Swiss Group for Clinical Cancer Reseach

1. Bevacizumab continuation versus no continuation after first-line chemo-bevacizumab therapy in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial Koeberle D, Betticher D, von Moos R, Dietrich D, Brauchli P, Baertschi D, Matter K, Winterhalder R, Borner M, Anchisi S, Moosmann P, Kollar A, Saletti P, Roth A, Frueh M, Kueng M, Popescu R, Schacher S, Hess V, Herrmann R Swiss Group for Clinical Cancer Reseach

2. Background • Chemotherapy plus Bevacizumab (BEV) is a standard option for first-line treatment in patients with metastatic colorectal cancer • In many countries duration of first line chemotherapy in the absence of disease progression or severe toxicity is usually limited to 4-6 months • After stopping first-line chemotherapy plus BEV the value of BEV monotherapy as maintenance strategy until disease progression is unknown

3. Study design BEV continuation (7.5 mg/kg q 3 w) until PD No PD First-linechemo-therapy + BEV for 4-6 months Randomization 1: 1 No antitumor treatment (no BEV) until PD • Stratification factors: • Best response during first-line chemotherapy + BEV (CR/PR vs SD) • Duration of first-line chemotherapy + BEV (16-20 vs 21-24 weeks) • Type of chemotherapy (Irinotecan + 5-FU vs Oxalipaltin + 5-FU vs • Fluoropyrimidine mono) • Disease burden (metastases in one organ vs multiple organs) • Center • Study conducted in 26 sites in Switzerland (accrual period 2007-2012)

4. Main eligibility criteria • Patients ≥ 18 years with pathologically confirmed diagnosis of colorectal adenocarcinoma • First-line chemotherapy for metastatic disease with oral or intravenous fluoropyrimidine alone, or in combination with irinotecan or oxaliplatin • Chemotherapy must have been given in combination with standard dose of BEV for at least 16, but no longer than 24 weeks as part of the first-line treatment • Last administration of BEV within 4 weeks before randomization • Stable disease (SD), partial response (PR) or complete response (CR) after end of chemotherapy/BEV first-line treatment (tumor assessment within 21 days before randomization)

5. Endpoints Primary endpoint: • Time to progression (TTP) • Measured by CT-scans q 6 weeks from randomization until PD Secondary endpoints: • Progression freesurvival (PFS) • Time tosecond-linetreatment • Overall survival (OS) • Adverseeventsrelatedto BEV • Treatment costs

6. Statistical considerations • Non-inferiority study • Assumption: TTP of ≤ 22 weeks for BEV continuation TTP of ≥16 weeks for no BEV • Hypothesis: BEV vs. no BEV Hazard Ratio (HR) HR ≥ 16/22 = 0.727 • 219 events required for a significance level of 10%, a power of 85% to detect a HR=1, one interim analysis • Analysis based on 262 evaluable patients (131 in each arm)

7. Patient characteristics

8. Based on a median follow-up time of 30.1 months (Range in living patients 2.7 - 54.9) RESULTS

9. TTP (from randomization)

10. TTP subgroup analysis

11. PFS (from start of first-line therapy)

12. Time to second-line treatment (from randomization)

13. Overall Survival (from start of first-line therapy)

14. Adverse events

15. Cost analysis Not included costs: Laboratory tests, out-patient AE treatments, other out-patient treatments/care 1) Swiss prices and Swiss health system

16. Cost analysis BEV NO BEV

17. Cost analysis Total costs USD

18. Summary • Non-inferiority could not be demonstrated • The difference in median TTP between BEV continuation versus no treatment after randomization is 5 weeks • Overall survival in both arms is not significantly different • Utility of BEV continuation needs to be balanced with significantly higher treatment costs

19. Acknowledgements • Patients • Investigators, study coordinators and nurses at SAKK coordination center and study sites Swiss Association of Social Health Insurance Companies Swiss Group for Clinical Cancer Research