(Continued) Results Results (Continued) Methods ...

Presented at the 2014 San Antonio Breast Cancer Symposium (SABCS); December 9-13, 2014; San Antonio, Texas, USA. Poster P3-06-04.

4EVER: The Impact of mTOR Inhibition on Bone Health in Postmenopausal Women With Hormone Receptor Positive (HR ) Advanced Breast Cancer Treated With Everolimus (EVE) in Combination With Exemestane (EXE) +

P. Hadji, H. Tesch, O. Stoetzer, T. Decker, C. Kurbacher, F. Marmé, A. Schneeweiss, C. Mundhenke, J. Distelrath, P.A. Fasching, M. Lux, D. Lueftner, W. Janni, M. Muth, J. Kreuzeder, E. Grischke 1

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Hospital North West GmbH, Frankfurt am Main, Germany; 2Department of Oncology, Bethanien Hospital, Frankfurt am Main, Germany; 3Department of Haemato-Oncology, Munich, Germany; 4Oncology Ravensburg, Ravensburg, Germany; 5Medical Centre Bonn Friedensplatz, Bonn, Germany; 6Department of Obstetrics and Gynecology, University Hospital Heidelberg, Heidelberg, Germany; 7 National Center for Tumor Diseases, Heidelberg, Germany; 8Department of Obstetrics and Gynecology, University Hospital Kiel, Kiel, Germany; 9Medical Healthcare Centre East Hessen GmbH, Fulda, Germany; 10Department of Obstetrics and Gynaecology, University Hospital Erlangen, Erlangen, Germany; 11 Med. Clinic for Haematology, Oncology, and Tumor Immunology, Charité Campus Benjamin Franklin, Berlin, Germany; 12Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany; 13Novartis Pharma GmbH, Nuremberg, Germany; 14Department of Obstetrics and Gynecology, University of Tuebingen, Germany

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TNF/RANKL PIP3

PIP3

PI3K PDK1 p110

Akt

p85

LY294002 auto P

Rac1

Cdc42 GGTI-2

TSC1/2

Figure 4. P1NP levels in patients with bone metastases with or without antiresorptive treatment.

● T he 4EVER trial further evaluated the efficacy and safety of EVE+EXE in a broader patient population than in BOLERO-2. In 4EVER there were no limitations on ○ Number of previous chemotherapy lines for advanced disease ○ Time of recurrence or progression after NSAI therapy ○ Previous EXE therapy ● Therefore, the patient population in the 4EVER trial was more advanced and heavily pretreated than in the BOLERO-2 study5 ● Our results are consistent with the results of the exploratory bone analysis from the BOLERO-2 study, which had suggested a possible bone-protective effect with EVE+EXE2 ○ Notably, these exploratory analyses include an additional timepoint (week 24) and a different bone metabolism biomarker (osteocalcin) than in BOLERO-2 ● Bone metabolism biomarker levels would generally be expected to show marked differences over baseline, especially in the absence of concomitant treatment with antiresorptive agents in patients with bone metastases. However, CTX, P1NP, and osteocalcin levels remained stable regardless of the use of antiresorptive agents in the 4EVER trial ○ These data suggest that the addition of EVE to EXE may have stabilized CTX, P1NP, and osteocalcin levels ● The results from this exploratory analysis from 4EVER should be treated as hypothesis generating, and should be interpreted in the context of the study limitations: ○ Limited sample size (especially for the bone turnover marker subset) ○ Lack of a placebo arm ● Additional exploratory analyses from 4EVER (into biomarkers of bone metabolism and endocrine hormones) will be reported in the future

Endpoints

● P  rimary endpoint was overall response rate (ORR; complete response + partial response) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 after week 24 ● Secondary endpoints include ○ PFS ○ ORR after week 48 ○ Overall survival (OS) ○ Safety assessed with the Common Terminology Criteria for Adverse Events, version 4.03 – Incidence of adverse events (AEs), serious AEs (SAEs), changes from baseline in vital signs, Eastern Cooperative Oncology Group performance status, and laboratory results (hematology, blood chemistry—if resulting in AE) were reported ● Exploratory endpoints include ○ Correlation of response to EVE+EXE, with pharmacogenetics 2 draft 1.1 7033 ○ Figure Presence and molecular characteristics of circulating tumor cells ○ Correlation of anxiety and depression with interleukin-6 levels ○ Changes in serum biomarkers of bone metabolism

RIP

IKKα IKKβ

Caspase-8

IKKγ

S6K

4E-BP1

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Figure 2. Study design. Primary Endpoint: ORR after 24 weeks PMW with HR+, HER2– ABC following NSAI

MST1

Objective ● T o further investigate the longer-term effect of mTOR inhibition on bone health as assessed by changes in marker levels of bone resorption (CTX) and bone formation (P1NP and osteocalcin) in the subset of patients with bone metastases in the 4EVER trial



T rial database lock occurred in June 2014 A total of 299 patients (Safety Set) were enrolled from May 2012 to November 2012 ○ The Full Analysis Set 1 included 281 patients Bone metastases were detected at baseline in 174 patients ○ CTX, P1NP, and osteocalcin levels were measured in patients with bone metastases The median relative differences from baseline in CTX (Figure 3), P1NP (Figure 4), and osteocalcin (Figure 5) levels were examined in patients with bone metastases at baseline with or without antiresorptive therapy ○ There were no significant differences in bone metabolism biomarker levels from baseline to week 24 regardless of the presence or absence of prior or concomitant antiresorptive treatment ○ Use of prior antiresorptive treatment was markedly different from the use of concomitant antiresorptive treatment – The majority of patients in this exploratory analysis did not receive prior antiresorptive treatment (Figures 3-5; Panel A for each) – However, most did receive concomitant antiresorptive treatment (Figures 3-5; Panel B for each)

7033 Figure 4 draft 1.2

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A. P1NP Levels With or Without Prior Antiresorptive Treatment 150

Prior Anresorpve Treatment No

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Yes

50 0 –50 –100 n = 74 n = 33

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n = 62 n = 20 8

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n = 31 n = 11 16

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B. P1NP Levels With or Without Concomitant Antiresorptive Treatment 80

Concomitant Anresorpve Treatment No

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40 20 0 –20

Acknowledgements

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n = 25 n = 82

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n = 14 n = 68 8

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n=5 n = 37 16

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Everolimus 10 mg/d + Exemestane 25 mg/d

Secondary Endpoints: PFS, ORR after 48 weeks, OS, Safety, QoL, ECOG-PS status, Pharmacoeconomics Exploratory Endpoints: Pharmacogenetics, CTC levels, IL-6 levels, Bone biomarkers

Treatment for 48 weeks or until progression, unacceptable toxicity, death, or consent withdrawal Abbreviations: ABC, advanced breast cancer; CTC, circulating tumor cell; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; HR+, hormone receptor–positive; HER2–, human epidermal growth factor receptor 2–negative; NSAI, nonsteroidal aromatase inhibitor; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PMW, postmenopausal women; QoL, quality-of-life.

Exploratory Bone Biomarker Analysis

● P  lanned exploratory analysis of changes in bone metabolism biomarker levels was conducted in the subset of patients with bone metastases at baseline ○ Analyses performed in patients with or without antiresorptive therapy ● Assessed changes of bone metabolism biomarker levels from day 1 to weeks 4, 12, and 24 ○ CTX (bone resorption) ○ P1NP (bone formation) ○ Osteocalcin (bone formation) – Changes in other bone metabolism and endocrine biomarkers (vitamin D, testosterone, estradiol, dehydroepiandrosterone, sex hormone-binding globulin, parathyroid hormone, thyroid-stimulating hormone, follicle-stimulating hormone) will be assessed in the future

Abbreviations: P1NP, amino-terminal propeptide of type 1 collagen; SD, standard deviation.

A. CTX Levels With or Without Prior Antiresorptive Treatment 200

Prior Antiresorptive Treatment

Figure 5. Osteocalcin levels in patients with bone metastases with or without antiresorptive treatment.

No

150

Yes

7033 Figure 5 draft 1.2

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The results are presented on behalf of all participating sites of the 4EVER study. We thank the patients for their participation, as well as the staff at each site—all of whom significantly contributed to the success of the study. Medical editorial and graphics assistance for this poster presentation was supported by Novartis Pharmaceuticals Corporation.

References

7033 Figure 3 draft 1.2

APOPTOSIS

● T he 4EVER trial further evaluated the efficacy and safety of EVE+EXE in a broader patient population than in BOLERO-2. In 4EVER there were no limitations on ○ Number of previous chemotherapy lines for advanced disease ○ Time of recurrence or progression after NSAI therapy ○ Previous EXE therapy ● The long-term influence of mTOR inhibition by EVE on bone health was investigated in the exploratory analyses of the 4EVER trial ○ Here we report changes in marker levels for bone resorption (CTX) and bone formation (P1NP and osteocalcin) in the subset of patients with bone metastases

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Caspase-3

Abbreviations: Akt, protein kinase B; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; P, phosphate; RANKL, receptor activator of nuclear factor-kappa B ligand; S6K, 40 S ribosomal S6 kinase; Src, steroid receptor coactivator; TNF, tumor necrosis factor; TSC, tuberous sclerosis complex. Reprinted from Glantschnig H, et al.4

Results

Figure 3. CTX levels in patients with bone metastases with or without antiresorptive treatment.

Translaon of survival factors/inhibion of apoptosis Caspase-9

● T he Safety Set includes all patients who received at least 1 dose of study drug and had at least 1 postbaseline safety assessment ● The Full Analysis Set 1 includes all patients who received at least 1 dose of study drug, with the exception of 18 patients from centers with issues of Good Clinical Practice noncompliance ● Descriptive statistics were used to summarize the single bone metabolism biomarkers by visit and difference from baseline; linear regression models were not used

Mean Relave Difference From Baseline (± SD), %

● M  ulticenter, open-label, single-arm, phase IIIB study examining everolimus (10 mg daily) and exemestane (25 mg daily; Figure 2) ● Postmenopausal women with HR+, HER2– metastatic or locally advanced breast cancer that recurred or progressed during or after an NSAI were enrolled ● Study treatment was for 48 weeks or until progression, unacceptable toxicity, death, or consent withdrawal ○ Further treatment after progression was at the investigator’s discretion ● Tumor evaluations through computed tomography were performed for screening, at 24 weeks, and at 48 weeks or end of treatment ● Study visits were performed at baseline (day 1) and at weeks 4, 12, 24, 36, and 48 or end of treatment

MAPK

Rapamycin

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Patient Populations and Statistical Methods

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MEK1/2 NEK6/7

Study Design and Treatment

Mean Relave Difference From Baseline (± SD), %

M-CSF

Discussion

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Y ardley DA, et al. Adv Ther. 2013;30(10):870-884. Gnant M, et al. J Natl Cancer Inst. 2013;105(9):645-663. Hadji P, et al. Crit Rev Oncol Hematol. 2013;87(2):101-111. Glantschnig H, et al. Cell Death Differ. 2003;10(10):1165-1177. Tesch H, et al. SABCS 2014. Poster P5-19-06.

A. Osteocalcin Levels With or Without Prior Antiresorptive Treatment

50 0 –50 –100

n = 76 n = 32

–150 0

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n = 66 n = 19 8

12 Time, weeks

n = 29 n = 13 16

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B. CTX Levels With or Without Concomitant Antiresorptive Treatment 250

Concomitant Antiresorptive Treatment No

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Mean Relave Difference From Baseline (± SD), %

Figure 1. Schematic illustration of mTOR/S6K intracellular signal transduction pathways in the osteoclast.3

Results (Continued)

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n = 75 n = 33

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n = 66 n = 21 8

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n = 31 n = 12 16

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B. Osteocalcin Levels With or Without Concomitant Antiresorptive Treatment

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n = 27 n = 81

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n = 15 n = 70 8

12 Time, weeks

n=5 n = 37 16

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Abbreviations: CTX, C-terminal cross-linking telopeptide of type 1 collagen; SD, standard deviation.

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Mean Relave Difference From Baseline (± SD), %

This tagline is for information only; DO NOT PRINT

Methods (Continued)

Mean Relative Difference From Baseline (± SD), %

● T he phase III BOLERO-2 trial demonstrated that everolimus (EVE) + exemestane (EXE) more than doubled median progression-free survival (PFS) compared with placebo (PBO) + EXE in postmenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer progressing after nonsteroidal aromatase inhibitor (NSAI) therapy1 ○ Final PFS by investigator review: 7.8 versus 3.2 months; hazard ratio (HR) = 0.45; 95% confidence interval (CI), 0.38-0.54; P < .0001 ○ Final PFS by central review: 11.0 versus 4.1 months; HR = 0.38; 95% CI, 0.31-0.48; P < .0001 ● An exploratory analysis of BOLERO-2 indicated a direct impact of EVE on bone health2 ○ Bone markers assessed in BOLERO-2 were – Bone-specific alkaline phosphatase (BSAP, osteoclast metabolism) – C-terminal cross-linking telopeptide of type 1 collagen (CTX, bone resorption) – Amino-terminal propeptide of type 1 collagen (P1NP, bone formation) ○ Bone marker levels at 6 and 12 weeks decreased with EVE+EXE versus increasing with PBO+EXE ○ The cumulative incidence rate of progressive disease in bone was lower with EVE+EXE versus PBO+EXE (P = .04, Gray’s test) ● Figure 1 depicts a schematic overview of intracellular mammalian target of rapamycin (mTOR) 7033 Figure 1 draft 1.1 signaling in the osteoclast

Methods

Mean Relative Difference From Baseline (± SD), %

Introduction

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Concomitant Anresorpve Treatment

Mobile Friendly e-Prints

No

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Text Message (SMS)

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Scan this QR code

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n = 26 n = 82

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n = 16 n = 71 8

12 Time, weeks

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Text: Qefbfd to: 8NOVA (86682) US Only +18324604729 North, Central and South Americas; Caribbean; China +447860024038 UK, Europe & Russia +46737494608 Sweden, Europe

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n=6 n = 37 16

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Abbreviation: SD, standard deviation.

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