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

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

Study design First-line chemo- therapy + BEV for 4-6 months No PD Randomization 1: 1 BEV continuation (7.5 mg/kg q 3 w) until PD 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 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 )

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)

Endpoints Primary endpoint: Time to progression (TTP) –Measured by CT-scans q 6 weeks from randomization until PD Secondary endpoints: Progression free survival (PFS) Time to second-line treatment Overall survival (OS) Adverse events related to BEV Treatment costs

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 = 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)

Patient characteristics Characteristic (% patients)BEV (n=131)No BEV (n=131) Age (range)63 (40-83)65 (23-85) Sex: male / female72 / 2873 / 27 WHO performance status: 0 / 174 / 2669 / 31 Adjuvant Chemotherapy28 Clinically significant comorbidities5850 Response first-line: CR+PR / SD62 / 3859 / 41 First-line duration: / weeks64 / 3669 / 31 First-line chemotherapy: Irinotecan + fluoropyrimidine Oxaliplatin + fluoropyrimidine Fluoropyrimidine mono

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

TTP (from randomization) BEVno BEV No. of events Median (95%CI) 4.1 months ( ) 2.9 months ( ) HR 95% CI 0.74 ( ) Non-inferiorityp = 0.47

TTP subgroup analysis

PFS (from start of first-line therapy) BEVno BEV No. of events Median (95%CI) 9.5 months ( ) 8.5 months (8-8.9) HR 95% CI 0.75 ( ) Differencep = 0.021

Time to second-line treatment (from randomization) BEVno BEV No. of events112 Median (95%CI) 5.9 months ( ) 4.8 months ( ) HR 95% CI 0.81 ( ) Differencep = 0.104

Overall Survival (from start of first-line therapy) BEV no BEV No. of events84 Median (95%CI) 25.1 months ( ) 22.8 months ( ) HR 95% CI 0.83 ( ) Differencep = 0.218

Adverse events BEV N=131 No BEV N=131 CTCAE grade Patients (%) Hemorrhage Hypertension Proteinuria Thrombosis GI-Perforation------

Cost analysis Included resource useBase case 1) Low (-30%)High (+30%) BEV continuationUSD 5.58/mg BEV administrationUSD 372 Control visit to oncologistUSD In-patientsUSD 1600/day1120/day2080/day CT-scanUSD 663 MRIUSD 735 1) Swiss prices and Swiss health system Not included costs: Laboratory tests, out-patient AE treatments, other out-patient treatments/care

Cost analysis BEVNO BEV

Cost analysis Total costs USD

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

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