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; AvastinTM) 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=paclitaxelMBC= metastatic breast cancer; NSCLC=non-small-cell lung cancer

Control BV Trial

Tumor Chemotherapy N Chemotherapy N

Hurwitz trial (2107)1

mCRC IFL 396 IFL or 5-FU/LV 501

Kabbinavar trial (2192)2

mCRC 5-FU/LV 104 5-FU/LV 100

Kabbinavar trial (0780)3

mCRC 5-FU/LV 35 5-FU/LV 67

Miller trial (2119)4

MBC CAP 215 CAP 229

Johnson trial (0757)5

NSCLC C/P 32 C/P 66

Total 782 963

1Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342; 2Kabbinavar F, et al. J Clin Oncol. 2005. In Press; 3Kabbinavar F, et al. J Clin Oncol. 2003;21:60-65; 4Miller K, et al. J Clin Oncol. 2005; 23:792-799; 5Johnson D, et al. J Clin Oncol. 2004;22:2184-2191

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 pectoris Myocardial infarction

Arterial thrombosis Myocardial ischemia

Cerebral infarction Embolism

Cerebral ischemia Arterial 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

Variable Description

Treatment BV or control Age <65 or ≥65 years Gender Male or female Use of lipid-lowering drugs Taken from medication at baseline (as well as

concomitant medications on study) History of atherosclerosis Any arterial disease or procedure from medical history

records in study databases History of ATEs A subset of “history of atherosclerosis” including

symptomatic ATEs associated with clinical consequences

HTN at baseline History of HTN, use of anti-HTN medication recorded in the study database, SBP >150mm Hg or DBP >100mm Hg at enrollment

METHODS: OTHER BASELINE VARIABLES USED FOR POTENTIAL RISK FACTOR ANALYSIS

Variable Description

Diabetes Any history of diabetes

Venous thrombosis Any history of venous thromboembolic disease or pulmonary embolism

History of myocardial infarction

Subset of history of ATEs

History of stroke or TIA Subset of history of ATEs 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

1Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342

Control BV Trial

Tumor ATE N ATE N

Hurwitz trial (2107)1 mCRC 5 396 20 501 Kabbinavar trial (2192)2 mCRC 5 104 10 100 Kabbinavar trial (0780)3 mCRC 1 35 3 67 Miller trial (2119)4 MBC 1 215 1 229 Johnson trial (0757)5 NSCLC 1 32 3 66 Total 13 782 37 963

RESULTS: INCIDENCE OF ATEs FOR EACH TREATMENT GROUP

1Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342; 2Kabbinavar F, et al. J Clin Oncol. 2005. In Press; 3Kabbinavar F, et al. J Clin Oncol. 2003;21:60-65; 4Miller K, et al. J Clin Oncol. 2005; 23:792-799; 5Johnson D, et al. J Clin Oncol. 2004;22:2184-2191

MBC= metastatic breast cancer; NSCLC=non-small-cell lung cancer

RESULTS: ATE ANALYSIS

CI=confidence interval*P=0.076; **P=0.03

Control (N=782)

BV (N=963)

Number of events (%) 13 (1.7) 37 (3.8)

Person-years of observation 419 673

Rate/100 person-years (95% CI)

3.1 (1.7-5.3)

5.5* (3.9-7.6)

Hazard ratio (95% CI)

1.99** (1.05-3.75)

Uncorrected for uneven time on treatment and shorter follow up for control patients

0 5 10 15 20 25Months

782 405 173 64 17 0control

963 683 421 260 111 15 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

1-3

Univariate

Risk factor Value Hazard ratio P-value

BV treatment Yes/No 1.99 0.03 Age ≥65 vs <65 years 3.00 <0.01 Gender Male vs female 1.74 0.05 HTN at baseline Yes/No 1.89 0.03 HTN on study* SBP >150mm Hg;

DBP >100mm Hg 1.94 0.04

History of diabetes mellitus

Yes/No 1.91 0.06

History of ATEs Yes/No 5.18 <0.01 Proteinuria >500mg/24 hours on study*†

Yes/No

3.23

<0.01

1Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342; 2Kabbinavar F, et al. J Clin Oncol. 2005. In Press; 3Miller K, et al. J Clin Oncol. 2005; 23:792-799

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

Control n/N ATE (%)

BV n/N ATE (%)

Proteinuria 3/22 (13.6) 5/66 (7.6) No Proteinuria 8/693 (1.2) 26/764 (3.4)

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

Significant baseline risk factors Hazard ratio P-value

BV treatment 1.95 0.04

Age ≥65 years 2.24 0.01

History of ATEs 3.65 <0.01

RESULTS: RISK/BENEFIT OF BV in mCRC

• To understand the risk/benefit of BV in mCRC, data from the pivotal trial AVF21071 were reanalyzed* for survival based on subgroups created using risk factors for ATEs

1Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342

*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

% of ATE

Baseline risk factor

(% of population)

Control

(n/N)

BV

(n/N)

All patients

(100)

1.7

(13/782)

3.8

(37/963)

None

(63)

1.0

(5/490)

1.8

(11/602)

Age ≥65 years*

(35)

2.5

(7/279)

7.1

(24/339)

History of ATEs*

(8.5)

3.4

(2/59)

15.7

(14/89)

Both

(6.5)

2.2

(1/46)

17.9

(12/67)

RESULTS: SURVIVAL HAZARD RATIOS IN mCRC BY RISK GROUP

1Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342

CI=confidence interval; PFS=progression-free survival*These groups are not mutually exclusive

Hazard ratio

Baseline risk factors

PFS (95% CI)

Overall survival (95% CI)

All patients 0.54 (0.45-0.66)

0.66 (0.54-0.81)

None 0.53 (0.43-0.66)

0.73 (0.57-0.94)

Age ≥65 years* 0.57 (0.41-0.80)

0.61 (0.42-0.89)

History of ATEs* 0.61 (0.29-1.28)

0.38 (0.19-0.77)

Both 0.55 (0.22-1.37)

0.59 (0.27-1.28)

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 trial1 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

1Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342