592017 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 ID: 775321
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Slide1
Hormone Receptor Positive Metastatic Breast Cancer
Slide25/9/2017
Slide3The Lancet July 11, 1895
ON THE TREATMENT OF INOPERABLECASES OF CARCINOMA OF THE MAMMA:SUGGESTIONS FOR A NEW METHODOF TREATMENT, WITH ILLUSTRA-TIVE CASES.1BY GEORGE THOMAS BEATSON, M.D. EDIN.,SURGEON TO THE GLASGOW CANCER HOSPITAL; ASSISTANT SURGEON,GLASGOW WESTERN INFIRMARY: AND EXAMINER IN SURGERYTO 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.”
Slide4Endocrine-Based Therapies for Breast Cancer
YearAgentMechanism1977SERMsTamoxifenToremifeneAntagonizes ER in breast tissue1990sAIsAnastrozoleExemestane LetrozoleInhibit estrogen production in postmenopausal women2000sERDFulvestrantImpairs ER dimerization, increases ER degradation, and disrupts nuclear localization of ER2010sCombinationsExemestane/everolimusLetrozole/palbociclibFulvestrant/palbociclibBlockade of estrogen signaling and prosurvival or cell cycle pathways
Slide credit:
clinicaloptions.com
Lim E, et al. Oncology (Williston Park). 2012;26:688-694.
Croxtall JD, et al. Drugs. 2011;71:363-380.
Vidula N, et al. Clin Breast Cancer. 2016;16:8-17.
Mustonen MV, et al. World J Clin Oncol. 2014;5:393-405.
Slide5Endocrine 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
Slide65/9/2017
Slide7Endocrine Therapy vs Chemotherapy in Endocrine Responsive Breast Cancer
Slide8Chemotherapy vs Endocrine TherapyMetastatic Disease
Taylor SG, et al. Ann Int Med 1986;104(4):455-461
Slide9Results
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
6.2 months
0.42
OS
20.9 months
23.3 months
0.20
Slide10International Consensus Guidelines for Advanced Breast cancerDefinitions
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
Slide11International Consensus Guidelines for Advanced Breast cancerDefinitions
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.
Slide12Major 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
Slide13Compare Survival with Stable Disease (Clinical Benefit) to Survival with CR or PR with Anastrozole Use in ABC
0
100
0
1
2
3
4
Years From Randomization
80
60
40
20
At 2-Year
Risk Deaths Estimate
CR or PR 33 10 85%
Stable
24wk 78 23 86%
Other 152 118 35%
Robertson JF, et al.
Breast Cancer Res Treat.
1999;58:157-162.
Survival (%)
Clinical Benefit = CR + PR + Stable
24 wks
Stable disease on hormone therapy provides similar benefit as CR or PR
ABC = advanced breast cancer, Clinical benefit = no prognosis for
>
24wks
Slide14R
E
S
I
STANCE
40%
30%
25%
15%
Patients with Disease Progression on One Hormone Therapy May Respond to Another Hormone Therapy
1st Line
2nd Line
3rdLine
4thLine
An optimal sequence of hormone therapies has not been defined
Bavior C, et al. Ann Oncol 2012. Epub Feb 8; Osborne Ck, Schiff R. Ann Res Med 2011;62:233-247
Slide15Endocrine Agents for Postmenopausal Breast Cancer
SERMsTamoxifenToremifeneRaloxifene EstrogensEstradiolDES, EE2 ER-Down RegulatorFulvestrant
Aromatase Inhibitors
Anastrozole
Letrozole
Exemestane
Progestins
Megestrol Acetate
MPA
Androgens
Fluoxymesterone
Slide16Initial 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]
Slide credit:
clinicaloptions.com
AIParameterAI vs Tamoxifen, MosAnastrozole[2]TTP10.7 vs 6.4Letrozole[3]TTP9.4 vs 6.0Exemestane[4]PFS9.9 vs 5.8
1. NCCN Guidelines. Breast Cancer. v2.2016.
2. Bonneterre J, et al. Cancer. 2001;92:2247-2258.
3. Mouridsen H, et al. J Clin Oncol. 2003;21:2101-2109.
4. Paridaens RJ, et al. J Clin Oncol. 2008;26:4883-4890.
5. Howell A, et al. J Clin Oncol. 2004;22:1605-1613.
6. Robertson FJ, et al. Breast Cancer Res Treat. 2012;136:503-511.
7. Ellis MJ, et al. J Clin Oncol. 2015;33:3781-3787.
Slide17Endocrine Therapy in Premenopausal Patients
CMF ~ Tamoxifen
CMF ~ Ovarian Suppression
Ovarian Suppression ~ Tamoxifen
Slide18Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of fourrandomized trials
Klijn
JG, et al J
Clin
Oncol
2001
Slide19Klijn, J. G.M. et al. J Clin Oncol; 19:343-353 2001
Fig 4. Progression-free survival curves for LHRH agonist and LHRH agonist + tamoxifen
Slide20Klijn, J. G.M. et al. J Clin Oncol; 19:343-353 2001
Fig 1. Overall survival curves for LHRH agonist and LHRH agonist + tamoxifen
Slide21Klijn, J. G.M. et al. J Clin Oncol; 19:343-353 2001
Fig 7. Objective response rate stratified by study
Response Rate 30% on LHRH agonist alone and 39% on the combined treatment
P=0.03
Slide22Endocrine Therapy for Postmenopausal Women: Recent Advances
Slide23Initial 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]
Slide credit:
clinicaloptions.com
AIParameterAI vs Tamoxifen, MosAnastrozole[2]TTP10.7 vs 6.4Letrozole[3]TTP9.4 vs 6.0Exemestane[4]PFS9.9 vs 5.8
1. NCCN Guidelines. Breast Cancer. v2.2016.
2. Bonneterre J, et al. Cancer. 2001;92:2247-2258.
3. Mouridsen H, et al. J Clin Oncol. 2003;21:2101-2109.
4. Paridaens RJ, et al. J Clin Oncol. 2008;26:4883-4890.
5. Howell A, et al. J Clin Oncol. 2004;22:1605-1613.
6. Robertson FJ, et al. Breast Cancer Res Treat. 2012;136:503-511.
7. Ellis MJ, et al. J Clin Oncol. 2015;33:3781-3787.
Slide24FALCON: First-line Fulvestrant vs Anastrozole for Advanced Breast Cancer
Primary endpoint: PFSSecondary endpoints including: OS, ORR, DoR, CBR, and safety
Postmenopausal women with previously untreated hormone receptor–positive advanced breast cancer(N = 462)
Fulvestrant 500 mg IM injectionDays 1, 14, 28, and every 28 days thereafter + Placebo PO daily(n = 232)
Anastrozole 1 mg/day PO + Placebo IM injectionDays 1, 14, 28, and every 28 days thereafter(n = 230)
Until disease progression or
other event requiring discontinuation
Robertson
JFR
, et al. The Lancet, Dec 2016.
Slide25FALCON: Progression-free survival in the intention-to-treat population
The Lancet
2016 388, 2997-3005DOI: (10.1016/S0140-6736(16)32389-3)
Copyright © 2016 Elsevier Ltd Terms and Conditions
Slide26FALCON: 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%)
82 (35%)
No Clinical Benefit
Total
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%)
5 (2%)
Slide27FALCON: 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 13.8 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 DoRFulvestrant was associated with an increased incidence of grade ≥ 3 AEs (22.4 % vs 17.7%) and all-grade arthralgia (16.7% vs 10.3%)
Ellis MJ, et al. ESMO 2016. Abstract LBA14_PR.
Slide credit:
clinicaloptions.com
Slide28Combination Therapy
Aromatase Inhibitors +/-
Fulvestrant
FACT
SWOG
Slide29Progression
Fulvestrant + Anastrozole
Fulvestrant i.m. 500mg day 0, 250mg day 14, 250mg day 28, then 250mg monthly+ Anastrozole 1mg p.o.
Survival
Progression
Survival
Anastrozole
Anastrozole 1mg p.o.
FACT: Internacional,
randomized
(1:1),
open label 1S0226: US, randomized (1:1), open label 2
1= Bergh et al. J Clin Oncol 20122= Mehta et al. San Antonio Breast Cancer Symposium 2011
SWOG encouraged
crossover to
fulvestrant
Slide30Study Rationale for the Combination
Brodie A et al, Cancer Res 65:5439-44, 2005
Macedo et al, Cancer Res 68, 3516-22, 2008
Slide31Results:
FACT
and
S0226
Time to Tumor Progression in FACT n= 514
Anastrozole
10.2
mos
Anastrozole
+
Fulvestrant
10.8mos
P=0.91
Slide32Differences between FACT and S0226
FACT (%)S0226 (%)Prior use of tamoxifen (adjuvant)6840Metastatic Disease de Novo7*39Adjuvant Chemotherapy4533
*
Estimado
Slide33Slide34Slide35Slide36First-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 = 0.007OS (mo): fulvestrant + anastrozole (47.7) vs anastrozole (41.3), P = 0.049In 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 S1-1 Bergh, et al. J Clin Oncol 2012;30(16):1919-25
*
Fulvestrant 500 mg d 1 IM, 250 mg d 14 and 28, 250 mg every 28 days thereafter.
Slide37Combination therapy Target Specific Agents
Slide38Slide39CDK
4/6
INHIBITORS
CDK
4/6 Inhibitors and Endocrine Therapy Target Cell
Proliferation Pathways in HR+/HER2- Breast Cancer
Slide40CDK
4/6 Inhibitors in Development
Slide41PALOMA-2: Palbociclib + Letrozole as Initial Therapy for Advanced ER+/HER2- MBC
Primary endpoint: PFSSecondary endpoints including: OS, ORR, QoL, and safety
Postmenopausal women with ER+/HER2- advanced BC and no prior systemic therapy (N = 666)
Palbociclib 125 mg QD3 wks on/1 wk off +Letrozole 2.5 mg QD(n = 444)
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)
Finn RS, et al. N Engl J Med. 2016;375:1925-1936.
Slide credit:
clinicaloptions.com
Slide42PALOMA-2: PFS
Finn RS, et al. N Engl J Med. 2016;375:1925-1936.
Slide credit:
clinicaloptions.com
100
80
60
40
20
0
PFS (%)
0
3
6
9
12
15
18
21
24
27
30
33
Mos
Palbociclib-Letrozole
Placebo-Letrozole
HR: 0.58
(95% CI: 0.46-0.72;
2-sided
P
< .001)
Slide43Best Overall Response in the Intention-to-Treat Population.
Finn RS et al. N Engl J Med 2016;375:1925-1936
Slide44Subgroup Analysis of Progression-free Survival.
Finn RS et al. N
Engl J Med 2016;375:1925-1936
Slide45Finn RS et al. N
Engl J Med 2016;375:1925-1936
Slide46Conclusions
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.
Slide47Slide48Slide49PALOMA-3: Fulvestrant ± Palbociclib for Previously Treated Adv HR+/HER2- MBC
Primary endpoint: investigator-assessed PFSSecondary endpoints: ORR, CBR (CR, PR, or SD for ≥ 24 wks), OS, pt-reported outcomes, safety
Pts with HR+/HER2- MBC; PD after endocrine therapy;≤ 1 chemotherapy regimen for advanced BC (N = 521)
Palbociclib 125 mg QD3 wks on/1 wk off +Fulvestrant 500 mg IM Q4W*(n = 347)
Treatment to PD, toxicity, study withdrawal,
or death
Placebo
QD3 wks on/1 wk off +Fulvestrant 500 mg IM Q4W*(n = 174)
Cristofanilli M, et al. Lancet Oncol. 2016;17:425-439.
Stratified by visceral metastases
(yes/no), sensitivity to previous endocrine therapy, menopausal status
*Q2W for cycle 1.
Slide credit:
clinicaloptions.com
Slide502
Median follow-up: 8.9 mosMedian PFS generally favored the palbociclib combination in all pt subgroups analyzed
PALOMA-3: PFS in Overall Population and Specific Pt Subgroups
Cristofanilli M, et al. Lancet Oncol. 2016;17:425-439.
100
80
60
40
20
0
0
4
6
8
10
12
14
Median PFS, Mos (95% CI)
Fulvestrant + palbociclib (n = 347):
9.5 (9.2-11.0)
Fulvestrant + placebo (n = 174):
4.6 (3.5-5.6)
HR: 0.46 (95% CI: 0.36-0.59;
P
= .0001)
PFS (%)
Mos
Slide credit:
clinicaloptions.com
Slide51Mechanisms of Resistance to Endocrine Therapy
51
ER+ = estrogen receptor-positive.
Moy B et al.
Clin Cancer Res
. 2006;12:4790-4793
Slide52PI3K/mTOR Pathway
mTORC1 activates ER in a ligand-independent fashion1Estradiol suppresses apoptosis induced by PI3K/mTOR blockade2Hyperactivation 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
Slide53Everolimus and Letrozole against Breast Cancer Cell line
Boulay A, et al. Clin Cancer Res 2005
Slide54Phase III Randomized Trial of Exemestane with our without Everoliums in Advanced BC: BOLERO-2
54
EVE 10 mg daily
+
EXE 25 mg daily (n = 485)
Placebo+EXE 25 mg daily (n = 239)
R
Endpoints
Primary: PFS (local assessment)Secondary: OS, ORR, QOL, safety, bone markers, PK
2:1
N = 724Postmenopausal ER+Unresectable locally advanced or metastatic BC Recurrence or progression after letrozole or anastrozole
Stratification: Sensitivity to prior hormone therapy and presence of visceral metastases
Baselga J, et al. New Engl J Med 2012
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.
Slide55BOLERO-2: Overall Response Rate and Clinical Benefit Rate by Local Assessment
P
< 0.0001
P
< 0.0001
Baselga
J, et al. N
Engl
J Med 2012;366(6):520-9.
Slide56BOLERO-2 Primary Endpoint: PFS Central Assessment
Time (weeks)
HR = 0.36 (95% CI: 0.27-0.47)
EVE + EXE: 10.6 Months
PBO + EXE: 4.1 Months
Log rank P value = 3.3 x 10 -15
0
12
6
18
24
30
36
48
60
42
54
72
66
78
80
60
40
20
100
0
Probability of Event (%)
Everolimus + Exemestane (E/N=114 / 485)
Placebo + Exemestane (E/N=104 / 239)
Baselga J, et al. N Engl J Med 2012;366(6):520-9.
Everolimus plus exemestane increased progression-free survival by 64%
Slide575/9/2017
Slide58Date of download: 4/12/2017
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
From:
Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†
Slide59BOLERO-2: Most Common G3/4 AEs
Everolimus + Exemestane (N = 482), %Placebo + Exemestane (N = 238), %All GradesGrade 3Grade 4All GradesGrade 3Grade 4Stomatitis56801110Fatigue333<12610Dyspnea184091<1Anemia165<14<1<1Hyperglycemia134<12<10AST133<1610Pneumonitis1230000
Baselga
J, et al. N
Engl
J Med 2012;366(6):520-9.
Slide60Tamoxifen
20 mg/day +
Everolimus 10 mg/day
Tamoxifen
20 mg/d +
Placebo
TAMRAD: Tamoxifen
+
Everolimus
(Phase II)
Phase 2 study; N=111 PMW with advanced HR+ HER2- BC Previously treated with non-steroidal aromatase inhibitor therapy in adjuvant or metastatic setting
Primary
CBR at 6 months
Secondary
Safety, TTP, OS, ORR
Bachelot
T, et al. J Clin Oncol 2012. Epub 1-7.
TAM+EVE n = 54
TAM n = 57
P-
value
CBR (6 mo)
61%
42%
0.045
TTP (
mo
)
8.6
4.5
0.002
Slide61TAMRAD: Time to Progression
Hazard Ratio (HR) = 0.53; 95% CI (0.35-0.81)
Exploratory log-rank: P = 0.0021
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
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
24
28
22
25
13
19
11
12
6
7
1
1
0
0
0
26
16
16
7
9
2
1
0
Everolimus plus tamoxifen reduced time to progression by 47%
Backetlot
T, et al. J
Clin
ONcol
2012.Epub 1-7
Slide62TAMRAD: Overall Survival
Everolimus plus tamoxifen increased overall survival by 55%
Slide63PrECOG 0102: Fulvestrant ± Everolimus in AI-Refractory Advanced BC
Primary endpoint: investigator-assessed PFSSecondary endpoints: ORR, CBR (CR, PR, or SD for ≥ 24 wks), OS, pt-reported outcomes, safety
Kornblum NS, et al. SABCS 2016. Abstract S1-02.
Postmenopausal women with hormone receptor+/HER2- advanced BC; PD after AI therapy; ≤ 1 chemotherapy regimen for MBC (N = 131)
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
Placebo
QD +Fulvestrant 500 mg IM Q4W*(n = 65)
Stratified by ECOG PS (0/1), measurable disease(yes/no), previous chemotherapy for MBC (yes/no)
*Q2W for cycle 1.
Slide credit:
clinicaloptions.com
Slide64PrECOG 0102: PFS
Kornblum NS, et al. SABCS 2016. Abstract S1-02.
Slide credit:
clinicaloptions.com
100
80
60
40
20
0
PFS (%)
Mos
0
6
12
18
24
HR: 0.60 (95% CI: 0.40-0.92;
stratified log-rank
P
= .02)
Everolimus
+
fulvestrant
(n = 66), median PFS: 10.4 mos
Placebo +
fulvestrant
(n = 65), median PFS: 5.1 mos
Pts at Risk, n
E +
Ful
E +
Plbo
66
65
41
25
17
12
6
4
1
0
Slide65Phase 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 lifeIn BOLERO-2 all grade stomatitis was 67%; 30% grade > 2 and 8% grade 3First stomatitis occurs within 8 weeks of initiating everolimus (median time 15 days)
Rugo
H, et al
ASCO
2016
Slide66NameTitleCompany Name
Slide67NameTitleCompany Name
Slide68NameTitleCompany Name
Slide69Slide70Epigenetics 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.
Slide71Epigenetics and Breast Cancer
Multiple genes are methylated and thus silenced in breast cancer
1
ER,
RARbeta
, cyclin D, Twist, RASSF1A, and HIN-1
ER has a
CpG
island
2
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 function
3
1. Pu RT. Mod
Pathol
2003: 2.
Ottaviano
YL. Cancer Res 1994: 3. Zhou Q. BCRT 2008
Slide72[TITLE]
Presented By Denise Aysel Yardley, MD at 2011 Breast Cancer Symposium
Slide73[TITLE]
Presented By Denise Aysel Yardley, MD at 2011 Breast Cancer Symposium
Slide74[TITLE]
Presented By Denise Aysel Yardley, MD at 2011 Breast Cancer Symposium
Yardley D A et al. JCO 2013;31:2128-2135
Slide75Phase II ENCORE301: Study Design
Entinostat: oral, histone deacetylase inhibitorPrimary endpoints: PFSSecondary endpoints: ORR (CR + PR), CBR (ORR + SD ≥ 6 mos), safetyExploratory endpoint: OS
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)
Slide credit:
clinicaloptions.com
Yardley DA, et al. J Clin Oncol. 2013;31:2128-2135.
Stratified by prior NSAI treatment setting
(adjuvant or metastatic); bone only metastases (yes or no); geographic region (North America or Central Europe/Russia)
Slide76ENCORE301: PFS and OS
Entinostat significantly improved PFS and OSMost 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;31:2128-2135.
PFS
OS
1.0
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
0
6
12
18
24
30
36
42
0
4
8
12
16
20
24
28
Exemestane + entinostat: median, 4.28 mos
Exemestane + placebo: median, 2.27 mos
HR: 0.73 (95% CI: 0.50-1.07);
P
= .055
Mos
PFS (Probability)
Exemestane + entinostat: median, 28.13 mos
Exemestane + placebo: median, 19.84 mos
HR: 0.59 (95% CI: 0.36-0.97);
P
= .036
Mos
OS (Probability)
Slide77ENCORE 301: Conclusions
Exemestane + Entinostat: Improved PFS, trend in OSTreatment well toleratedDevelopment of Phase III randomized Trial ECOG 2112
5/9/2017
Slide78Phase III E2112: Exemestane ± Entinostat in Advanced Breast Cancer
Entinostat: oral, histone deacetylase inhibitorPrimary endpoints: OS, PFSSecondary endpoints: ORR (CR or PR), TTD, toxicityOther 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)
Placebo
PO Days 1, 8, 15, 22 + Exemestane PO QD Days 1-28(n ≈ 300)
Slide credit:
clinicaloptions.com
ClinicalTrials.gov. NCT02115282.
Until disease progression or unacceptable toxicity
*Pre/perimenopausal female and all male pts receive goserelin acetate SC Day 1.
Slide79THANK YOU
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