1. Bevacizumab taxan Första linjens behandling vid metastaserande Her2- bröstcancer

2. 3 randomiserade studier E2100 E2100 AVADO AVADO RIBBON 1 RIBBON 1 2 METAANALYSER 2 METAANALYSER

3. E2100 722 patienter 722 patienter 90 mg paklitaxel/m2 dag 1, 8, 15 +/- bevacizumab 10 mg/kg dag 1, 15 90 mg paklitaxel/m2 dag 1, 8, 15 +/- bevacizumab 10 mg/kg dag 1, 15 Primär endpoint: PFS Primär endpoint: PFS

4. Progressionsfri överlevnad

5. AVADO 736 patienter 736 patienter Docetaxel 100mg/m2 + placebo Docetaxel 100mg/m2 + placebo Docetaxel 100mg/m2 + bevacizumab 7,5 mg eller 15 mg qW 3 Docetaxel 100mg/m2 + bevacizumab 7,5 mg eller 15 mg qW 3

6. Bevacizumab 7.5mg/kg q3w + docetaxel (n=248) 9.0 AVADO: updated PFS 7.5mg dose PFS estimate Time (months) 1.0 0.8 0.6 0.4 0.2 0 061218243036 Placebo + docetaxel (n=241) Unstratified HR=0.86 (0.72–1.04), p=0.1163* 8.2 Intent-to-treat analysis; *p values are of exploratory nature ‡ censored for non-protocol therapy prior to progressive disease Stratified HR ‡ =0.80 (0.65–1.00), p=0.0450* 8.1

7. Bevacizumab 15mg/kg q3w + docetaxel (n=247) AVADO: updated PFS 15mg dose PFS estimate Time (months) 1.0 0.8 0.6 0.4 0.2 0 061218243036 Placebo + docetaxel (n=241) 10.1 Unstratified HR=0.77 (0.64–0.93), p=0.0061* 8.2 Intent-to-treat analysis; *p values are of exploratory nature ‡ censored for non-protocol therapy prior to progressive disease Stratified HR ‡ =0.67 (0.54–0.83), p=0.0002* 10.0 8.1

8. AVADO: updated efficacy ORR and 1-year survival Placebo + docetaxel Bev 7.5* + docetaxel Bev 15* + docetaxel Patients with measurable disease at baseline n=207n=201n=206 ORR, %46.455.264.1 Difference vs placebo8.817.7 p value vs placebo0.0739 ‡ 0.0003 ‡ *mg/kg q3w ‡ p values are of exploratory nature ITT populationn=241n=248n=247 1-year survival rate, %768184 Difference vs placebo4.98.5 p value vs placebo0.198 ‡ 0.02 ‡ Patients still at risk, n178195201

9. RIBBON 1 1237 patienter 1237 patienter Bevacizumab 15 mg qW 3 gavs som tilläggsbehandling till capecitabin, taxan- eller anthracyklingbehandling Bevacizumab 15 mg qW 3 gavs som tilläggsbehandling till capecitabin, taxan- eller anthracyklingbehandling

10. Study Design Capecitabine (1000 mg/m 2 BID x 14d) Taxane (docetaxel q3w or protein-bound paclitaxel q3w) Anthracycline-based chemotherapy (AC, EC, FAC, FEC) Placebo or bevacizumab (15 mg/kg q3w) CHOICE OF CHEMO BY INVESTIGATOR Capecitabine or Taxane or Anthracyclin e Previously untreated MBC (n=1237) Stratification Factors: Disease-free interval Previous adjuvant chemotherapy Number of metastatic sites Cape, T or Anthra Chemo + bevacizumab q3w Chemo + placebo q3w Optional 2 nd -line Chemo + bevacizumab Treat until PD RANDOMIZE 2:1

11. Capecitabine: PFS by Investigator Median, mo5.78.6 HR (95% CI)0.69 (0.56–0.84) p-valuep=0.0002 Median, mo6.29.8 HR (95% CI)0.68 (0.54–0.86) p-valuep=0.0011 PL (n=206) BV (n=409) IRC INV

12. Taxane/Anthra: PFS by Investigator Median, mo8.09.2 HR (95% CI)0.64 (0.52–0.80) p-valuep<0.0001 Median, mo8.310.7 HR (95% CI)0.77 (0.60–0.99) p-valuep=0.040 PL (n=207) BV (n=415) IRC INV

13. Analysis of PFS by stratification factors: Cape and T/Anthra Cohorts Analysis of PFS by stratification factors: Cape and T/Anthra Cohorts + BV better + PL better Baseline Factor Total n Hazard Ratio All Patients6150.67 Disease-free interval (mo) ≤121540.81 >124610.63 Number of metastatic sites <33450.63 ≥32700.74 Prior adjuvant chemotherapy Yes4440.64 No1710.80 + BV better + PL better Total n Hazard Ratio CapeT/Anthra 622 0.66 239 0.62 383 0.69 341 0.65 281 0.64 283 0.67 339 0.64

14. Objective Response Rate Measurable disease (n) 161325 177 345 Includes only patients with measurable disease at baseline. 23.6 35.4 37.9 51.3 Cape p=0.0097 T/Anthra p=0.0054 % BVPLBVPL

15. Metaanalys Lee et al

16. Metaanalys