everolimus in postmenopausal hormone-receptor–positive advanced breast cancer

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Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer José Baselga, M.D., Ph.D., Mario Campone, M.D., Ph.D., Martine Piccart, M.D., Ph.D., Howard A. Burris III, M.D., Hope S. Rugo, M.D., Tarek Sahmoud, M.D., Ph.D., Shinzaburo Noguchi, M.D., Michael Gnant, M.D., Kathleen I. Pritchard, M.D., Fabienne Lebrun, M.D., J. Thaddeus Beck, M.D., Yoshinori Ito, M.D., Denise Yardley, M.D., Ines Deleu, M.D., Alejandra Perez, M.D., Thomas Bachelot, M.D., Ph.D., Luc Vittori, M.Sc., Zhiying Xu, Ph.D., Pabak Mukhopadhyay, Ph.D., David Lebwohl, M.D., and Gabriel N. Hortobagyi, M.D. N Engl J Med 2012;366:520-9

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Page 1: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

José Baselga, M.D., Ph.D., Mario Campone, M.D., Ph.D., Martine Piccart, M.D., Ph.D., Howard A. Burris III, M.D., Hope S. Rugo, M.D., Tarek Sahmoud,

M.D., Ph.D., Shinzaburo Noguchi, M.D., Michael Gnant, M.D., Kathleen I. Pritchard, M.D., Fabienne Lebrun, M.D., J. Thaddeus Beck, M.D., Yoshinori

Ito, M.D., Denise Yardley, M.D., Ines Deleu, M.D., Alejandra Perez, M.D., Thomas Bachelot, M.D., Ph.D., Luc Vittori, M.Sc., Zhiying Xu, Ph.D., Pabak

Mukhopadhyay, Ph.D., David Lebwohl, M.D., and Gabriel N. Hortobagyi, M.D.

N Engl J Med 2012;366:520-9

Page 2: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

Disclosures

• Study supported by funding from Novartis

– ClinicalTrials.gov identifier NCT00863655

• J Baselga, MD, PhD, is a consultant to Novartis, Roche, Merck, Sanofi-Aventis, Verastem, Bayer, Chugai, Exelixis, Onyx, Constellation

2

Page 3: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

Crosstalk between ER and mTOR Signaling

• mTORC1 activates ER in a ligand-independent fashion1

• Estradiol suppresses apoptosis induced by PI3K/mTOR blockade2

• Hyperactivation of the PI3K/mTOR pathway is observed in endocrine-resistant breast cancer cells3

• mTOR is a rational target to enhance the efficacy of hormonal therapy

1. Yamnik, RL. J Biol Chem 2009; 284(10):6361-6369.2. Crowder, RJ. Cancer Res 2009;69:3955-62.3. Miller, TW. J Clin Invest 2010; 120(7):2406-2413. 3

Page 4: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

Everolimus Enhances Activity of Letrozole

*P < 0.001 (synergistic drug interaction).

Boulay A, et al. Clin Cancer Res 2005;11:5319-28.

* *0

20

40

60

80

100

0 0.2 2

Rela

tive

prol

ifera

tion

(%)

Everolimus (nM)

Vehicle100 nM Letrozole500 nM Letrozole

**

4

Page 5: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

Ph II Neoadjuvant Letrozole ± Everolimus:Proof of Concept

Everolimus 10 mg/day +Letrozole 2.5 mg/day

Placebo +Letrozole 2.5 mg/day

ORR

Biomarkers:D14 and surgical

specimen

N= 270Postmenopausal ER+ early breast

cancer

Results:•Significantly higher response rate (primary endpoint) Everolimus arm 68% vs placebo arm 59%•Significantly greater decrease in Ki67 proliferation index Everolimus arm 57% vs placebo arm 30%

Surgery

Page 6: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

2

1

Everolimus 10 mg/day +Exemestane 25 mg/day

(N = 485)

Placebo +Exemestane 25 mg/day

(N = 239)

BOLERO-2: Trial Design

ABC: advanced breast cancer, NSAI: non steroidal aromatase inhibitors, HER2-: human epidermal growth factor receptor 2 – negative; PFS: progression-free survival; PK: pharmacokinetics

Stratification:

1. Sensitivity to prior hormonal therapy

2. Presence of visceral disease

No cross-over

J. Baselga et al. N Engl J Med 2012;366:520-9 6

N = 724

Postmenopausal

ER+ HER2- ABC refractory to letrozole or anastrozole

PFS

OSORR

Bone MarkersSafety

PK

Page 7: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

BOLERO-2: Statistical Design

• Primary end point: progression-free survival

– 26% risk reduction (hazard ratio = 0.74)

– 528 events to achieve 90% power– One interim analysis after ~60% of events

– O’Brien-Fleming boundary: P < 0.0065

– Assessment by investigator and independent central review

PFS crossed prespecified boundaries at interim analysis,cut-off February 11, 2011

Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.

7J. Baselga et al. N Engl J Med 2012;366:520-9

Page 8: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

BOLERO-2: Baseline Characteristics

Characteristic

Everolimus +Exemestane(N=485), %

Placebo +Exemestane(N=239), %

Median age (range), years 62 (34-93) 61 (28-90)

Race

Caucasian 74 78

Asian 20 19

Performance status 0 60 59

Liver involvement 33 30

Lung involvement 29 33

Measurable diseasea 70 68

a All other patients had ≥ 1 bone lesion.

8J. Baselga et al. N Engl J Med 2012;366:520-9

Page 9: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

BOLERO-2: Prior Therapy

Therapy

Everolimus + Exemestane(N=485), %

Placebo +Exemestane(N=239), %

Sensitivity to prior hormonal therapy 84 84

LET or ANA as most recent treatment 74 75

Purpose of most recent treatment

Adjuvant therapy 21 16

Treatment of advanced or metastatic disease

79 84

Previous treatment with tamoxifen 47 49

Previous treatment with fulvestrant 17 16

Previous chemotherapy for treatment of metastatic disease*

26 26

Number of prior therapies: ≥3 54 53LET: letrozole, ANA: anastrozole * with or without neoadjuvant or adjuvant therapy

9J. Baselga et al. N Engl J Med 2012;366:520-9

Page 10: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

BOLERO-2: Patient Disposition

Disposition

Everolimus + Exemestane(N=485), %

Placebo +Exemestane (N=239), %

Protocol therapy ongoing 47 29

Discontinued 53 71

Disease progression 37 66

Adverse event 6.6 2.5

Subject withdrew consent 6.8 2.1

Death due to AE 1.4 0.4

New cancer therapy 0.4 0

Protocol deviation 0.6 0

Abnormal laboratory value 0 0.4

Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 10

Page 11: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

BOLERO-2 Primary Endpoint: PFS Local Assessment

Everolimus 458 398 294 212 144 108 75 51 34 18 8 3 3 0 Placebo 239 177 109 70 36 26 16 14 9 4 3 1 0 0

Time (weeks)

No. of Patients Still at Risk:

0 126 18 24 30 36 48 6042 54 7266 78

80

60

40

20

100

0

Pro

ba

bil

ity

of

Ev

en

t (%

)

Everolimus + Exemestane (E/N=202/485)Placebo + Exemestane (E/N=157/239)

HR = 0.43 (95% CI: 0.35–0.54)

EVE + EXE: 6.9 monthsPBO + EXE: 2.8 months

P<0.001 by log-rank test

11J. Baselga et al. N Engl J Med 2012;366:520-9

Page 12: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

BOLERO-2 Primary Endpoint: PFS Central Assessment

Time (weeks)

HR = 0.36 (95% CI: 0.27–0.47)

EVE + EXE: 10.6 MonthsPBO + EXE: 4.1 Months

P<0.001 by log-rank test

0 126 18 24 30 36 48 6042 54 7266 78

80

60

40

20

100

0

Pro

ba

bil

ity

of

Ev

en

t (%

)

Everolimus + Exemestane (E/N=114/485)Placebo + Exemestane (E/N=104/239)

No. of Patients Still at Risk: Everolimus 458 385 281 201 132 102 67 43 28 18 9 3 2 0Placebo 239 168 94 55 33 20 11 11 6 3 3 1 0 0

12J. Baselga et al. N Engl J Med 2012;366:520-9

Page 13: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

BOLERO 2: PFS Subgroup Analyses

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5

All (724)

Subgroups (N)

Hazard Ratio

Favors PBO + EXEFavors EVE + EXE

Sensitivity to prior hormonal therapyYes (610)No (114)

RegionAsia (137)Europe (275)North America (274)Other (38)

Age<65 (449)≥65 (275)

Last therapyAromatase inhibitor (532)Antiestrogen (122)Other (70)

Last therapy settingMetastatic (586)Adjuvant (138)

Prior chemotherapyAdjuvant only (306)Metastatic (186)None (232)

Visceral metastasisYes (406)No (318)

13J. Baselga et al. N Engl J Med 2012;366:520-9

Page 14: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

BOLERO-2: Overall Response Rate and Clinical Benefit Rate by Local Assessment

P < 0.0001

P < 0.0001

Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 14

Page 15: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

BOLERO-2: Overall Survival

As of PFS interim analysis: 83 deaths 10.7% in everolimus arm 13.0% in placebo arm

OS interim analysis after 173 events

OS final analysis at 392 events 80% power to detect 26% reduction in

hazard ratio (0.74)

15Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.

Page 16: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

BOLERO-2: Most Common G3/4 AEs

Everolimus + Exemestane

(N = 482), %Placebo + Exemestane

(N = 238), %

All Grades

Grade 3

Grade 4

All Grades

Grade 3

Grade 4

Stomatitis 56 8 0 11 1 0

Fatigue 33 3 <1 26 1 0

Dyspnea 18 4 0 9 1 <1

Anemia 16 5 1 4 <1 <1

Hyperglycemia 13 4 <1 2 <1 0

AST 13 3 <1 6 1 0

Pneumonitis 12 3 0 0 0 0

AE: Adverse Event; AST: Aspartate aminotransferase

16J. Baselga et al. N Engl J Med 2012;366:520-9

Page 17: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

Global Health Status EORTC-QLQ30 QoL Scale Score: Time to ≥5% deterioration

100

90

80

70

60

50

40

30

20

10

0

0 6 12 18 24 30 36 42 48 54 60 66 72 78

Time, weeksNo. of patients still at riskEverolimusPlacebo

485 404 236239 190 94

161 112 84 5662 41 23 13

37 23 18 129 5 2 1

2 1 00 0 0

Pro

bab

ilit

y o

f E

ven

t, %

Everolimus + Exemestane (E/N = 226/485)Placebo + Exemestane (E/N = 98/239)

EVE + EXE: 4.5 monthsPBO + EXE: 4.4 months

Log rank P value = 0.217HR = 0.91 (95% CI: 0.68–1.20)

Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 17

Page 18: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

BOLERO-2: Summary

• Addition of everolimus to exemestane prolongs PFS in patients with ER+ HER2- breast cancer refractory to initial non-steroidal aromatase inhibitors

– Local: median 6.9 vs 2.8 months, HR = 0.43, P < 0.001

– Central: median 10.6 vs 4.1 months, HR = 0.36, P < 0.001

• Benefit is observed in all subgroups

• Adverse events are consistent with previous experience with everolimus including stomatitis, fatigue, non-infectious pneumonitis and hyperglycemia

18J. Baselga et al. N Engl J Med 2012;366:520-9

Page 19: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

BOLERO-2: Conclusions

Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.

• Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory ER+ patients

• Our results could represent a paradigm shift in the management of patients with hormone receptor-positive breast cancer

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Page 20: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

Participating Countries

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Page 21: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

Acknowledgments

• The patients participating in this trial, and the study investigators

• Independent data monitoring committee members–Edith A. Perez

–Toru Watanabe

–David Harrington

–Xavier Pivot

• Steering committee members:– José Baselga

– Gabriel N. Hortobagyi

– Martine Piccart

– Howard Burris

– Hope S. Rugo

– Shinzaburo Noguchi

– Michael Gnant

– Kathleen I. Pritchard

– Pabak Mukhopadhyay

– Luc Vittori

– Tarek Sahmoud

Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 21