1 confidential – do not distribute aries mcrc: effectiveness and safety of 1st- and 2nd-line...

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

Elderly PatientsMark Kozloff, MD

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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.

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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

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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)

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

Pat

ient

s, %

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

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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)

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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

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

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

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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.

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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)

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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

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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

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

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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.

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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)

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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