Hormone Receptor Positive Metastatic Breast Cancer

Hormone Receptor Positive Metastatic Breast Cancer
11/8/ :41 PM Hormone Receptor Positive Metastatic Breast Cancer © 2007 Microsoft Corporation. All rights reserved. Microsoft, Windows, Windows Vista and other product names are or may be registered trademarks and/or trademarks in the U.S. and/or other countries. The information herein is for informational purposes only and represents the current view of Microsoft Corporation as of the date of this presentation. Because Microsoft must respond to changing market conditions, it should not be interpreted to be a commitment on the part of Microsoft, and Microsoft cannot guarantee the accuracy of any information provided after the date of this presentation. MICROSOFT MAKES NO WARRANTIES, EXPRESS, IMPLIED OR STATUTORY, AS TO THE INFORMATION IN THIS PRESENTATION.

11/8/2018

ON THE TREATMENT OF INOPERABLE CASES OF CARCINOMA OF THE MAMMA:
The Lancet July 11, 1895 ON THE TREATMENT OF INOPERABLE CASES OF CARCINOMA OF THE MAMMA: SUGGESTIONS FOR A NEW METHOD OF TREATMENT, WITH ILLUSTRA- TIVE CASES.1 BY GEORGE THOMAS BEATSON, M.D. EDIN., SURGEON TO THE GLASGOW CANCER HOSPITAL; ASSISTANT SURGEON, GLASGOW WESTERN INFIRMARY: AND EXAMINER IN SURGERY TO THE UNIVERSITY OF EDINBURG “Apsley-place, May 6th, 1895 “Dear Dr. Beatson,-The bearer is, and has been, suffering, I fear, from a malignant breast. She has been in the Royal Infirmary before she came to me. My own opinion is that nothing can be done for her, but as she is a woman of great courage you might have a look at it for my sake, and perhaps you can order her something in the way of dress- ing. Even this little will be accepted by her as a great deal. “With kindest regards, yours very truly, “James W. Wallace.”

Endocrine-Based Therapies for Breast Cancer
Year Agent Mechanism 1977 SERMs Tamoxifen Toremifene Antagonizes ER in breast tissue 1990s AIs Anastrozole Exemestane Letrozole Inhibit estrogen production in postmenopausal women 2000s ERD Fulvestrant Impairs ER dimerization, increases ER degradation, and disrupts nuclear localization of ER 2010s Combinations Exemestane/everolimus Letrozole/palbociclib Fulvestrant/palbociclib Blockade of estrogen signaling and prosurvival or cell cycle pathways AI, aromatase inhibitor; ERD, estrogen receptor downregulator; SERM, selective estrogen receptor modulator. Lim E, et al. Oncology (Williston Park). 2012;26: Croxtall JD, et al. Drugs. 2011;71: Vidula N, et al. Clin Breast Cancer. 2016;16:8-17. Mustonen MV, et al. World J Clin Oncol. 2014;5: Slide credit: clinicaloptions.com

Endocrine Therapy is the preferred option for hormone receptor positive disease, even in the presence of visceral disease, unless there is concern or proof of endocrine resistance or there is disease needing a fast response

11/8/2018

Endocrine Therapy vs Chemotherapy in Endocrine Responsive Breast Cancer

Chemotherapy vs Endocrine Therapy Metastatic Disease
First Line Metastatic Breast Cancer Age > 65 N= 181 CMF TAMOXIFEN Taylor SG, et al. Ann Int Med 1986;104(4):

Results Chemotherapy Tamoxifen P value ORR 38% 45% 0.29 CR 5% 11% PR
33% 34% Duration of response 7.9 months 10.4 months 0.25 Time to Treatment Failure 6.2 months 0.42 OS 20.9 months 23.3 months 0.20

International Consensus Guidelines for Advanced Breast cancer Definitions
Visceral Crisis is defined as severe organ dysfunction as assessed by signs and symptoms, laboratory studies and rapid progression of disease Visceral crisis is not the mere presecne of visceral metastases, but implies important visceral compromise leading to a clinical indication for a more rapidly efficacious therapy

International Consensus Guidelines for Advanced Breast cancer Definitions
Endocrine Resistance is defined as Primary: relapse while on the first 2 years of adjuvant endocrine therapy or progression within the first 6 months of first line endocrine therapy Secondary: relapse while on adjuvant endocrine therapy but after the first 2 years or a relapse within 12 months of completing adjuvant endocrine therapy or progression > 6 months after initiating endocrine therapy for metastatic breast cancer.

Major Goals of Endocrine Therapy in MBC
Reduce cancer-related symptoms Increase progression-free survival Increase time to chemotherapy Improve quality of life Increase overall survival The goals of endocrine therapy for patients with hormone receptor–positive breast cancer depend on the stage of the disease. In patients with metastatic disease, endocrine therapy is used to limit disease burden, improve quality of life, and improve disease-free survival and overall survival. In patients with early breast cancer, endocrine therapy aims to prolong disease-free survival and overall survival while minimizing side effects. In the prevention setting, the risk/benefit ratio will determine the usefulness of endocrine treatment.

Stable disease on hormone therapy provides similar benefit as CR or PR
Compare Survival with Stable Disease (Clinical Benefit) to Survival with CR or PR with Anastrozole Use in ABC Clinical Benefit = CR + PR + Stable  24 wks 100 80 At 2-Year Risk Deaths Estimate CR or PR % Stable  24wk % Other % 60 Survival (%) 40 20 1 2 3 4 Years From Randomization Stable disease on hormone therapy provides similar benefit as CR or PR ABC = advanced breast cancer, Clinical benefit = no prognosis for > 24wks Robertson JF, et al. Breast Cancer Res Treat. 1999;58:

Patients with Disease Progression on One Hormone Therapy May Respond to Another Hormone Therapy
C 40% 30% 25% 15% 1st Line 2nd Line 3rd Line 4th Line An optimal sequence of hormone therapies has not been defined Bavior C, et al. Ann Oncol Epub Feb 8; Osborne Ck, Schiff R. Ann Res Med 2011;62:

Endocrine Agents for Postmenopausal Breast Cancer
SERMs Tamoxifen Toremifene Raloxifene Estrogens Estradiol DES, EE2 ER-Down Regulator Fulvestrant Aromatase Inhibitors Anastrozole Letrozole Exemestane Progestins Megestrol Acetate MPA Androgens Fluoxymesterone

Initial Treatment of Hormone Receptor–Positive Advanced Breast Cancer
Premenopausal SOC: ovarian suppression or ablation plus endocrine therapy as recommended for postmenopausal women[1] Postmenopausal SOC: AIs due to improved efficacy vs tamoxifen[1] Fulvestrant has demonstrated similar efficacy vs tamoxifen[5] Preliminary evidence suggests that fulvestrant may demonstrate improved efficacy vs anastrozole[6,7] TTP, fulvestrant vs anastrozole: 23.4 vs 13.1 mos[6] AI Parameter AI vs Tamoxifen, Mos Anastrozole[2] TTP 10.7 vs 6.4 Letrozole[3] 9.4 vs 6.0 Exemestane[4] PFS 9.9 vs 5.8 AI, aromatase inhibitor; SOC, standard of care; TTP, time to progression. 1. NCCN Guidelines. Breast Cancer. v Bonneterre J, et al. Cancer. 2001;92: Mouridsen H, et al. J Clin Oncol. 2003;21: Paridaens RJ, et al. J Clin Oncol. 2008;26: Howell A, et al. J Clin Oncol. 2004;22: Robertson FJ, et al. Breast Cancer Res Treat. 2012;136: Ellis MJ, et al. J Clin Oncol. 2015;33: Slide credit: clinicaloptions.com

Endocrine Therapy in Premenopausal Patients
CMF ~ Tamoxifen CMF ~ Ovarian Suppression Ovarian Suppression ~ Tamoxifen

Klijn JG, et al J Clin Oncol 2001
Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials Klijn JG, et al J Clin Oncol 2001

Fig 4. Progression-free survival curves for LHRH agonist and LHRH agonist + tamoxifen
Klijn, J. G.M. et al. J Clin Oncol; 19:

Fig 1. Overall survival curves for LHRH agonist and LHRH agonist + tamoxifen
Klijn, J. G.M. et al. J Clin Oncol; 19:

Fig 7. Objective response rate stratified by study
Response Rate 30% on LHRH agonist alone and 39% on the combined treatment P=0.03 Fig 7. Objective response rate stratified by study Klijn, J. G.M. et al. J Clin Oncol; 19:

Endocrine Therapy for Postmenopausal Women: Recent Advances

Initial Treatment of Hormone Receptor–Positive Advanced Breast Cancer
Premenopausal SOC: ovarian suppression or ablation plus endocrine therapy as recommended for postmenopausal women[1] Postmenopausal SOC: AIs due to improved efficacy vs tamoxifen[1] Fulvestrant has demonstrated similar efficacy vs tamoxifen[5] Preliminary evidence suggests that fulvestrant may demonstrate improved efficacy vs anastrozole[6,7] TTP, fulvestrant vs anastrozole: 23.4 vs 13.1 mos[6] AI Parameter AI vs Tamoxifen, Mos Anastrozole[2] TTP 10.7 vs 6.4 Letrozole[3] 9.4 vs 6.0 Exemestane[4] PFS 9.9 vs 5.8 AI, aromatase inhibitor; SOC, standard of care; TTP, time to progression. 1. NCCN Guidelines. Breast Cancer. v Bonneterre J, et al. Cancer. 2001;92: Mouridsen H, et al. J Clin Oncol. 2003;21: Paridaens RJ, et al. J Clin Oncol. 2008;26: Howell A, et al. J Clin Oncol. 2004;22: Robertson FJ, et al. Breast Cancer Res Treat. 2012;136: Ellis MJ, et al. J Clin Oncol. 2015;33: Slide credit: clinicaloptions.com

Until disease progression or other event requiring discontinuation
FALCON: First-line Fulvestrant vs Anastrozole for Advanced Breast Cancer Fulvestrant 500 mg IM injection Days 1, 14, 28, and every 28 days thereafter + Placebo PO daily (n = 232) Postmenopausal women with previously untreated hormone receptor–positive advanced breast cancer (N = 462) Until disease progression or other event requiring discontinuation Anastrozole 1 mg/day PO + Placebo IM injection Days 1, 14, 28, and every 28 days thereafter (n = 230) Primary endpoint: PFS Secondary endpoints including: OS, ORR, DoR, CBR, and safety CBR, clinical benefit rate; DoR, duration of response. The FALCON trial randomized patients, very much like this woman, receiving their first hormone therapy for advanced disease to either fulvestrant using typical escalating or loading doses in the first month or anastrozole with appropriate placebos. The primary endpoint was progression‑free survival. Robertson JFR, et al. The Lancet, Dec 2016.

FALCON: Progression-free survival in the intention-to-treat population
Kaplan-Meier curve for progression-free survival in the intention-to-treat population Circles represent censored observations. HR=hazard ratio. The Lancet , DOI: ( /S (16) ) Copyright © 2016 Elsevier Ltd Terms and Conditions

FALCON: Clinical Benefit
Fulvestrant 500 mg (n=230) Anastrozole 1 mg (n=232) Clinical Benefit Total Complete Response Partial Response Stable Disease > 24 weeks 180 (78%) 7(3%) 86 (37%) 87 (38%) 172 (74%) 8 (3%) 82 (35%) No Clinical Benefit Stable Disease > 8 and < 24 weeks Progression RECIST progression Death Not assessable 50 (22%) 9 (4%) 30 (13%) 27 (12%) 3 (1%) 11 (5%) 60 (26%) 22 (9%) 33 (14%) 28 (12%) 5 (2%)

FALCON: Fulvestrant Extends PFS Compared With Anastrozole
Median PFS of 16.6 mos with fulvestrant vs 13.8 mos with anastrozole (HR: 0.797; P = .0486) No visceral disease (n = 208): 22.3 mos with fulvestrant vs mos with anastrozole (HR: 0.59; P < .01) Visceral disease (n = 254): 13.8 mos with fulvestrant vs 15.9 mos with anastrozole (not significant) No significant differences in ORR, CBR, or median DoR Fulvestrant was associated with an increased incidence of grade ≥ 3 AEs (22.4 % vs 17.7%) and all-grade arthralgia (16.7% vs %) AE, adverse event; CBR, clinical benefit rate; DoR, duration of response. They found a significant improvement, about a 3‑month absolute improvement in progression‑free survival from 13.8 months with anastrozole to 16.6 months with fulvestrant. In those patients who had visceral disease, there was no difference with the outcome. The improvement was even more striking with fulvestrant in those that did not have visceral disease—no differences in any of the other efficacy endpoints. Fulvestrant did have a slight increase in the risk of all grade 3 events, primarily infusion-site discomfort, but there was a bit more arthralgia with fulvestrant as well. Slide credit: clinicaloptions.com Ellis MJ, et al. ESMO Abstract LBA14_PR.

Combination Therapy Aromatase Inhibitors +/- Fulvestrant FACT SWOG

Fulvestrant + Anastrozole Fulvestrant i.m. 500mg day 0, 250mg day 14,
FACT: Internacional, randomized (1:1), open label 1 S0226: US, randomized (1:1), open label 2 Fulvestrant + Anastrozole Fulvestrant i.m. 500mg day 0, 250mg day 14, 250mg day 28, then 250mg monthly + Anastrozole 1mg p.o. Anastrozole Anastrozole 1mg p.o. Progression Progression SWOG encouraged crossover to fulvestrant Survival Survival 1= Bergh et al. J Clin Oncol 2012 2= Mehta et al. San Antonio Breast Cancer Symposium 2011

Study Rationale for the Combination
Brodie A et al, Cancer Res 65: , 2005 Macedo et al, Cancer Res 68, , 2008

Results: FACT and S0226 Time to Tumor Progression in FACT n= 514
Anastrozole 10.2 mos Anastrozole + Fulvestrant 10.8mos P=0.91

Differences between FACT and S0226
Prior use of tamoxifen (adjuvant) 68 40 Metastatic Disease de Novo 7* 39 Adjuvant Chemotherapy 45 33 * Estimado

First-Line Phase III Studies Fulvestrant (250, loading )
First-Line Phase III Studies Fulvestrant (250, loading )* + Anastrozole vs Anastrozole In SWOG S0226 (n = 694), fulvestrant addition improved: PFS (mo); fulvestrant + anastrozole (15.0) vs anastrozole (13.3), P = 0.007 OS (mo): fulvestrant + anastrozole (47.7) vs anastrozole (41.3), P = 0.049 In FACT (n=514), fulvestrant addition had: no effect on PFS or OS seen: OS (mo): fulvestrant + anastrozole (37.8) vs anastrozole (38.2), P = 1.00 Mixed results for fulvestrant 250, loading Mehta, et al. SABCS 2011, Abst S Bergh, et al. J Clin Oncol 2012;30(16): *Fulvestrant 500 mg d 1 IM, 250 mg d 14 and 28, 250 mg every 28 days thereafter.

Combination therapy Target Specific Agents

CDK 4/6 Inhibitors and Endocrine Therapy Target Cell
Proliferation Pathways in HR+/HER2- Breast Cancer CDK 4/6 INHIBITORS

CDK 4/6 Inhibitors in Development

PALOMA-2: Palbociclib + Letrozole as Initial Therapy for Advanced ER+/HER2- MBC
Palbociclib 125 mg QD 3 wks on/1 wk off + Letrozole 2.5 mg QD (n = 444) Postmenopausal women with ER+/HER2- advanced BC and no prior systemic therapy (N = 666) Treatment to objective tumor progression, death, toxicity, or study withdrawal Placebo QD 3 wks on/1 wk off + Letrozole 2.5 mg QD (n = 222) BC, breast cancer; DoR, duration of response; MBC, metastatic breast cancer; QoL, quality of life. Now, the experts all suggested letrozole and palbociclib for this patient and that’s really driven by the results of the PALOMA‑2 trial. This trial also randomized patients receiving their first hormone therapy for advanced disease to either letrozole and placebo or letrozole and palbociclib. The primary endpoint was progression‑free survival, with secondary endpoints being overall survival, response rate, quality of life, and safety. Primary endpoint: PFS Secondary endpoints including: OS, ORR, QoL, and safety Slide credit: clinicaloptions.com Finn RS, et al. N Engl J Med. 2016;375:

HR: 0.58 (95% CI: 0.46-0.72; 2-sided P < .001)
PALOMA-2: PFS 100 80 Palbociclib-Letrozole 60 PFS (%) 40 HR: 0.58 (95% CI: ; 2-sided P < .001) 20 Placebo-Letrozole Now, shown for you here are the progression‑free survival results. You’ll see that the curves separate quite early, and they remain widely separate throughout that period of follow‑up with a significant improvement in progression‑free survival with the addition of palbociclib, hazard ratio being 0.58, so over a 40% improvement. 3 6 9 12 15 18 21 24 27 30 33 Mos Slide credit: clinicaloptions.com Finn RS, et al. N Engl J Med. 2016;375:

Best Overall Response in the Intention-to-Treat Population.
Table 3 Best Overall Response in the Intention-to-Treat Population. Finn RS et al. N Engl J Med 2016;375:

Subgroup Analysis of Progression-free Survival.
Figure 2 Subgroup Analysis of Progression-free Survival. Shown are the hazard ratios with 95% confidence intervals for disease progression or death in various subgroups. Newly metastatic disease (referred to as “de novo metastatic” in the protocol) applies to patients who had not received any prior systemic therapy, for whom a determination of disease-free interval was not possible. Eastern Cooperative Oncology Group (ECOG) performance status is measured on a 5-point scale, with 0 indicating no symptoms and higher numbers indicating increasing disability. Ductal carcinoma includes diffuse adenocarcinoma, mixed adenocarcinoma, adenocarcinoma and ductal carcinoma. Data from patients with miscellaneous histopathological features are not reported owing to the small sample size. Finn RS et al. N Engl J Med 2016;375:

Table 2 Adverse Events from Any Cause That Occurred in at Least 10% of the Patients in Either Study Group in the As-Treated Population. Finn RS et al. N Engl J Med 2016;375:

Conclusions Among patients with previously untreated ER-positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with letrozole alone, although the rates of myelotoxic effects were higher with palbociclib–letrozole.

Treatment to PD, toxicity, study withdrawal,
PALOMA-3: Fulvestrant ± Palbociclib for Previously Treated Adv HR+/HER2- MBC Stratified by visceral metastases (yes/no), sensitivity to previous endocrine therapy, menopausal status Palbociclib 125 mg QD 3 wks on/1 wk off + Fulvestrant 500 mg IM Q4W* (n = 347) Pts with HR+/HER2- MBC; PD after endocrine therapy; ≤ 1 chemotherapy regimen for advanced BC (N = 521) Treatment to PD, toxicity, study withdrawal, or death Placebo QD 3 wks on/1 wk off + Fulvestrant 500 mg IM Q4W* (n = 174) *Q2W for cycle 1. Adv, advanced; BC, breast cancer; CBR, clinical benefit rate; HR, hormone receptor; MBC, metastatic breast cancer; PD, disease progression; SD, stable disease. We do have data from the PALOMA‑3 trial looking at the addition of palbociclib for fulvestrant. This would certainly be applying to this patient if she had not received palbociclib in the first‑line setting. So those of you who thought perhaps hormone therapy alone was appropriate for her may want to reconsider palbociclib at the time of disease progression. This trial also had a simple 1‑to‑1 randomization of placebo or palbociclib in addition to fulvestrant. Primary endpoint: investigator-assessed PFS Secondary endpoints: ORR, CBR (CR, PR, or SD for ≥ 24 wks), OS, pt-reported outcomes, safety Slide credit: clinicaloptions.com Cristofanilli M, et al. Lancet Oncol. 2016;17:

PALOMA-3: PFS in Overall Population and Specific Pt Subgroups
Median follow-up: 8.9 mos Median PFS generally favored the palbociclib combination in all pt subgroups analyzed 100 Median PFS, Mos (95% CI) Fulvestrant + palbociclib (n = 347): 9.5 ( ) Fulvestrant + placebo (n = 174): 4.6 ( ) 80 60 PFS (%) 40 20 AI, aromatase inhibitor; ITT, intent to treat; NE, not evaluable. Significant improvement in progression‑free survival, essentially a doubling of progression‑free survival from 4.6 months to 9.5 months with the combination. Toxicities very much like we had seen in the original trials. HR: 0.46 (95% CI: ; P = .0001) 2 4 6 8 10 12 14 Mos Slide credit: clinicaloptions.com Cristofanilli M, et al. Lancet Oncol. 2016;17:

Mechanisms of Resistance to Endocrine Therapy
ER+ = estrogen receptor-positive. Moy B et al. Clin Cancer Res. 2006;12:

PI3K/mTOR Pathway 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 1. Yamnick RL, et al. J Biol Chem 2009 2. Crowder RJ, et al. Cancer Res 2009 3. Miller TW, et al. J Clin Inv 2010

Everolimus and Letrozole against Breast Cancer Cell line
Boulay A, et al. Clin Cancer Res 2005

Phase III Randomized Trial of Exemestane with our without Everoliums in Advanced BC: BOLERO-2
Postmenopausal ER+ Unresectable locally advanced or metastatic BC Recurrence or progression after letrozole or anastrozole R EVE 10 mg daily + EXE 25 mg daily (n = 485) Placebo + EXE 25 mg daily (n = 239) 2:1 Stratification: Sensitivity to prior hormone therapy and presence of visceral metastases Endpoints Primary: PFS (local assessment) Secondary: OS, ORR, QOL, safety, bone markers, PK BC = breast cancer; ER+ = estrogen receptor-positive; EVE = everolimus; EXE = exemestane; ORR, overall response rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; QOL = quality of life. Baselga J, et al. New Engl J Med 2012 54

BOLERO-2: Overall Response Rate and Clinical Benefit Rate by Local Assessment
Response rates, as per local assessment, were 9.5% and 0.4% in the combination and exemestane arms, respectively (P<0.0001); and central assessment showed consistent results Everolimus + exemestane activity was also conformed by the superior clinical benefit rate (33.4% vs. 18.0% in the control arm; p<0.0001). As the interim analysis was performed soon after end of randomization, many patients are yet to qualify for a response assessment. So, these numbers can only improve with additional follow-up. Baselga J, et al. N Engl J Med 2012;366(6):520-9. 55

BOLERO-2 Primary Endpoint: PFS Central Assessment
12 6 18 24 30 36 48 60 42 54 72 66 78 80 40 20 100 Probability of Event (%) Everolimus + Exemestane (E/N=114 / 485) Placebo + Exemestane (E/N=104 / 239) HR = 0.36 (95% CI: ) Log rank P value = 3.3 x EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months The analysis of PFS based on independent central radiological assessment was very consistent and showed a 2.6-fold prolongation in median PFS (10.58 months versus 4.14 months), resulting in a 64% risk reduction of progression or death (HR 0.36) Time (weeks) Everolimus plus exemestane increased progression-free survival by 64% Baselga J, et al. N Engl J Med 2012;366(6):520-9. 56

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From: Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2† Ann Oncol. 2014;25(12): doi: /annonc/mdu456 Figure Legend: Kaplan–Meier estimates of overall survival. CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo. Date of download: 4/12/2017 © The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please 58

BOLERO-2: Most Common G3/4 AEs
Everolimus + Exemestane (N = 482), % Placebo + Exemestane (N = 238), % All Grades Grade 3 Grade 4 Stomatitis 56 8 11 1 Fatigue 33 3 <1 26 Dyspnea 18 4 9 Anemia 16 5 Hyperglycemia 13 2 AST 6 Pneumonitis 12 The most common grade 3 and 4 AEs were stomatitis, anemia, dyspnea, hyperglycemia, fatigue, and pneumonitis. The side effects observed in the BOLERO-2 trial are consistent with those reported with everolimus. Nevertheless, a high percentage of patients discontinued everolimus because of lack of tolerability. Being the first large multinational trial with everolimus in breast cancer and the longer treatment duration in the combination arm might have contributed in part to the high discontinuation rate. Baselga J, et al. N Engl J Med 2012;366(6):520-9. 59

TAMRAD: Tamoxifen + Everolimus (Phase II)
Phase 2 study; N= PMW with advanced HR+ HER2- BC Previously treated with non-steroidal aromatase inhibitor therapy in adjuvant or metastatic setting Tamoxifen 20 mg/day + Everolimus 10 mg/day Primary CBR at 6 months Secondary Safety, TTP, OS, ORR Tamoxifen 20 mg/d + Placebo Bolero-2 (Study Y2301) a randomised Phase III study evaluating everolimus in combination with exemestane was conducted in post-menopausal women with ER positive refractory ABC (with recurrence or progression following prior therapy with letrozole or anastrozole). 724 women were randomized in a 2:1 ratio to receive either everolimus or matching placebo in addition to open-label exemestane. Randomization was stratified by documented sensitivity to prior hormonal therapy (yes vs. no) and by the presence of visceral metastasis (yes vs. no). Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥ 24 weeks) to at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence. The primary endpoint for the trial was PFS evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on the investigators (local radiology) assessment. Supportive PFS analyses, were based on an independent central radiology review. Secondary endpoints included overall survival (OS), Overall Response Rate (ORR), Clinical Benefit Rate (CBR), Safety, change in Quality of Life (QoL) and time to ECOG PS deterioration. Additional endpoints included changes in bone turnover markers at 6 and 12 weeks. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. No cross-over after disease progression was allowed. TAM+EVE n = 54 TAM n = 57 P-value CBR (6 mo) 61% 42% 0.045 TTP (mo) 8.6 4.5 0.002 Bachelot T, et al. J Clin Oncol Epub 1-7. 60

TAMRAD: Time to Progression
Hazard Ratio (HR) = 0.53; 95% CI ( ) Exploratory log-rank: P = TAM: 4.5 mo. TAM + EVE: 8.6 mo. Month 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Probability of Survival TAM TAM + EVE Patients at risk TAM + RAD: n = TAM : n = 54 57 45 44 39 30 34 25 13 19 11 7 1 9 Time to progression increased from 4.5 months in the TAM arm to 8.6 months in the TAM + RAD arm. The hazard ratio of progression was 0.53 with a 95% CI of and an exploratory P value of Everolimus plus tamoxifen reduced time to progression by 47% Backetlot T, et al. J Clin ONcol 2012.Epub 1-7 61

TAMRAD: Overall Survival
With regard to survival, as of October 2010, 25 patients had died in the TAM arm and 9 patients had died in the TAM + RAD arm. The hazard ratio is 0.32 with a 95% CI of and an exploratory P value of Everolimus plus tamoxifen increased overall survival by 55% 62

PrECOG 0102: Fulvestrant ± Everolimus in AI-Refractory Advanced BC
Stratified by ECOG PS (0/1), measurable disease(yes/no), previous chemotherapy for MBC (yes/no) Everolimus 10 mg QD + Fulvestrant 500 mg IM Q4W* (n = 66) Treatment to PD or unacceptable toxicity for up to 12 cycles If no PD or unacceptable toxicity unblended and continued therapy Postmenopausal women with hormone receptor+/HER2- advanced BC; PD after AI therapy; ≤ 1 chemotherapy regimen for MBC (N = 131) Placebo QD + Fulvestrant 500 mg IM Q4W* (n = 65) AI, aromatase inhibitor; BC, breast cancer; CBR, clinical benefit rate; ECOG, Eastern Cooperative Oncology Group; MBC, metastatic breast cancer; PD, progressive disease; PS, performance status. We do have data from a phase II study looking at the combination of everolimus with fulvestrant also in AI‑refractory patients . . . *Q2W for cycle 1. Primary endpoint: investigator-assessed PFS Secondary endpoints: ORR, CBR (CR, PR, or SD for ≥ 24 wks), OS, pt-reported outcomes, safety Slide credit: clinicaloptions.com Kornblum NS, et al. SABCS Abstract S1-02.

PrECOG 0102: PFS 100 Everolimus + fulvestrant (n = 66), median PFS: 10.4 mos Placebo + fulvestrant (n = 65), median PFS: 5.1 mos 80 60 PFS (%) 40 20 HR: 0.60 (95% CI: ; stratified log-rank P = .02) . . . that also found a very similar doubling of progression‑free survival from 5.1 months in this case to 10.4 months. So both of those, I think, would be quite reasonable options for this patient. 6 12 18 24 Mos Pts at Risk, n E + Ful E + Plbo 66 65 41 25 17 12 6 4 1 0 Slide credit: clinicaloptions.com Kornblum NS, et al. SABCS Abstract S1-02.

11/8/ :41 PM Phase 2 study of a steroid-based mouthwash to prevent stomatitis in women being treated with everolimus plus exemestane: SWISH Trial Stomatitis is a common side effect of everolimus that can impact adherence and quality of life In BOLERO-2 all grade stomatitis was 67%; 30% grade > 2 and 8% grade 3 First stomatitis occurs within 8 weeks of initiating everolimus (median time 15 days) Rugo H, et al ASCO 2016 © 2007 Microsoft Corporation. All rights reserved. Microsoft, Windows, Windows Vista and other product names are or may be registered trademarks and/or trademarks in the U.S. and/or other countries. The information herein is for informational purposes only and represents the current view of Microsoft Corporation as of the date of this presentation. Because Microsoft must respond to changing market conditions, it should not be interpreted to be a commitment on the part of Microsoft, and Microsoft cannot guarantee the accuracy of any information provided after the date of this presentation. MICROSOFT MAKES NO WARRANTIES, EXPRESS, IMPLIED OR STATUTORY, AS TO THE INFORMATION IN THIS PRESENTATION.

Name Title Company Name
11/8/ :41 PM Name Title Company Name © 2007 Microsoft Corporation. All rights reserved. Microsoft, Windows, Windows Vista and other product names are or may be registered trademarks and/or trademarks in the U.S. and/or other countries. The information herein is for informational purposes only and represents the current view of Microsoft Corporation as of the date of this presentation. Because Microsoft must respond to changing market conditions, it should not be interpreted to be a commitment on the part of Microsoft, and Microsoft cannot guarantee the accuracy of any information provided after the date of this presentation. MICROSOFT MAKES NO WARRANTIES, EXPRESS, IMPLIED OR STATUTORY, AS TO THE INFORMATION IN THIS PRESENTATION.

Name Title Company Name 11/8/2018 10:41 PM
© 2007 Microsoft Corporation. All rights reserved. Microsoft, Windows, Windows Vista and other product names are or may be registered trademarks and/or trademarks in the U.S. and/or other countries. The information herein is for informational purposes only and represents the current view of Microsoft Corporation as of the date of this presentation. Because Microsoft must respond to changing market conditions, it should not be interpreted to be a commitment on the part of Microsoft, and Microsoft cannot guarantee the accuracy of any information provided after the date of this presentation. MICROSOFT MAKES NO WARRANTIES, EXPRESS, IMPLIED OR STATUTORY, AS TO THE INFORMATION IN THIS PRESENTATION.

Epigenetics and Cancer
Cancer is a consequence of genetic alterations. Disruption of epigenetic mechanisms is also a hallmark of the disease. Epigenetic mechanisms help control the expression of genes –whether they are turned on or off – without affecting the DNA sequence itself. Inappropriate epigenetic activity plays a significant role in cancer development but, unlike DNA mutations, which are permanent, epigenetic changes can be reversed.

Epigenetics and Breast Cancer
Multiple genes are methylated and thus silenced in breast cancer1 ER, RARbeta, cyclin D, Twist, RASSF1A, and HIN-1 ER has a CpG island2 ER CpG island often methylated in ER-negative human breast cancer cell lines and primary tumor specimens Inhibitors of DNMT or HDAC restore ER expression and function3 1. Pu RT. Mod Pathol 2003: 2. Ottaviano YL. Cancer Res 1994: 3. Zhou Q. BCRT 2008

Presented By Denise Aysel Yardley, MD at 2011 Breast Cancer Symposium
[TITLE] Presented By Denise Aysel Yardley, MD at 2011 Breast Cancer Symposium

Presented By Denise Aysel Yardley, MD at 2011 Breast Cancer Symposium
[TITLE] Yardley D A et al. JCO 2013;31: Presented By Denise Aysel Yardley, MD at 2011 Breast Cancer Symposium

Phase II ENCORE301: Study Design
Entinostat: oral, histone deacetylase inhibitor Primary endpoints: PFS Secondary endpoints: ORR (CR + PR), CBR (ORR + SD ≥ 6 mos), safety Exploratory endpoint: OS Stratified by prior NSAI treatment setting (adjuvant or metastatic); bone only metastases (yes or no); geographic region (North America or Central Europe/Russia) Postmenopausal women with HR+, locally recurrent or metastatic BC, with progression NSAI therapy (N = 130) Entinostat 5 mg PO once/wk + Exemestane 25 mg/day (n = 64) Placebo PO once/wk + Exemetane 25 mg/day (n = 66) BC, breast cancer; CBR, clinical benefit rate; HR, hormone receptor; NSAI, nonsteroidal aromatase inhibitor; SD, stable disease. Slide credit: clinicaloptions.com Yardley DA, et al. J Clin Oncol. 2013;31:

ENCORE301: PFS and OS PFS OS
1.0 Exemestane + entinostat: median, 4.28 mos Exemestane + placebo: median, 2.27 mos 1.0 Exemestane + entinostat: median, mos Exemestane + placebo: median, mos 0.8 HR: 0.73 (95% CI: ); P = .055 0.8 0.6 0.6 PFS (Probability) OS (Probability) 0.4 0.4 0.2 0.2 HR: 0.59 (95% CI: ); P = .036 4 8 12 16 20 24 28 6 12 18 24 30 36 42 Mos Mos AE, adverse event. Entinostat significantly improved PFS and OS Most common grade 3/4 AEs: neutropenia (15% entinostat vs 0% placebo) and fatigue (13% entinostat vs 3% placebo) Protein hyperacetylation in entinostat-treated pts associated with prolonged PFS for all cell types tested (B and T cells, monocytes) Slide credit: clinicaloptions.com Yardley DA, et al. J Clin Oncol. 2013;31:

ENCORE 301: Conclusions Exemestane + Entinostat: Improved PFS, trend in OS Treatment well tolerated Development of Phase III randomized Trial ECOG 2112 11/8/2018

Phase III E2112: Exemestane ± Entinostat in Advanced Breast Cancer
Entinostat: oral, histone deacetylase inhibitor Primary endpoints: OS, PFS Secondary endpoints: ORR (CR or PR), TTD, toxicity Other outcomes: adherence, QoL, protein lysine acetylation Pre/peri/postmenopausal women and men with HR+/HER2-, inoperable, locally advanced or metastatic BC, with progression on/after NSAI therapy (N ≈ 600) Entinostat PO Days 1, 8, 15, 22 + Exemestane PO QD Days 1-28 (n ≈ 300) Until disease progression or unacceptable toxicity Placebo PO Days 1, 8, 15, 22 + Exemestane PO QD Days 1-28 (n ≈ 300) *Pre/perimenopausal female and all male pts receive goserelin acetate SC Day 1. BC, breast cancer; HR, hormone receptor; NSAI, nonsteroidal aromatase inhibitor; QoL, quality of life; TTD, time to deterioration. Slide credit: clinicaloptions.com ClinicalTrials.gov. NCT

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