10.4 BLEEDING 10.4..1.. OBSTRUCTION/GI......10.4 CARDIAC ISCHEMIA....10.4.. * Include grade 5

30 Treatment Cycles Patients %

31 Bevacizumab XELOX-BEV s/a BEV + + N Median + Mean (CI 95%) XELOX-BEV328 800+ 893 (833 - 951) s/a BEV328 770+ 649 (621 - 678)

32 + + Capecitabine Mean (CI 95%) Median (N) XELOX-BEV 250.993 (227.983 – 274.004) 212.796 (328) s/a BEV 133.131 (126.043 – 140.249) 153.425 (328) + + +