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)

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

Study Design R N=239 Progression N=480 N=241 Capecitabine Oxaliplatin Bevacizumab x6 cycles q3w until progression N=480 N=239 N=241 sample size refres to IIT population. Check demographics etc to see if all are PP

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)

Study Objectives Primary endpoint Secondary endpoints 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

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

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

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

Patient characteristics XELOX-BEV (N=239) s/a BEV (N=241) Age median, years (range) 63 (30-80) 64 (33-82) Sex: Male/Female, % 64/36 ECOG PS 0/1/2 % 49/49/2 59/39/2 Site of primary tumor rectum/colon/both % 31/57/12 23/67/10 Metastases confined to liver % 39 35 Previous Adjuvant CT / RDT % 13/8 17/8 Nº of organs affected 2 (1-5) 3 (1-12) Surgery of primary tumor % 69 75

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

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

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

Summary of efficacy XELOX-BEV (N=239) s/a BEV (N=241) HR (CI 95%) 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 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)* Moreover this post hoc change raises some multiplicity concerns too. With 3 arms there is a multiplicity of hypothesis test leading to a alpha risk inflation. To be confirmatory, the trial must control this inflation by using a signification level adjustment (Bonferroni, etc.). In the reported analysis, no such a method was performed. So given the post hos change of hypothesis and the multiplicity concern these results are only exploratory, not confirmatory. The present conclusion is a little bit stronger given these restrictions. For the calculation of the sample size, the underlying incidence (in the control group) is missing. The sample size calculation presented here is for 2 groups, I guess that in the protocol a sample size calculation for 3 arms was performed initially Is this trial registered into a clinical trial register (if yes what are the change in the protocol compared with the description put in the register) In the abstract the trial was described as a phase II/III trial, here it’s a phase III only The methodology of this trial seems like meta analysis or others? One more point may be that the number of patients enrolled is not so large which may make people challenge the results. *Odds Ratio

Surgery XELOX-BEV (N=239) s/a BEV (N=241) Salvage surgery N (%) 28 (11.7) 23 (9.5) R0 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) 3 (1.2) Time to surgery median (months) range 6.8 (3.5-30-0) 8.7 (3.8-17.6)

Chemotherapy: 2nd lines Patients %

Treatment-related AEs 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 (%) AEs G3-4 SAEs AEs leading to death Death 60 days Treatment-related AEs

Safety: Treatment-related NCI Grade 3-4* AEs   XELOX-BEV N=238 s/a BEV N=238 N % NEUROPATHY SENSORY 59 24.8 18 7.6 DIARRHEA 26 10.9 33 13.9 HAND FOOT SKIN REACTION 29 12.2 16 6.7 FATIGUE 24 10.5 10 4.2 HYPERTENSION 9 3.8 17 7.1 PROTEINURIA 1 0.4 4 1.7 THROMBOSIS 2 0.8 3 1.3 PERFORATION, GI BLEEDING OBSTRUCTION/GI . CARDIAC ISCHEMIA * Include grade 5

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

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.

BACK-UP

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

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

Objective Best Tumor Response (RECIST)   XELOX-BEV N=239 s/a BEV N=241 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) Not confirmed Complete Partial 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

Safety: NCI Grade 3-4* AEs XELOX-BEV N=238 s/a BEV N=238 N % DIARRHEA 26 10.9 35 14.7 OBSTRUCTION/GI 9 3.8 13 5.5 PERFORATION, GI 4 1.7 2 0.8 NEUROPATHY SENSORY 59 24.8 18 7.6 HAND FOOT SKIN REACTION 29 12.2 16 6.7 FATIGUE 31 13,0 12 5 HYPERTENSION 11 4.6 CARDIAC ISCHEMIA 1 0.4 THROMBOSIS PROTEINURIA BLEEDING 3 1.3 * Include grade 5

Safety: NCI Grade 3-4 AEs XELOX-BEV N=238 s/a BEV N238 % NEUROPATHY SENSORY 59 24.8 . 18 7.6 DIARRHEA 26 10.9 34 14.3 1 0.4 HAND FOOT SKIN REACTION 29 12.2 16 6.7 FATIGUE 30 12.6 12 5.0 HYPERTENSION 11 4.6 OBSTRUCTION/GI 7 2.9 2 0.8 8 3.4 5 2.1 THROMBOSIS 4 1.7 PERFORATION, GI PROTEINURIA BLEEDING CARDIAC ISCHEMIA * Include grade 5

Safety: Treatment-related NCI Grade 3-4 AEs XELOX-BEV N=238 s/a BEV N=238 NCI Grade 3 NCI Grade 4 N % %  NEUROPATHY SENSORY 59 24.8 . 18 7.6 DIARRHEA 26 10.9 32 13.5 1 0.4 HAND FOOT SKIN REACTION 29 12.2 16 6.7 FATIGUE 23 9.7 10 4.2 HYPERTENSION 9 3.8 17 7.1 PROTEINURIA 4 1.7 THROMBOSIS 3 1.3 PERFORATION, GI 2 0.8 BLEEDING OBSTRUCTION/GI CARDIAC ISCHEMIA * Include grade 5

Treatment-related AEs leading to death XELOX-BEV N=238 s/a BEV N=238 N % PERFORATION, GI 2 0.8 UNEXPECTED SUDDEN DEATH 1 0.4 DIARRHEA . CARDIOPULMONARY ARREST OBSTRUCTION/GI GASTROINTESTINAL/OTHER Total 4 1.7 8 (*) 3.4 * Seven deaths cycles 1-6; one death cycle 42

Treatment Cycles Patients %