1 CONFIDENTIAL – DO NOT DISTRIBUTE ARIES mCRC: Effectiveness and Safety of 1st- and 2nd-line...

1CONFIDENTIAL – DO NOT DISTRIBUTE

ARIES mCRC: Effectiveness and Safety of 1st- and 2nd-line Bevacizumab Treatment in

Elderly PatientsMark Kozloff, MD

2CONFIDENTIAL–DO NOT DISTRIBUTE

BackgroundBackground

• 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 y1

• In the BRiTE OCS of BV with 1st-line CT, median PFS was similar across age subgroups, while median OS declined with increasing age2

• 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 setting1,2

• 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.


Objective and Patient PopulationObjective 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


Enrollment, Follow-up, and Enrollment, Follow-up, and Baseline CharacteristicsBaseline 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)


Baseline Chemotherapy by Age: Baseline Chemotherapy by Age: 1st-line Cohort1st-line Cohort

Pat

ient

s, %

(n=1126) (n=311) (n=113)


2nd-line Treatment by Age:2nd-line Treatment by Age:1st-line Cohort1st-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)


Effectiveness Outcomes by Age: Effectiveness Outcomes by Age: 1st-line Cohort1st-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, mos 10.3 10.1 9.4

Deaths, no. (%) 735 (65.3) 227 (73.0) 93 (82.3)

Median OS, mos 25.1 20.8 18.5


Kaplan-Meier Estimate of PFS Kaplan-Meier Estimate of PFS in the 1st-line Cohortin the 1st-line Cohort


Kaplan-Meier Estimate of OS Kaplan-Meier Estimate of OS in the 1st-line Cohortin the 1st-line Cohort


Multivariate Analysis in Multivariate Analysis in 1st-line Cohort1st-line Cohort

Outcome Hazard 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.


Timing of Targeted Adverse Events Timing of Targeted Adverse Events by Age: 1st-line Cohortby 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)


Baseline Chemotherapy by Age: Baseline Chemotherapy by Age: 2nd-line Cohort2nd-line Cohort

Pat

ient

s, %

(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


Effectiveness Outcomes by Age: Effectiveness Outcomes by Age: 2nd-line Cohort2nd-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, mos 7.9 8.0 6.7

Deaths, no. (%) 261 (77.7) 87 (82.1) 34 (85.0)

Median OS, mos 18.6 17.5 14.9


Kaplan-Meier Estimate of OS Kaplan-Meier Estimate of OS in the 2nd-line Cohortin the 2nd-line Cohort


Multivariate Analysis Multivariate Analysis in 2nd-line Cohortin 2nd-line Cohort

Outcome Hazard 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.


Timing of Targeted Adverse Events Timing of Targeted Adverse Events by Age: 2nd-line Cohortby 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)


Summary and ConclusionsSummary 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

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