ARTERIAL THROMBOEMBOLIC EVENTS IN A POOLED ANALYSIS OF 5 RANDOMIZED, CONTROLLED TRIALS OF BEVACIZUMAB WITH CHEMOTHERAPY JR Skillings Genentech, Inc, South San Francisco, CA

BACKGROUND Bevacizumab (BV; Avastin TM ) is a recombinant, humanized, anti-vascular endothelial growth factor (VEGF) monoclonal antibody BV combined with first-line irinotecan, 5-fluorouracil (5-FU), and leucovorin (IFL) chemotherapy increases survival in patients with metastatic colorectal cancer (mCRC) Safety reports from several randomized, controlled trials suggested that adding BV to chemotherapy may increase the risk of arterial thromboembolic events (ATEs)

OBJECTIVE To evaluate the risk of ATEs in patients with metastatic cancer receiving BV with chemotherapy using data pooled from 5 randomized, controlled trials

METHODS: STUDY DESIGN CAP=capecitabine; C=carboplatin; P=paclitaxel MBC= metastatic breast cancer; NSCLC=non-small-cell lung cancer 1 Hurwitz H, et al. N Engl J Med. 2004;350: ; 2 Kabbinavar F, et al. J Clin Oncol In Press; 3 Kabbinavar F, et al. J Clin Oncol. 2003;21:60-65; 4 Miller K, et al. J Clin Oncol. 2005; 23: ; 5 Johnson D, et al. J Clin Oncol. 2004;22:

METHODS: IDENTIFICATION OF ATE CASES The pooled database was broadly queried for adverse event terms that might be associated with the clinical consequences of ATEs The following COSTART terms were used for the initial search: cerebrovascular accident, cerebral ischemia, subarachnoid hemorrhage, cerebral infarction, angina pectoris, myocardial infarction, myocardial ischemia, and arterial thrombosis. Thrombosis and verbatim terms including left ventricle were added Death due to causes other than progressive disease were clinically reviewed for text fields including cerebrovascular accident, myocardial infarction or ATE. A case of ischemic bowel was added The safety database was reviewed using broad search criteria and one additional case of right leg arterial occlusion was added Cases of subarachnoid hemorrhage were removed because these were interpreted as bleeding events Cases of cardiac arrest were removed when review of narratives suggested that the cases were related to progressive disease A combined list of cases was identified

METHODS: IDENTIFIED TREATMENT-EMERGENT ATEs Angina pectorisMyocardial infarction Arterial thrombosisMyocardial ischemia Cerebral infarctionEmbolism Cerebral ischemiaArterial occlusion Cerebrovascular accident Left ventricle thrombosis Ischemic bowel

METHODS: STATISTICAL ANALYSIS Incidence of ATEs was tabulated for each treatment group Kaplan-Meier plots of time-to-ATE were generated for each treatment group and median values estimated. A Cox proportional hazards regression was used to calculate hazard ratios, and P-values were calculated by the log-rank test ATE rates per 100 person-years with 95% confidence intervals were computed by standard methods. The number of person- years of observation was defined as the sum of the time-to-ATE for all patients (for patients without an ATE, the observation time was defined as the last date of treatment plus 30 days) Poisson regression was used to formally compare rates per 100 person-years between BV-treated patients and controls

METHODS: BASELINE VARIABLES USED FOR POTENTIAL RISK FACTOR ANALYSIS DBP=diastolic blood pressure; HTN=hypertension; SBP=systolic blood pressure

METHODS: OTHER BASELINE VARIABLES USED FOR POTENTIAL RISK FACTOR ANALYSIS TIA=transient ischemic attack

METHODS: POTENTIAL RISK FACTOR ANALYSIS For each risk factor, numbers of patients with and without the factor were tabulated Fisher’s exact test was used to compare the frequency of ATEs between BV-treated and control patients for each risk factor Cox’s proportional hazards regression was used to compute hazard ratios and P-values for the effect of each factor on the hazard of ATEs Backward elimination in a multivariate Cox model was used to assess the significance of each baseline risk factor that was significant in univariate analysis Pooled population patients were assigned to subgroups based on significant baseline risk factors, and ATE rates per 100 person-years were calculated as described above within each subgroup by treatment Irinotecan-treated patients from the pivotal trial in mCRC (AVF2107g) 1 were assigned to subgroups based on these risk factors. Median PFS and overall survival were estimated for each subgroup using Kaplan-Meier methods, and hazard ratios were calculated from a Cox proportional hazards model 1 Hurwitz H, et al. N Engl J Med. 2004;350:

RESULTS: INCIDENCE OF ATEs FOR EACH TREATMENT GROUP 1 Hurwitz H, et al. N Engl J Med. 2004;350: ; 2 Kabbinavar F, et al. J Clin Oncol In Press; 3 Kabbinavar F, et al. J Clin Oncol. 2003;21:60-65; 4 Miller K, et al. J Clin Oncol. 2005; 23: ; 5 Johnson D, et al. J Clin Oncol. 2004;22: MBC= metastatic breast cancer; NSCLC=non-small-cell lung cancer

RESULTS: ATE ANALYSIS CI=confidence interval *P=0.076; **P=0.03

Uncorrected for uneven time on treatment and shorter follow up for control patients Months control chemo/AVF Patients at risk by time point RESULTS: KAPLAN-MEIER TIME-TO-ATE

RESULTS: ATE POTENTIAL RISK FACTORS IN UNIVARIANT ANALYSIS DBP=diastolic blood pressure; HTN=hypertension; SBP=systolic blood pressure *On study indicates occurrence during treatment (and prior to an ATE if one occurred) † Collected in selected trials Hurwitz H, et al. N Engl J Med. 2004;350: ; 2 Kabbinavar F, et al. J Clin Oncol In Press; 3 Miller K, et al. J Clin Oncol. 2005; 23:

RESULTS: RELATIONSHIP BETWEEN ATEs AND PROTEINURIA Patients with proteinuria (>500mg/24 hours) are at risk of ATEs regardless of treatment. The explanation for this finding is unclear Proteinuria (>500mg/24 hours) n=subset; N=total number

RESULTS: BASELINE ATE RISK FACTORS SIGNIFICANT IN MULTIVARIATE ANALYSIS In a multivariate analysis with both baseline and on-study factors, no on-study factors were significant except presence of proteinuria >500mg/24 hours In a separate multivariate analysis with only on-study factors, presence of proteinuria alone was significant

RESULTS: RISK/BENEFIT OF BV in mCRC To understand the risk/benefit of BV in mCRC, data from the pivotal trial AVF were reanalyzed* for survival based on subgroups created using risk factors for ATEs 1 Hurwitz H, et al. N Engl J Med. 2004;350: *The dataset used to support the preplanned final analysis for AVF2107g was used for this analysis

RESULTS: ATE INCIDENCE BY RISK GROUP n=subgroup; N=total number *These groups are not mutually exclusive

RESULTS: SURVIVAL HAZARD RATIOS IN mCRC BY RISK GROUP 1 Hurwitz H, et al. N Engl J Med. 2004;350: CI=confidence interval; PFS=progression-free survival *These groups are not mutually exclusive

CONCLUSIONS Bevacizumab is associated with an approximately 2-fold increased risk of ATEs in patients with metastatic cancer receiving chemotherapy Age ≥65 years and a history of ATEs are independent baseline risk factors for these events

CONCLUSIONS (cont’d) Despite this risk, analysis of data from the pivotal trial 1 indicate that bevacizumab confers a consistent survival benefit in mCRC patients overall, in all prespecified subgroups, and in these ATE risk subgroups Oncologists must use their own clinical judgment in assessing the overall risk/benefit of adding bevacizumab to chemotherapy in patients at risk of ATEs 1 Hurwitz H, et al. N Engl J Med. 2004;350: