the evolution of endocrine therapy in advanced breast cancer: a...
TRANSCRIPT
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The evolution of endocrine therapy in advanced breast cancer: a moving target?
Massimo Cristofanilli, M.D., F.A.C.P. Professor of Medicine
G. Morris Dorrance Jr. Endowed Chair in Medical Oncology Fox Chase Cancer Center, Philadelphia, PA
Medellin, Colombia, November 17, 2012
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There is still a role for single agent endocrine therapy?
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ENDOCRINE THERAPY FOR
METASTATIC BREAST CANCER
• Response rate (RR) to first-line hormonal therapy (tamoxifen/AI) 21% to 33%1-2
• RR to second-line hormonal therapies (exemestane or fulvestrant) 7%3
• EFECT trial: Time to progression (TTP) for exemestane or fulvestrant 3.7 months3
• Novel approaches to improve the efficacy of endocrine therapy urgently required
1. Nabholtz. JCO 2000; 2. Mouridsen JCO 2003; 3. Chia JCO 2008
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Leary et al, Br J Cancer. 2006 September 18;95(6):661-666.
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Outline
• Combinations with GFR inhibitors: - Trastuzumab (TAnDEM) - Gefitinib (AZ225, 713) - AZD8931(MINT) - Lapatinib
• Combinations with SERMs: - Fulvestrant
• Combinations with rapamycin-analogs • Combinations with HDACs inhibitors
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Endocrine Therapy combined with growth factor receptor
inhibitors
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The ErbB/HER receptor family
2 3 1 4
erbB1 EGFR HER1
erbB2 HER2
(no ligand)
erbB3 HER3
(kinase dead)
erbB4 HER4
NRG2
NRG1
Ligands
Receptors
TGFa
EGF
AR
EPR
HB-EGF
BTC
NRG4
NRG3
EPR
HB-EGF
BTC
NRG2
NRG1
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Trial Regimen Population No. of patients
Median PFS, mo
Endocrine therapy alone
Endocrine therapy + anti-ErbB
TAnDEM 1
Phase III Anastrozole +/-
trastuzumab HER2+ 208 2.4 * 4.8 *
Osborne et al2
Randomized, placebo-controlled phase II
Tamoxifen +/- gefitinib
ITT
HER2+ subset
206†
37
8.8
5.8
10.9
6.7
Cristofanilli et al3
Randomized, placebo-controlled phase II
Anastrozole +/- gefitinib ITT 93 8.2 14.5
Clinical Evidence for Co-Targeting Growth Factor Receptors in ER+ MBC
*Increased slightly in exploratory analysis of centrally confirmed ER status, 3.8 vs 5.6 mo. †Stratum 1 of trial defined as never receiving tamoxifen or completed adjuvant tamoxifen > 1 year prior.
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TAnDEM (Trastuzumab and Anastrozole Directed Against ER-Positive HER2-Positive Mammary Carcinoma) patient enrollment and study flow.
Kaufman B et al. JCO 2009;27:5529-5537
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Kaplan-Meier curves showing estimated (A) progression-free survival (PFS) for the intent-to-treat (ITT) population, (B) PFS for patients with centrally confirmed hormone receptor–
positive tumors, (C) time to progression (TTP) for ITT population, (D) TTP for...
Kaufman B et al. JCO 2009;27:5529-5537
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Gefitinib in ER+ postmenopausal breast cancer
Tamoxifen 20mg od
Iressa 250mg od
&
Tamoxifen 20mg od
Placebo
&
or
n = 206
12m post adjuvant therapy
Newly diagnosed
ER+ve advanced breast cancer
Osborne et al
Dec 2007
n = 93
ER+ve advanced breast cancer
Arimidex 1mg od
Iressa 250mg od
& Arimidex 1mg od
Placebo
&
Cristofanilli et al
June 2008
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Tamoxifen + Iressa
Tamoxifen + Placebo
n=157
Time To Progression (Days)
HR 0.78 (0.52-1.15)
Arimidex + Iressa
Arimidex + Placebo
n=42
Time To Progression (Months)
HR 0.39 (0.16-0.97)
40%
Arimidex + Iressa
Arimidex + Placebo
n=93
Time To Progression (Days)
HR 0.55 (0.32-0.94)
Data for endocrine therapy naïve patients only
Positive treatment effect for Iressa in
overall* population
Figure 11.3.1.4 : Kaplan-Meier Curves for Time to Progression - Stratum 1Intent-to-Treat Population
Time to progression is equivalent to progression free survival.
Treatment Group tamoxifen + gefitinib tamoxifen + placebo
proportio
n progres
sion-free
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
time (days)0 100 200 300 400 500 600 700 800 900 1000 1100
Tamoxifen + Iressa
Tamoxifen + Placebo
Stratum 1 n=206
Time To Progression (Days)
HR 0.84 (0.59-1.19)
Treatment effect in endocrine therapy naïve
population only Interaction test
positive (p=0.07)
Osborne Study (225) San Antonio 07
Cristofanilli Study 713 ASCO 08
Gefitinib demonstrated POC in Endocrine Naïve ER+ve
Combined HR in endocrine therapy naïve pts = 0.7 * Overall population in stratum 1 of Osborne study
225
713
Endo naive
HR=0.78 N=157, e = 104
HR=0.39 N=42, e=23
Sensi;ve+resistant
HR=1.22 N=132, e=87
HR=0.74 N=45, e=29
Interac;on p (2-‐sided)
P=0.12
P=0.25
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Osborne et al Study
Prior Endocrine Rx No Prior Endocrine Rx Interaction Test p = 0.43 (so 43% chance differences in subpopulations are by chance)
HR = 0.78
95% CI HR 0.52 – 1.15 p = 0.2
157 pts (77%) of 206 pts 49 pts (22%) of 206 pts HR = 1.47
95% CI HR 0.63 – 3.45 p = 0.37
J Clin Oncol 2009;15s(suppl; abstr 1014)
48%
52%
STRATUM 1: (endocrine naive or >12m post adj tam)
100%
Iressa/tam
placebo/tam
100%
placebo/tam
Iressa/tam
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AZD8931 is equipotent vs erbB1, erbB2 and erbB3 in cells, unlike Iressa and Lapatinib
Differentiation of AZD8931
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The MINT Study
D0102C00004
A Phase II, Randomised, Double-blind, Placebo-
controlled, Multi-centre Study to Assess the Efficacy
and Safety of AZD8931 In Combination with
Anastrozole, Compared to Anastrozole alone, in Post-
menopausal Women With Hormone Receptor-positive,
Endocrine Therapy-naive, Locally-advanced or Metastatic Breast Cancer (MINT)
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First-Line Therapy With Lapatinib Combined with Letrozole vs Letrozole Alone for Postmenopausal Hormone Receptor Positive MBC: First
Results from the Phase III Double-Blind EGF30008 Trial
S. Johnston1, M. Pegram2, M. Press3, J. Pippen4, X. Pivot5, H. Gomez6,
A. Florance7, L. O’Rourke7, J. Maltzman7
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• Binds to intracellular ATP binding site of EGFR (ErbB-1) and HER2 (ErbB-2) preventing phosphorylation and activation
• Blocks downstream signaling through homodimers and heterodimers of EGFR (ErbB-1) and HER2 (ErbB-2)
• Dual blockade of signaling
1+2
Downstream signaling cascade
1+1 2+2
Geyer CE, ASCO 2006 Konecny GE et al., Cancer Res 2006 66(3):1630 Rusnak DW et al., Mol Cancer Ther 2001 1(2):85
Xia W et al., Oncogene 2002 21(41):6255
Lapatinib Mechanism of Action
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Letrozole 2.5 mg daily + Lapatinib 1500 mg daily
Phase III, Randomized, Double-Blind Controlled Trial: Study Design
Patient Population • ER+ and/or PgR+ • Postmenopausal • HER2+ , HER2-ve / Unknown • Stage IIIb/IIIc/IV • No prior treatment for MBC
Stratification • Disease sites
• Bone only / visceral or soft tissue
• Interval since adjuvant tamoxifen therapy
• < 6 mo / ≥ 6 mo or none
R A N D O M I Z E
N=1286 (including n=219 HER2+)
Letrozole 2.5 mg daily + Placebo
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Endpoints
• Primary – Progression-free survival (PFS) as assessed by investigator
in patients with HR+, HER2+ MBC
• Secondary – PFS in HR+ ITT population (HER2+, HER2-ve/unknown) as
assessed by investigator – Overall survival (OS) – Overall response rate (ORR) – Clinical benefit rate (CBR) – Safety
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Progression-Free Survival: HER2+ Population
Letrozole
(N = 108)
Letrozole + Lapatinib (N = 111)
Progressed or died 89 (82%) 88 (79%)
Median PFS, mo 3.0 8.2
Hazard ratio (95% CI) 0.71 (0.53, 0.96)
p-value 0.019
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PFS: HER2-ve Patients (N=952) < 6 Mo Since D/C
of Tam
• Median tam duration 2.8 y • Median time since d/c 1 mo
Let (N=370)
Let + Lap (N=382)
Median PFS, mo 15.0 14.7
Hazard ratio (95% CI), p-value
0.94 (0.79, 1.13); p=0.522
Let (N=104)
Let + Lap (N=96)
Median PFS, mo 3.1 8.3
Hazard ratio (95% CI), p-value
0.78 (0.57, 1.07); p=0.117
≥ 6 Mo Since D/C of Tam (33%) or No Tam (67%)
• Median tam duration 5 y • Median time since d/c 3.5 y
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Efficacy Summary
• In postmenopausal women with HR+, HER2+ MBC the combination of letrozole and lapatinib showed: – 29% reduction in risk of disease progression (p=0.019), with an
improvement in median PFS from 3.0 to 8.2 months – Significant improvement in clinical benefit rate
(29% to 48%; p=0.003)
• In postmenopausal women with HR+, HER2- ve MBC: – No significant treatment benefit on PFS [HR 0.90 (0.77, 1.05;
p=0.188)] – 23% reduction in risk of disease progression by preplanned Cox
analysis [adjusted treatment HR 0.77 (0.64, 0.94; p=0.010)] • Prior tamoxifen exposure was a significant covariate • Biomarker studies ongoing
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Endocrine Therapy combined with SERMs
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Combination anastrozole and fulvestrant in metastatic breast cancer
Mehta RS et al. N Engl J Med 2012;367:435-444.
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Baseline Characteristics of the Patients and the Disease, According to Treatment Group.
Mehta RS et al. N Engl J Med 2012;367:435-444.
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Kaplan–Meier Curves for Progression-free Survival, According to Treatment Group.
Mehta RS et al. N Engl J Med 2012;367:435-444.
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Kaplan–Meier Curves for Progression-free Survival, According to Treatment Group.
Mehta RS et al. N Engl J Med 2012;367:435-444.
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Everolimus for postmenopausal women with advanced breast cancer:
updated results of the BOLERO-2 trial
G. N. Hortobagyi, M. Piccart, H. Rugo, H. Burris, M. Campone, S. Noguchi, M. Gnant, K. I. Pritchard, L. Vittori, P. Mukhopadhyay, T. Sahmoud, D. Lebwohl, J.
Baselga On behalf of the BOLERO-2 Investigators
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Neoadjuvant (Ph II): Letrozole ± Everolimus
BC = breast cancer; ER+ = estrogen receptor-positive; RR = response rate. Baselga J et al. JCO. 2009;27:2630-2637
Primary endpoint: RR at 16 weeks (palpaFon)
270 postmenopausal women with ER+ early BC
Everolimus 10 mg/day + Letrozole 2.5 mg/day
Placebo + Letrozole 2.5 mg/day
Surgery
R A N D O M I Z E
• Higher RR: 68% vs. 59% (P = 0.062) • Greater antiproliferative response: È Ki67 by 57% vs. 30% (P < 0.01)
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TAMRAD (Ph II): Tamoxifen ± Everolimus in Advanced BC
• 111 postmenopausal women with ER+ advanced BC previously treated with an AI were randomized in a phase II trial
AI = aromatase inhibitor; BC = breast cancer; ER+ = estrogen receptor-positive; EVE = everolimus; TAM = tamoxifen. Bourgier C et al. ECCO/ESMO 2011 (Abstract #5005)
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Prob
abili
ty o
f Pro
gres
sion
TAM: 4.5 mos TAM + EVE: 8.6 mos
Months
HR = 0.54 Log-rank P = 0.002
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BOLERO-2 (Ph III): Everolimus in Advanced BC
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 = 724 • Postmenopausal ER+
• Unresectable locally advanced or metastaFc BC
• Recurrence or progression a]er letrozole or anastrozole
Stratification: Sensitivity to prior hormone therapy and presence of visceral metastases
Hortobagyi G et al. SABCS 2011 (Abstract #S3-7) 31 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.
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BOLERO-2: Baseline Characteristics 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 31 Lung involvement 29 33 Measurable diseasea 70 68
aAll other patients had ≥1 bone lesion.
32
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BOLERO-2: Prior Therapy
Everolimus + Exemestane (n = 485), %
Placebo + Exemestane (n = 239), %
Sensitivity to prior hormonal therapy 84 84
Last treatment: LET/ ANA 74 75 Last treatment
Adjuvant 21 15 Metastatic 79 85
Prior tamoxifen 47 50 Prior fulvestrant 17 16 Prior chemotherapy for metastatic BC 26 26
Number of prior therapies: ≥3 54 53 33 Hortobagyi G et al. SABCS 2011 (Abstract #S3-7)
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BOLERO-2 (12-month f/up): PFS Local
CI = confidence interval; EVE = everolimus; EXE = exemestane; HR = hazard ratio; PBO = placebo; PFS = progression-free survival.
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (weeks)
Prob
abili
ty (
%) o
f Eve
nt
HR = 0.44 (95% CI: 0.36-0.53) Log rank P value: <1 x 10-16 EVE + EXE: 7.4 months PBO + EXE: 3.2 months
EVE + EXE (E/N = 267/485) PBO + EXE (E/N = 190/239)
Everolimus Placebo
Number of patients still at risk
485 436 365 303 246 188 136 96 64 45 34 21 13 9 2 2 0 239 190 131 95 63 45 29 19 12 8 6 6 4 2 0 0 0
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BOLERO-2 (12 mo f/up): PFS Central
CI = confidence interval; EVE = everolimus; EXE = exemestane; HR = hazard ratio; PBO = placebo; PFS = progression-free survival.
Everolimus Placebo
Number of patients still at risk
485 422 351 284 224 176 119 86 57 38 32 22 12 7 2 2 0 239 179 112 74 56 36 23 18 8 5 4 4 3 1 0 0 0
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Prob
abili
ty (%
) of E
vent
HR = 0.36 (95% CI: 0.28-0.45) Log rank P value: <1 x 10-16
EVE + EXE: 11.0 months PBO + EXE: 4.1 months
EVE + EXE (E/N = 155/485) PBO + EXE (E/N = 127/239)
Time (weeks)
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BOLERO-2 (12 mo f/up): PFS in Subgroups
<65 (449) ≥65 (275)
YES (610) NO (114)
YES (406) NO (318)
0 (435) 1, 2 (274)
YES (493) NO (231)
1 (118) 2 (217) ≥3 (389)
YES (398) NO (326)
YES (523) NO (184)
0.0 0.2 0.4 0.6 0.8 1.0 1.2 Hazard Ratio
All (724) Age
Hormonal sensitivity
Visceral metastasis
Baseline ECOG PS
Prior chemotherapy
No. of prior therapies
Non-NSAI hormonal therapy
PgR status positive
Subgroups (N)
Favors Placebo + Exemestane Favors Everolimus + Exemestane
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BOLERO-2 (12 mo f/up): Response and Clinical Benefit
12.0%
50.5%
1.3%
25.5%
0
10
20
30
40
50
60
Response Clinical Benefit
Everolimus + ExemestanePlacebo + Exemestane
P < 0.0001
P < 0.0001
Perc
ent
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BOLERO-2 (12 mo f/up): Most Common Adverse Events
Everolimus + Exemestane (n = 482), %
Placebo + Exemestane (n = 238), %
All Grades Grade 3 Grade 4
All Grades
Grade 3
Grade 4
Stomatitis 59 8 0 11 <1 0
Rash 39 1 0 6 0 0
Fatigue 36 4 <1 27 1 0
Diarrhea 33 2 <1 19 <1 0
Appetite decreased 30 1 0 12 <1 0
Nausea 29 <1 <1 28 1 0
Non-infectious Pneumonitis* 15 3 0 0 0 0
Hyperglycemia* 14 5 <1 2 <1 0
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BOLERO-2 (12 mo f/up): Summary • Addition of everolimus to exemestane
prolongs PFS in patients with ER+ HER2- breast cancer refractory to nonsteroidal aromatase inhibitors – Local: median 7.4 vs. 3.2 months,
HR = 0.44, P < 1 x 10-16
– Central: median 11.0 vs. 4.1 months, HR = 0.36, P < 1 x 10-16
• Benefit is observed in all subgroups 39 ER+ = estrogen receptor-positive; HER2- = human epidermal growth factor receptor 2-negative; HR = hazard ratio; PFS = progression-free survival.
Hortobagyi G et al. SABCS 2011 (Abstract #S3-7)
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BOLERO-2 (12 mo f/up): Conclusion
• Everolimus is the first agent to significantly enhance the efficacy of hormonal therapy in patients with ER+, HER2- breast cancer
• The addition of everolimus in advanced breast cancer could represent a paradigm shift in the management of this patient population
• Everolimus was approved by the FDA 40 BC = breast cancer; ER+ = estrogen receptor-positive.
Hortobagyi G et al. SABCS 2011 (Abstract #S3-7)
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Endocrine therapy combined with HDACs inhibitors
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CMAJ 2006;174(3):341-‐8
E P I G E N E T I C S A S A T H E R A P E U T I C
T A R G E T I N B R E A S T C A N C E R
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ENCORE 301: ADVERSE EVENTS Adverse Event1
AROM+ ENT (N=63) AROM + PBO (N=66)
Any G3 G4 Any G3 G4 Fatigue 29 ( 46%) 7 11% 1 2% 17 ( 26%) 2 3% -
Nausea 25 ( 40%) 3 5% - 10 ( 15%) 1 2% -
Neutropenia2, 3 16 ( 25%) 7 11% 1 2% 0 ( 0%) - -
Oedema peripheral 13 ( 21%) - - 3 ( 5%) - -
Vomiting 13 ( 21%) 3 5% - 3 ( 5%) - -
Anemia2 12 ( 19%) 1 2% - 8 ( 12%) 1 2% 1 2%
Dyspnoea 12 ( 19%) 2 3% - 7 ( 11%) - -
Weight decreased 11 ( 17%) - - 12 ( 18%) - -
Thrombocytopenia2 11 ( 17%) - - 4 ( 6%) - 1 2%
Diarrhoea 10 ( 16%) - - 8 ( 12%) 1 2% -
Pain 10 ( 16%) 1 2% - 4 ( 6%) 1 2% -
Back pain 9 ( 14%) - - 11 ( 17%) 1 2% -
Arthralgia 7 ( 11%) 1 2% - 11 ( 17%) - -
Constipation 6 ( 10%) - - 10 ( 15%) 1 2% -
45 Courtesy of P Ordentlich
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E N C O R E 3 0 1 : R E S U LT S ( P F S )
Courtesy of P Ordentlich
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E N C O R E R E S U L T S ( O S ) : F E B
2 0 1 2
Courtesy of P Ordentlich
Intent-to-treat population
Exemestane + En;nostat: median OS 28.1 months
Exemestane + Placebo: median OS 19.8 months
Hazard Ra;o 0.59 (95% CI: 0.36, 0.97) P=0.04 (2-‐sided) ; P=0.02 (1-‐sided)
Median Follow-‐up for OS = 25 months
28.1 months
19.8 months Improvement in OS
has stayed consistent with > 2 yr median
follow up
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A C E T Y L AT I O N A S A P O T E N T I A L B I O M A R K E R O F R E S P O N S E
(#events/#at risk)
EE HA-
EE HA+
EE HA-: median PFS 2.76 months
EE HA+: median PFS 8.55 months
Hazard ratio 0.317 (95% CI: 0.127, 0.787)
7/14 3/7 2/3 0/1 0/1 0/1 0/1 0/1 1/1
1/13 1/12 2/11 2/8 3/5 0/2 0/0 0/0 0/0
Prog
ress
ion
Prob
abilit
y
0.00
0.25
0.50
0.75
1.00
Months
0 2 4 6 8 10 12 14 16 18
Aromasin® + En;nostat HA+ : median PFS 8.5 months (N=13) Aromasin® + En;nostat HA-‐ : median PFS 2.8 months (N=14) Hazard ra;o 0.32 (95% CI: 0.13, 0.79)
(#events/#at risk)
EE HA-
EE HA+
EE HA-: median PFS 2.76 months
EE HA+: median PFS 8.55 months
Hazard ratio 0.317 (95% CI: 0.127, 0.787)
7/14 3/7 2/3 0/1 0/1 0/1 0/1 0/1 1/1
1/13 1/12 2/11 2/8 3/5 0/2 0/0 0/0 0/0
Progression Probability
0.00
0.25
0.50
0.75
1.00
Months
0 2 4 6 8 10 12 14 16 18
Potential to benefit may be determined by blood test within 1st two weeks of treatment
Kaplan-Meier Estimates of PFS by Acetylation (n=27)
8.5 months
2.8 months
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Eligible:
Advanced breast cancer
ER/PR+, HER2-‐
Progression/no progression on prior non-‐steroidal AI
Exemestane plus En;nostat
Exemestane plus Placebo
FES-‐PET and FDG-‐PET: baseline (at selected sites)
Blood sampling: baseline, 2 wks
Treatment un;l Progression/Intolerance: Exemestane 25mg daily po AND En;nostat/Placebo 5mg po weekly.
E2112-‐ Proposed Schema RANDOMIZE
N≈ 600
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ELIGIBILITY • Postmenopausal men/women • Histologically confirmed invasive breast cancer • Locally advanced or metastatic • ER/PR-positive (>1% staining), HER2-negative • Measurable or evaluable disease • 1st line: no prior endocrine therapy in the metastatic setting
OR prior adjuvant non-steroidal AI use allowed but completed ≥ 12 months prior to enrollment
• Refractory: intolerance/disease progression after non-steroidal AI use in the metastatic setting OR prior adjuvant non-steroidal AI use allowed but completed ≤ 12 months prior to enrollment
• Prior everolimus permitted, but not exemestane • One prior chemo permitted in metastatic setting • ECOG 0-1 and adequate organ function
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Conclusions • The management of hormone-receptor positive
MBC has significantly evolved in the last few years: - Newly diagnosed HER2+-> Combination with T or L - Newly diagnosed HER2 - AI/SERM - Refractory disease AI/Everolimus - EGFR-targeting agents?
• Future directions - HDACs, IGFRs in MBC - Everolimus in adjuvant setting
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There is still a role for single agent endocrine therapy?
NO