1. 1 CONFIDENTIAL – DO NOT DISTRIBUTE ARIES mCRC: Effectiveness and Safety of 1st- and 2nd-line Bevacizumab Treatment in Elderly Patients Mark Kozloff, MD

2. 2 CONFIDENTIAL–DO NOT DISTRIBUTE Background A pooled analysis of 4 randomized trials showed that BV treatment was associated with statistically significant increases in PFS (HR 0.58) and OS (HR 0.85) in patients aged ≥65 y 1 In the BRiTE OCS of BV with 1st-line CT, median PFS was similar across age subgroups, while median OS declined with increasing age 2 With the exception of a higher incidence of ATEs in elderly patients, there do not appear to be substantial age-related increases in grade 3–5 AEs with BV treatment in the 1st-line setting 1,2 No studies to date have evaluated outcomes in elderly patients receiving BV with 2nd-line treatment 1. Cassidy J, et al. J Cancer Res Clin Oncol. 2010;136:737–743. 2. Kozloff MF, et al. Oncology. 2010;78:329–339.

3. 3 CONFIDENTIAL–DO NOT DISTRIBUTE Objective and Patient Population Objective –To evaluate baseline characteristics, effectiveness, and safety associated with different age subgroups among patients receiving BV + CT in the 1st- or 2nd-line treatment of mCRC, with a special emphasis on the elderly Patient population –This analysis evaluated outcomes in 3 age-based subgroups of patients receiving either 1st- or 2nd-line therapy: <70 y, 70–79 y, and ≥80 y

4. 4 CONFIDENTIAL–DO NOT DISTRIBUTE Enrollment, Follow-up, and Baseline Characteristics Median follow-up of 20.7 and 16.9 months in 1st- and 2nd-line cohorts, respectively Baseline characteristics –In general, a higher percentage of patients in the 70–79 y and ≥80 y subgroups had an ECOG PS ≥1 (except in the ≥80 y 2nd-line subgroup), the colon as the primary tumor site, a history of cardiovascular disease, baseline hypertension requiring medication, and baseline hypercholesterolemia requiring medication compared with patients in the ≤70 y subgroup within the 1st- and 2nd-line cohorts <70 y (n=1126) ≥80 y (n=113) 1st-line mCRC patients (N=1550) 70–79 y (n=311) <70 y (n=336) ≥80 y (n=40) 2nd-line mCRC patients (N=482) 70–79 y (n=106)

5. 5 CONFIDENTIAL–DO NOT DISTRIBUTE Baseline Chemotherapy by Age: 1st-line Cohort Patients, % (n=1126)(n=311)(n=113)

6. 6 CONFIDENTIAL–DO NOT DISTRIBUTE 2nd-line Treatment by Age: 1st-line Cohort A higher percentage of patients <70 y received 2nd-line treatment (with or without BV) and had exposure to 3 active chemotherapy agents compared with the older age subgroups Treatment 1st-line patients <70 y (n=1126) 70–79 y (n=311) ≥80 y (n=113) Patients receiving 2nd-line therapy, no. (%) 734 (65)179 (58)50 (44) Patients receiving BV in 2nd-line therapy, no. (%) 334 (30)76 (24)17 (15) Patients with exposure to 3 active chemotherapies, no. (%) 617 (55)130 (42)31 (27)

7. 7 CONFIDENTIAL–DO NOT DISTRIBUTE Effectiveness Outcomes by Age: 1st-line Cohort According to Kaplan-Meier analysis, 1st-line patients in the 70–79 y and ≥80 y subgroups had a similar PFS but significantly lower OS compared with 1st-line patients <70 y Outcome 1st-line patients <70 y (n=1126) 70–79 y (n=311) ≥80 y (n=113) Patients with a PFS event, no. (%)1000 (88.8)284 (91.3)105 (92.9) Median PFS, mos10.310.19.4 Deaths, no. (%)735 (65.3)227 (73.0)93 (82.3) Median OS, mos25.120.818.5

8. 8 CONFIDENTIAL–DO NOT DISTRIBUTE Kaplan-Meier Estimate of PFS in the 1st-line Cohort

9. 9 CONFIDENTIAL–DO NOT DISTRIBUTE Kaplan-Meier Estimate of OS in the 1st-line Cohort

10. 10 CONFIDENTIAL–DO NOT DISTRIBUTE Multivariate Analysis in 1st-line Cohort OutcomeHazard ratio (95% CI) PFS in 1st-line patients <70 y 70–79 y ≥80 y 1.0 (reference) 1.07 (0.93, 1.22) 1.18 (0.95, 1.46) OS in 1st-line patients <70 y 70–79 y ≥80 y 1.0 (reference) 1.15 (0.98, 1.34) 1.55 (1.23, 1.96) According to multivariate analyses, all age subgroups had a similar PFS profile in the 1st-line cohort Patients ≥80 y had an elevated risk of all-cause mortality compared to those <70 y Patients 70–79 y had a similar risk of all-cause mortality as those <70 y Adjusted for the following baseline covariates: sex, race, ECOG PS, diabetes, hypertension, hypercholesterolemia, cardiovascular disease history, albumin level, alkaline phosphatase level, site of primary tumor, surgical resection,and adjuvant therapy.

11. 11 CONFIDENTIAL–DO NOT DISTRIBUTE Timing of Targeted Adverse Events by Age: 1st-line Cohort Outcome <70 y (n=1126) 70–79 y (n=311) ≥80 y (n=113) Targeted AEs by interval, n (%) Any time Months 0–<3 Months 3–<6 Months 6–<9 Months 9–53 253 (22.5) 107 (9.5) 65 (6.6) 29 (3.6) 52 (8.9) 75 (24.1) 28 (9.0) 20 (7.6) 9 (4.4) 18 (12.5) 21 (18.6) 9 (8.0) 5 (5.6) 4 (6.0) 3 (8.1) Serious AEs by interval, n (%) Any time Months 0–<3 Months 3–<6 Months 6–<9 Months 9–53 102 (9.1) 41 (3.6) 24 (2.3) 9 (1.0) 28 (4.2) 42 (13.5) 14 (4.5) 10 (3.6) 6 (2.7) 12 (7.5) 11 (9.7) 7 (6.2) 2 (2.2) 1 (1.4) 1 (2.4) GI perforations at any time, n (%)11 (1.0) 3 (1.0)0 (0) Grade 3–5 bleeding at any time, n (%)27 (2.4)14 (4.5)6 (5.3) ATEs at any time, n (%)19 (1.7)13 (4.2)3 (2.7) VTEs at any time, n (%)84 (7.5)21 (6.8)6 (5.3) Hypertension requiring management, n (%)105 (9.3)21 (6.8)4 (3.5)

12. 12 CONFIDENTIAL–DO NOT DISTRIBUTE Baseline Chemotherapy by Age: 2nd-line Cohort Patients, % (n=336)(n=106)(n=40) 76%, 64%, and 55% of patients in <70y, 70–79 y, and ≥80 y subgroups had exposure to 3 active chemotherapy agents

13. 13 CONFIDENTIAL–DO NOT DISTRIBUTE Effectiveness Outcomes by Age: 2nd-line Cohort In the 2nd-line cohort, no significant differences in PFS or OS by age were observed according to Kaplan-Meier analysis Outcome 2nd-line patients <70 y (n=336) 70–79 y (n=106) ≥80 y (n=40) Patients with a PFS event, no. (%)311 (92.6)103 (97.2)35 (87.5) Median PFS, mos7.98.06.7 Deaths, no. (%)261 (77.7)87 (82.1)34 (85.0) Median OS, mos18.617.514.9

14. 14 CONFIDENTIAL–DO NOT DISTRIBUTE Kaplan-Meier Estimate of OS in the 2nd-line Cohort

15. 15 CONFIDENTIAL–DO NOT DISTRIBUTE Multivariate Analysis in 2nd-line Cohort OutcomeHazard ratio (95% CI) PFS in 2nd-line patients <70 y 70–79 y ≥80 y 1.0 (reference) 0.96 (0.76, 1.22) 0.95 (0.66, 1.36) OS in 2nd-line patients <70 y 70–79 y ≥80 y 1.0 (reference) 1.07 (0.82, 1.39) 1.54 (1.06, 2.24) As in the 1st-line cohort, all age subgroups had a similar PFS profile in the 2nd-line cohort according to multivariate analyses Patients ≥80 y, but not patients 70–79 y, had an elevated risk of all- cause mortality (ie, OS) compared to those <70 y Adjusted for the following baseline covariates: sex, race, ECOG PS, diabetes, hypertension, hypercholesterolemia, cardiovascular disease history, albumin level, alkaline phosphatase level, site of primary tumor, surgical resection,and adjuvant therapy.

16. 16 CONFIDENTIAL–DO NOT DISTRIBUTE Timing of Targeted Adverse Events by Age: 2nd-line Cohort Outcome <70 y (n=336) 70–79 y (n=106) ≥80 y (n=40) Targeted AEs by interval, n (%) Any time Months 0–<3 Months 3–<6 Months 6–<9 Months 9–50 50 (14.9) 17 (5.1) 7 (2.3) 7 (2.9) 19 (11.8) 17 (16.0) 7 (6.6) 2 (2.1) 3 (3.9) 5 (10.2) 11 (27.5) 4 (10.0) 2 (6.3) 3 (15.0) 2 (15.4) Serious AEs by interval, n (%) Any time Months 0–<3 Months 3–<6 Months 6–<9 Months 9–50 17 (5.1) 7 (2.1) 2 (0.6) 1 (0.4) 7 (4.1) 8 (7.5) 4 (3.8) 2 (2.1) 0 (0) 2 (3.8) 7 (17.5) 1 (2.5) 1 (2.9) 3 (13.6) 2 (14.3) GI perforations at any time, n (%)1 (0.3)2 (1.9)1 (2.5) Grade 3–5 bleeding at any time, n (%)4 (1.2)2 (1.9)2 (5.0) ATEs at any time, n (%)4 (1.2)1 (0.9)3 (7.5) VTEs at any time, n (%)22 (6.5)5 (4.7)1 (2.5) Hypertension requiring management, n (%)15 (4.5)4 (3.8)2 (5.0)

17. 17 CONFIDENTIAL–DO NOT DISTRIBUTE Summary and Conclusions ARIES is the first study to describe the effects of 2nd-line BV treatment for mCRC in a large population of elderly patients In ARIES, PFS was similar across all age subgroups in both treatment lines; OS was shorter in patients ≥80 y compared with the youngest age subgroup, as is seen in the general population –These results are consistent with observations from the BRiTE OCS The incidence of targeted AEs and SAEs appeared to decrease over time in the first 9 months from the start of BV treatment, and there were no remarkable differences in the incidence patterns according to age In general, patients in the 70–79 y and ≥80 y age subgroups had a low overall incidence of targeted AEs and SAEs that was similar to that reported in patients <70 y This preliminary analysis suggests that BV treatment in elderly patients with mCRC may not be associated with poorer clinical or safety outcomes than in younger patients