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Extending adjuvant therapy beyond 5 years

William Gradishar (Feinberg School of Medicine, Northwestern University, Chicago, IL, USA)

Thousands of patients currently completing tamoxifen therapy

• Most women on adjuvant endocrine therapy in the EU (> 450,000) are on tamoxifen (> 300,000)1

• Estimated 80,000–100,000 patients finish 5 years of tamoxifen each year in the EU1

• These women exposed to continuing risk of relapse

– Majority of breast cancer deaths and recurrences occur post-tamoxifen2

• Risk of late recurrence (> 5 years after diagnosis) particularly high in women with HR+ disease3

1Fletcher-Louis M, Ireland S. Onkos Study 48: Breast Cancer. Decision Resources Inc., Waltham, MA; 20002Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

3Saphner et al. J Clin Oncol 1996;14:2738–46

Recurrences Breast cancer deaths

Most breast cancer recurrences and deaths occur post-tamoxifen

Adapted with permission. Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

Years

85.2

73.7

0

20

40

60

80

100

0 5 10 15

TamoxifenControl

15% 17%

0

20

40

60

80

100

0 5 10 15

87.8

Years

TamoxifenControl

9% 18%

91.4

% o

f p

atie

nts

% o

f p

atie

nts

54.9

68.2 73.0

64.0

Hortobagyi et al. Proc ASCO 2004;23:23s(abstract 585)

Years post-diagnosis

ER/PgR– (n = 430)

ER+ and/or PgR+ (n = 778)

p < 0.001Pro

po

rtio

n d

isea

se-f

ree

2015105

1.0

0.9

0.8

0.7

0.6

0.5

0.4

N+ and N– disease

RFS continues to decrease regardless of ER/PgR status

• Late recurrences (> 5 years) more frequent in ER+ and/or PgR+ tumors

RFS: relapse-free survival

MA.17: trial design

• Eligibility criteria: postmenopausal, HR+/unknown, recurrence-free, completed 4.5–6 years’ tamoxifen, ECOG PS 0–2

• Primary endpoint: DFS (ipsilateral, chest wall, local, metastatic, contralateral new)

• Secondary endpoints: OS, rate of contralateral BC, safety, QoL

• Substudies:Substudies: BMD/bone markers, lipid profile

Goss et al. J Natl Cancer Inst 2005;97:1262–71Goss et al. N Engl J Med 2003;349:1793–802

Randomization(all patients disease-free)

Tamoxifen

Approx. 5 years adjuvant 5 years extended adjuvant

0–3months

Letrozole 2.5 mg qd (n = 2582)

Placebo qd † (n = 2586)

March Aug

Toxicity Efficacy

2003

1998 2003 2004

Oct

MA.17: initial and final analyses

1Goss et al. N Engl J Med 2003;349:1793–802; 2Goss et al. J Natl Cancer Inst 2005;97:1262–71

Interim analysis1 Final analysis2

DFS events 207 247

Deaths 73 113

No. of patients at 40 months 384 1115

Median follow-up (months) 27.5 30

DFS: letrozole significantly decreased risk of recurrence

p = 0.00004

Letrozole Placebo

0

20

40

60

80

100

Time from randomization (months)

No. at risk (letrozole)

No. at risk (placebo)

0

2583

2587

10

2497

2489

20

1905

1874

30

1110

1075

40

541

519

50

176

164

60

6

8

% o

f p

atie

nts

Goss et al. Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentationGoss et al. J Natl Cancer Inst 2005;97:1262–71

Distant DFS: letrozole reduced risk of distant metastases by 40%

All patients

No. at risk (placebo)

p = 0.002

0

20

40

60

80

100

Time from randomization (months) No. at risk (letrozole)

0

2583

2587

10

2497

2489

20

1905

1874

30

1110

1075

40

541

519

50

176

164

60

6

8

% o

f p

atie

nts

Letrozole Placebo


OS: letrozole reduced mortality by 39% in patients with N+ disease

Letrozole

Placebo

Months from randomization 0 10 20 30 40 50 60

% S

urv

ivin

g

0

20

40

60

80

100

p = 0.04

• No significant increase in OS in total study population or N– disease

• Similar reduction in breast cancer events occurred in N– and N+ diseaseGoss et al. J Natl Cancer Inst 2005;97:1262–71

N+disease

HR 0.61*(95% CI 0.45–0.84)

HR 0.53*(95% CI 0.36–0.78)

HR 0.61*(95% CI 0.38–0.98)

DFS*DistantDFS* OS

N– disease

HR 0.45*(95% CI 0.27–0.75)

HR 0.63(95% CI 0.31–1.27)

HR 1.52(95% CI 0.76–3.06)

MA.17: summary of key efficacy results

A similar reduction in local recurrences, new primaries, and distant recurrences occurred in patients with N+ and N– disease

*Statistically significant benefit of letrozole


MA.17 safety profileLetrozole is comparable to placebo

% of patients

Letrozole Placebo p value

Hot flashes 58 54 0.003

Arthritis/arthralgia 25 21 < 0.0001

Muscle pain 15 12 0.04

Vaginal bleeding 6 8 0.005

Hypercholesterolemia 16 16 0.79

Cardiovascular events 6 6 0.76

Osteoporosis 8 6 0.003

Discontinuations due to AEs 5 4 0.02

Discontinuations for other reasons 4 5 0.1

*90% of AEs grade 1or 2 Goss et al. J Natl Cancer Inst 2005;97:1262–71

ABSCG-6a extended adjuvant trial

Jakesz et al. J Clin Oncol 2005;23:10S(abstract 527)

• Postmenopausal women completing 5 years’ tamoxifen (n = 450) or tamoxifen plus aminoglutethimide (n = 409)

• Re-randomized to anastrozole or no treatment for 3 years (no placebo control)

• Median follow-up 5 years• Anastrozole significantly reduced recurrence:

HR = 0.64, 95% CI 0.41–0.99, p = 0.047• No significant difference in OS• No safety data reported

NCIC CTG MA.17 update

• Duration of therapy• Ingle et al. Breast Cancer Res Treat

March 2006 published online • Post-unblinding analysis

• Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)

Increasing benefit of letrozole with longer duration of treatment

• Purpose• To assess impact of duration of treatment on outcomes for

extended adjuvant letrozole vs placebo in MA.17 as measured by hazard ratios over 48 months

• End points: DFS (primary), distant DFS, OS• Cohorts evaluated

• All randomized patients (n = 5170)• N+ (n = 2360) • N– (n = 2568)

Ingle et al. Breast Cancer Res Treat Mar 2006 published online

Letrozole 2583 2531 2425 2060 1555 1110 768 464244

Placebo 2587 2528 2409 2020 1530 1075 723 436231

Hazard rates for DFS over 48 months(letrozole vs placebo)

Ha

zard

ra

te

Months after randomization

Letrozole

Placebo

0.0000

0.0005

0.0010

0.0015

0.0020

0.0025

0.0030

0.0035

0 6 12 18 24 30 36 42 48


Hazardratio 0.52 0.35 0.45 0.19

0.0

0.2

0.4

0.6

0.8

0 6 12 18 24 30 36 42 48

Haz

ard

rat

io

Months after randomization

Upper 95% confidence limit

Lower 95% confidence limit

Ratio estimate

p < 0.0001 for HR trends based on time-dependent Cox model


Increasing benefit of letrozole with longer duration of treatment: DFS

0.52 I

0.19 I

Increasing benefit of letrozole with longer duration of treatment: summary

• Significant improvements in HR between 12 and 48 months of letrozole vs placebo for DFS and distant DFS overall, for all three endpoints in N+ disease and for DFS in N– disease


DFS Distant DFS OS HR 0.52–0.19 HR 0.43–0.21 HR 0.87–0.79 p < 0.0001 p = 0.0013 p = NS

HR ~0.6–~0.25 HR ~0.35–~0.25 HR ~0.55–~0.4 p = 0.0004 p = 0.0005 p = 0.038

HR ~0.7–~0.5 HR ~0.25–~0.2 HR ~2.0–~2.25 p = 0.027 p = NS p = NS

N+disease

N–disease

*Statistically significant benefit of letrozole

• Recent guidelines recommend • ASCO 2004: a minimum of 2.5 years of extended letrozole

consistent with median follow-up of MA.17• NCCN 2006: 5 years of letrozole following 5 years of tamoxifen• St Gallen: switch to AI (letrozole) after 5 years of tamoxifen

• Ingle et al. study shows that, at least to about 48 months, longer duration of letrozole is associated with greater benefit

• Based on these data* extended adjuvant letrozole therapy should be for at least 4 years

Winer et al. J Clin Oncol 2005;23:1609–10; Goldhirsch et al. Ann Oncol 2005;16:1569–83; National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology – v.2.2006, Breast Cancer. At:

www.nccn.org/professionals/physician_gls/PDF/breast.pdf; *Ingle et al. Breast Cancer Res Treat Mar 2006 published online

Increasing benefit of letrozole with longer duration of treatment:

conclusions

http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf

Late extended adjuvant therapy Analysis post-unblinding

Tamoxifenn = 5187 Placebo n = 2594

5 years

Letrozole n = 2593 Letrozole (Let) n = 2457

No Letrozole (Plac) n = 613

Letrozole (Plac–Let) n = 1655

Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)

Purpose: compare placebo–letrozole vs placebo to determine benefits/safety of starting letrozole after prolonged periods (1–5 years) off tamoxifen

Median F/U (months)

30 54Unblinding

0–3 mo

Significantly different baseline characteristics (all p < 0.01)


92

49 49

66

96

57

33

80

0

20

40

60

80

100

120

Age < 70 years ECOG = 0 N– Prior CTx

Pe

r ce

nt

Plac–Let

Plac

Time from randomization (months)

DFSAdjusted HR: 0.31 (0.18–0.55); p < 0.0001

0

20

40

60

80

100

0 20 40 60 80

Plac–LetPlac

Per

cen

tag

e d

isea

se-f

ree


Late extended adjuvant therapy analysis post-unblinding: DFS

Late extended adjuvant therapy analysis post-unblinding

p < 0.0001p = 0.002

p = 0.05

p = 0.012

Haz

ard

rat

io(p

lace

bo

–let

rozo

le v

s p

lace

bo

)


Summary of efficacy

0.310.28

0.53

0.23

0

0.1

0.2

0.3

0.4

0.5

0.6

DFS Distant DFS OS CBC

Plac–Let Plac

p = 0.60

p = 0.007

p = 0.84

Inci

den

ce (

%)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

Fracture New osteoporosis CV disease


Late extended adjuvant therapy analysis post-unblinding

Adverse events

MA.17: updated analysis safety conclusions

• Letrozole associated with low-grade estrogen depletion symptoms • Overall QoL unaffected (in ~3600 women)

• No changes in CV events or lipid profiles• Mild decreases in bone density, but no significant

increase in fracture risk • Bone density changes can be easily monitored

and corrected

• AEs with letrozole after unblinding similar to those in the main trial for osteoporosis, fractures, and CV disease

MA.17: updated analysis efficacy conclusions

• Letrozole significantly increased DFS and distant DFS (all patients) and OS (patients with N+ disease)

• Benefit with letrozole increased with treatment duration

• Late extended adjuvant letrozole (after prolonged treatment-free interval) significantly improved all outcomes

• Women with long tamoxifen-free periods should be considered for letrozole therapy

• International guidelines*: based on MA.17 findings postmenopausal women with HR+ EBC finishing 5 years of tamoxifen should consider treatment with letrozole

• Updated analysis suggests extended adjuvant letrozole therapy should be for at least 4 years

*Winer et al. J Clin Oncol 2005;23:1609–10; Goldhirsch et al. Ann Oncol 2005;16:1569–83; National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology – v.2.2006, Breast Cancer. At:

www.nccn.org/professionals/physician_gls/PDF/breast.pdf

MA.17R re-randomization study

5 15100

Years post-surgery

Tamoxifen

Placebo

Letrozole*

MA.17+

Non-study patients

n = 900

n = 900MA.17R

*Women remaining disease-free

Non-study patients

MA.17 n= 800

Goss et al. Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentation

These slides were released by the speaker for internal use by Novartis

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