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Evolution of Endocrine Therapy in Breast Cancer
Sara A. Hurvitz, MD, FACP Associate Professor of Medicine
University of California Los Angeles
Los Angeles, California
Endocrine Therapy of Breast Cancer in the 19th Century
Historical Timeline of Therapies for HR+ Advanced Breast Cancer
Oopho-
rectomy2,3
AI, aromatase inhibitor; ERDs, estrogen receptor downregulators; HR+; hormone-receptor positive; SERMs, selective estrogen receptor modulators
* Marginal improvement over lower dose fulvestrant.
1. Advanced Breast Cancer Community Website. Available at:
http://www.advancedbreastcancercommunity.org/treatment/drugs.html. Accessed April 20, 2015; 2. Beatson GT. Lancet.
1896;2:104-107; 3. Beatson GT. Lancet. 1896;2:162-165; 4. Cohen MH, et al. Oncologist. 2001;6(1):4-11; 5. Faslodex®
[package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2011.
SERMs4 • Tamoxifen
• Toremifene
AIs4
• Anastrozole
• Letrozole
• Exemestane
ERDs5 • Fulvestrant
ERDs5 • High-dose
fulvestrant*
1896 1977 1990s 2002 2010
Targeting
mTOR,
CDK4/6
HDAC…
2012 Endocrine
Therapy
Chemo-
therapy
1990s 1980s 2000s
Others1
• Capecitabine
• Gemcitabine
• Ixabepilone
• Eribulin
• Nab-paclitaxel
Taxanes1
• Paclitaxel
• Docetaxel
Anthracyclines1
• Doxorubicin
• Epirubicin
Endocrine Therapy for HR+ Advanced Breast Cancer
Cytoplasm
Nucleus
LBD
LBD
Cofactor complex
AF1 DBD
DBD AF1
Estrogen
Cell
growth
Estrogen
receptor
Aromatase inhibitors (AIs)
• Nonsteroidal AIs
− Anastrozole
− Letrozole
• Steroidal AIs
− Exemestane
SOS
E
GF
R
Shc
RAF PI3K
Akt/
m-TOR
MEK
H
ER
2
P
P P
MAPK
Growth factor
receptor
GRB2
Selective estrogen
receptor modulators
(SERMs)
• Tamoxifen
• Raloxifene
• Toremifene
Yardley DA, et al. J Clin Oncol. 2011;29(suppl 27). Abstract 268.
Estrogen receptor
downregulator
(ERD)
• Fulvestrant
RAS
Oophorectomy
ABC1 treatment guidelines for advanced breast cancer:1,2
Endocrine therapy (ET) 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
rapidly progressive disease needing a fast response
1. Cardoso F, et al. Breast. 2012;21(3):242-252; 2. Wilcken N, et al. Cochrane Database Syst Rev. 2003;2:CD002747.
1st-Line Hormone Receptor–Positive MBC
Efficacy of AIs in 1st-Line MBC
Trial Treatment # Patients TTP/PFS,
months
ORR, % CBR, %
Ai
vs T
am
oxif
en
Bonneterre et al
Anastrozole vs
Tamoxifen
340
328
8.2
8.3
32.9
32.6
56.2
55.5
Nabholtz et al
Anastrozole vs
Tamoxifen
171
182
11.1
5.6
21.1
17.0
59.1
45.6
Mouridsen et al
Letrozole vs
Tamoxifen
453
454
9.4
6.0
32
21
50
38
Paridaens et al
Exemestane vs
Tamoxifen
182
189
9.9
5.8
46
31
NR
NR
Chernozemsky et al
Exemestane vs
Tamoxifen
83
84
12
8.3
37.4
29.8
79.5
78.6
Cardoso F, et al. Cancer Treat Rev. 2013;39:457-65.
AI, aromatase inhibitor; CBR, clinical benefit rate; NR, not reported; ORR, objective response rate; PFS, progression-free survival;
TTP, time to progression
FIRST Trial Fulvestrant in First-Line MBC
• Randomized 1:1 fulvestrant (500 mg IM day 0,
14, 28, q28) vs anastrozole (1 mg daily)
• 205 patients
• 74% endocrine naïve (in adjuvant setting)1
• Clinical benefit rate same
– 72.5% fulv vs 67.0% anast, OR 1.30, HR 0.3861
• TTP fulvestrant better with fulvestrant
– 23.4 months vs 13.1 months, HR 0.66, P = .012
1. Robertson JF, et al. J Clin Oncol. 2009;27(27):4530-4535; 2. Robertson JF, et al. Breast Cancer Res
Treat. 2012;136(2):503-511.
Robertson JF, et al. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014;
San Antonio, Texas. Abstract S6-04.
FIRST Trial: Overall Survival
Bergh J, et al. J Clin Oncol. 2012;30(16):1919-1925.
FACT Trial: Anastrozole +/- Fulvestrant TTP
• Fulvestrant: 500 mg loading
250 mg day 14, day 29, and
monthly thereafter
• N = 514
• No de novo MBC
• 2/3 prior endocrine therapy
Mehta RS, et al. N Engl J Med. 2012;367(5):435-444.
SWOG 0226: Anastrozole +/- Fulvestrant • Fulvestrant: 500 mg loading
followed by 250 mg day 14, day 28 and monthly thereafter
• N = 707
• 40% de novo MBC
• 60% no prior tamoxifen (PFS 12.6 vs 17 mos, HR 0.74, P = .006)
• 40% prior TAM (PFS 14.1 vs 13.5 mos HR 0.89, P = .37)
Efficacy of AIs in 1st-Line MBC
Trial Treatment # Patients TTP/PFS, months ORR, % CBR, %
Ai
vs T
am
oxif
en
Bonneterre et al1
Anastrozole vs
Tamoxifen
340
328
8.2
8.3
32.9
32.6
56.2
55.5
Nabholtz et al1
Anastrozole vs
Tamoxifen
171
182
11.1
5.6
21.1
17.0
59.1
45.6
Mouridsen et al1
Letrozole vs
Tamoxifen
453
454
9.4
6.0
32
21
50
38
Paridaens et al1
Exemestane vs
Tamoxifen
182
189
9.9
5.8
46
31
NR
NR
Chernozemsky et al1
Exemestane vs
Tamoxifen
83
84
12
8.3
37.4
29.8
79.5
78.6
AI vs
AI +
fu
lvest
Mehta et al2
Anastrozole vs
Anastrozole +
Fulvestrant
345
349
13.5
15.0
NR
NR
70
73
Bergh et al3 Anastrozole vs
Anastrozole +
Fulvestrant
256
258
10.2
10.8
33.6
31.8
55.1
55.0
AI
vs
fulv
est
Robertson et al4, 5 Anastrozole vs
Fulvestrant
103
102
13.1
23.4
21.7
23.4
46
31
1. Cardoso F, et al. Cancer Treat Rev. 2013;39:457-65; 2. Bergh J, et al. J Clin Oncol. 2012;30(16):1919-1925; 3. Mehta RS, et al. N
Engl J Med. 2012;367(5):435-444; 4. Robertson JF, et al. Breast Cancer Res Treat. 2012;136(2):503-511; 5. Robertson JF, et al.
Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract S6-04.
Rb as Master-Regulator of the R-Point in Cell Cycle
palbociclib
Palbociclib Preferentially Inhibits Proliferation of Luminal Estrogen Receptor–Positive Human Breast
Cancer Cell Lines In Vitro
Subtype
Luminal Non-luminal/post EMT
HER2 amplified Non-luminal
Immortalized
0
100
200
300
400
500
600
700
800
900
1000
MB-175
ZR75
-30
CAMA-1
MB13
4
HCC20
2
UACC-893
EFM
19
SUM19
0
EFM
192A
MB-361
HCC15
00
HCC14
19
HCC38
MB-415
MCF-
10A
UACC-812
HCC22
18
ZR75
-1
MDAMB45
3
184A
1
T47D
MCF7
BT-
20
MDAMB43
5
BT4
74
SKBR3
KPL-
1
HCC11
43
MDAMB23
1
HCC13
95
SUM-225
HS57
8T
184B
5
UACC73
2
CAL-51
BT5
49
COLO
824
DU44
75
HCC11
87
HCC15
69
HCC18
06
HCC19
37
HCC19
54
HCC70
MB-436
MB15
7
MDAMB46
8
IC5
0, n
M
Finn RS, et al. Breast Cancer Res. 2009;11(5):R77.
Phase II Study Design ER+, HER2– Locally Recurrent or Metastatic Breast
Cancer
N = 66
1:1
Part 1
• Post-
menopausal
• ER+, HER2–
BC status
• No prior
treatment for
advanced
disease
R
A
N
D
O
M
I
Z
A
T
I
O
N
Palbociclib
125 mg QDa +
Letrozole
2.5 mg QD
Letrozole
2.5 mg QD
Part 2
N = 99
1:1
• Post-
menopausal
• ER+, HER2–
BC with
CCND1
amplification
and/or loss
of p16
• No prior
treatment for
advanced
disease
R
A
N
D
O
M
I
Z
A
T
I
O
N
Palbociclib
125 mg QDa +
Letrozole
2.5 mg QD
Letrozole
2.5 mg QD
Stratification Factors
• Disease site (visceral vs bone only vs other)
• Disease-free interval (>12 vs ≤12 mo from end of
adjuvant to recurrence or de novo advanced disease)
aSchedule 3/1
Key Eligibility Criteria
• Measurable disease (RECIST 1.0) or bone-only disease
• ECOG PS of 0 or 1
• Adequate blood counts and organ function
• No prior/current brain metastases
100
90
80
70
60
50
40
30
20
10
0 Pro
gre
ss
ion
-Fre
e S
urv
iva
l P
rob
ab
ilit
y, %
0 4 8 12 16 20 24 28 32 36 40
84
81
67
48
60
36
47
28
36
19
28
14
21
6
13
3
8
3
5
1
1
PAL + LET
LET
Number of patients at risk Time, Months
PAL, palbociclib
Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.
PAL + LET
(N = 84)
LET
(N = 81)
Median PFS, months
(95% CI)
20.2
(13.8, 27.5)
10.2
(5.7, 12.6)
Hazard Ratio
(95% CI)
0.488
(0.319, 0.748)
P value .0004
Progression-Free Survival (ITT)
PFS Subgroup Analysis
062 0 . 0 . 125 0 . 25 0 . 50 1 . 0 2 . 0 4 . 0
Hazard Ratio ( log scale )
Time from End of Adju . Trt to Dis . Recur . Ms
Time from End of Adju . Trt to Dis . Recur . > 12 Ms
Time from End of Adju . Trt to Dis . Recur . Ms or De Novo
Prior Systemic Therapy : No
Prior Systemic Therapy : Yes
Previous Antihormonal Therapy : No
Previous Antihormonal Therapy : Yes
Previous Chemotherapy : No
Previous Chemotherapy : Yes
Disease Site : Other
Disease Site : Bone Only
Disease Site : Visceral
Baseline ECOG : 1
Baseline ECOG : 0
Age ≥ 65
Age < 65
Part 2
Part 1
All patients
15
25
59
44
40
57
27
71
13
30
17
37
38
46
37
47
50
34
84
14
30
51
37
44
53
28
65
16
26
12
43
36
45
39
42
49
32
81
Number of Patients
PAL + LET LET Population In Favor of PAL + LET In Favor of LET
≤12
≤12
Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.
Most Common Treatment-Related AEs ≥10% (AT)
• Neutropenia was self-limited and not associated with infectious complications
PAL + LET
N = 83
LET
N = 77
G1/2, % G3, % G4, % G1/2, % G3, % G4, %
Neutropenia 19 48 6 1 1 0
Leukopenia 23 18 0 0 0 0
Anemia 23 4 1 0 0 0
Fatigue 22 2 0 14 0 0
Alopecia 22 0 0 3 0 0
Hot flush 18 0 0 10 0 0
Arthralgia 17 0 0 9 1 0
Thrombocytopenia 14 2 0 0 0 0
Nausea 14 1 0 1 0 0
Decreased appetite 8 1 0 0 0 0
Stomatitis 10 0 0 0 0 0
Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.
TRIO-022/PALOMA-2 (Phase III)
• Primary endpoint
– PFS
• Secondary endpoints
– OS
– Response
– Response duration
– Disease control
– Safety
– PK/PD
– Biomarkers
– QoL
Finn RS, et al. J Clin Oncol. 2013;31(Suppl): Abstract TPS652.
MONALEESA (Ribociclib Ph III ER+ MBC)
Abemaciclib: Phase I (MBC Data) MTD single agent, continuous dosing 200 mg q12 hours
Patnaik A, et al. Cancer Res. 2014;74(19 Suppl): Abstract CT232.
Primary endpoint: Progression-free survival (PFS) Stratification Factors: • Nature of disease (visceral metastases versus bone only metastases versus other)
• Prior (neo)adjuvant endocrine therapy (AI therapy versus other versus no prior endocrine therapy)
Women with HR+, HER2-
Locoregionally Recurrent or
Metastatic Breast Cancer
with DFI >12 mos following
(neo)adjuvant ET or
presenting de novo with
metastatic disease (N = 450)
R
LY2835219 + NSAI until PD
Placebo + NSAI until PD
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Nonsteroidal
Aromatase Inhibitors (Anastrozole or Letrozole) Plus LY2835219, a CDK4/6 Inhibitor, or
Placebo in Postmenopausal Women With Hormone Receptor-Positive, HER2-Negative
Locoregionally Recurrent or Metastatic Breast Cancer with No Prior Systemic Therapy in
This Disease Setting
2:1
NCT02246621
Phase III Study of Abemaciclib: MONARCH 3
Patnaik A, et al. Cancer Res. 2014;74(19 Suppl): Abstract CT232.
Trial Treatment # Patients TTP/PFS, months ORR, % CBR, %
Ai v
s T
am
ox
ife
n
Bonneterre et al1
Anastrozole vs
Tamoxifen
340
328
8.2
8.3
32.9
32.6
56.2
55.5
Nabholtz et al1
Anastrozole vs
Tamoxifen
171
182
11.1
5.6
21.1
17.0
59.1
45.6
Mouridsen et al1
Letrozole vs
Tamoxifen
453
454
9.4
6.0
32
21
50
38
Paridaens et al1
Exemestane vs
Tamoxifen
182
189
9.9
5.8
46
31
NR
NR
Chernozemsky et al1
Exemestane vs
Tamoxifen
83
84
12
8.3
37.4
29.8
79.5
78.6
AI vs
AI +
fu
lvest
Mehta et al2
Anastrozole vs
Anastrozole +
Fulvestrant
345
349
13.5
15.0
NR
NR
70
73
Bergh et al3 Anastrozole vs
Anastrozole +
Fulvestrant
256
258
10.2
10.8
33.6
31.8
55.1
55.0
AI v
s
fulv
est
Robertson et al4, 5 Anastrozole vs
Fulvestrant
103
102
13.1
23.4
21.7
23.4
46
31
AI v
s
AI-
CD
Ki
Finn et al6 Letrozole vs
Letrozole + Palbociclib
77
83
10.2
20.2
33
43
58
81
1. Cardoso F, et al. Cancer Treat Rev. 2013;39:457-65; 2. Bergh J, et al. J Clin Oncol. 2012;30(16):1919-1925; 3. Mehta RS, et al. N
Engl J Med. 2012;367(5):435-444; 4. Robertson JF, et al. Breast Cancer Res Treat. 2012;136(2):503-511; 5. Robertson JF, et al.
Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract S6-04; 6. Finn RS,
et al. Lancet Oncol. 2015;16(1):25-35.
Endocrine Trials in 1st-Line MBC
Conclusions: First-Line MBC • Aromatase inhibitors demonstrated improved efficacy
compared with tamoxifen and became the standard of care for
initial treatment of postmenopausal women with HR+ advanced
breast cancer
• Fulvestrant (250 mg monthly) has demonstrated similar efficacy
compared with tamoxifen
• Fulvestrant (500 mg initial dose 250) + anastrozole
conflicting results compared to anastrozole alone
• Fulvestrant high dose (500 mg with loading regimen) improved
TTP and OS compared to anastrozole (PHASE II)
– Await FALCON study results (PHASE III)
• CDK 4/6 inhibitor (palbociclib) plus letrozole significantly improves median PFS with acceptable safety profile
– FDA approved February 2015
– Await PALOMA-2 results
Second Line and Beyond
R E S I S T A N C E
40% 30% 25% 15%
1st
Line
2nd
Line 3rd
Line
4th
Line
Barrios C, et al. Ann Oncol. 2012;23(6):1378-1386; Osborne CK, et al. Annu Rev Med. 2011;62:233-247.
Chance of Response by Line of Endocrine Therapy
Treatment Guidelines for HR+ Advanced Breast Cancer Following Progression on
Initial Endocrine Therapy
Trial of new
endocrine
therapy
Chemotherapy Continue
endocrine
therapy until
progression or
unacceptable
toxicity
No clinical benefit
after 3 consecutive
endocrine therapy
regimens
Or
Symptomatic visceral
disease
Yes
No
Progression
NCCN treatment guidelines1:
• Hormone receptor–positive advanced breast cancer may benefit from
sequential use of ET at time of progression and should receive additional
ET for second-line and subsequent therapy2
• Approaches to switching endocrine therapy3
Tamoxifen AI
Nonsteroidal AI steroidal AI
Tamoxifen or AI ERD
Other endocrine approaches
AI, aromatase inhibitor; ET, endocrine therapy; ERD, estrogen receptor downregulator
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer.
V.3.2012; 2. Wilcken N, et al. Cochrane Database Syst Rev. 2003;2:CD002747; 3. Hurvitz SA, et al. Cancer.
2008;113(9):2385-2397.
Fulvestrant vs AI After Endocrine Therapy
• Two phase III studies demonstrated
fulvestrant 250 mg/mo similar efficacy
compared to anastrozole after prior endocrine
therapy1
• EFECT: fulvestrant (500 mg D1, 250 D14, D28,
qmo) similar to exemestane after prior NSAI2
• SoFEA: fulvestrant (250 mg/mo) + anastrozole
similar to fulvestrant or exemestane3
1. Robertson JF, et al. Cancer. 2003;98(2):229-238; 2. Chia S, et al. J Clin Oncol. 2008;26(10):1664-1670; 3. Johnston
SR, et al. Lancet Oncol. 2013:14(10):989-998.
CONFIRM: Fulvestrant 500 mg Is Better Than 250 mg in Postmenopausal Women With ER+ Advanced
Breast Cancer Following Prior Endocrine Therapy
Phase III study; N = 736
Postmenopausal women with ER+ advanced
breast cancer
Progressed after endocrine therapy in adjuvant or first-line
metastatic setting (~45% were endocrine therapy–
naïve in advanced setting)
Primary endpoint PFS
Secondary endpoints
ORR, CBR, DoCR, OS,
TTD, QoL
Abbreviations: CBR, clinical benefit rate; DoCB, duration of clinical benefit; ER, estrogen receptor; ORR, objective
response rate; OS, overall survival; PFS, progression-free survival; TTD, time to death; QoL, quality of life.
Di Leo A, et al. J Clin Oncol. 2010;28(30):4594-4600.
Fulvestrant 500 mg/mo
Fulvestrant 250 mg/mo
Fulvestrant 500 n = 362
Fulvestrant 250 n = 374 P value
PFS (mo) 6.5 5.5 .006
ORR (%) 9.1 10.2 .795
CBR (%) 45.6 39.6 .100
DoCB (mo) 16.6 13.9 —
TTD (mo) 25.1 22.8 .091
Di Leo A, et al. J Natl Cancer Inst. 2014;106(1):djt337.
CONFIRM: Fulvestrant 500 mg Is Better Than 250 mg in Postmenopausal Women With ER+ Advanced
Breast Cancer Following Prior Endocrine Therapy
Mechanisms of Resistance to Endocrine Therapy
Second
messengers
Johnston SR. Clin Cancer Res. 2010;16(7):1979-1987.
BOLERO-2: Study Design
EVE 10 mg daily +
EXE 25 mg daily (n = 485)
Placebo +
EXE 25 mg daily (n = 239)
Endpoints • Primary: PFS (local assessment)
• Secondary: OS, ORR, CBR, QOL, safety, PK
• Exploratory: Biomarkers
Stratification:
• Sensitivity to prior hormone therapy
• Presence of visceral metastases
31
BC, breast cancer; CBR, clinical benefit rate; ER+, estrogen receptor-positive; EVE, everolimus; EXE, exemestane;
HER2–, human epidermal growth factor receptor-2–negative; ORR, overall response rate; OS, overall survival; PD, progressive disease;
PFS, progression-free survival; PK, pharmacokinetics; QOL, quality of life.
Baselga J, et al. N Engl J Med. 2012;366(6):520-529.
N = 724 •Postmenopausal women
•ER+, HER2– unresectable
locally advanced or metastatic
BC
•Recurrence or progression
after letrozole or anastrozole
Randomize
2:1
BOLERO-2 Final PFS Analysis (18-mo) (Local Assessment)
1.0
0.8
0.6
Pro
ba
bil
ity o
f
Pro
gre
ss
ion
-Fre
e S
urv
iva
l
0.4
0.2
0
28 26 24 22 20 18 16 14
Time, Months
12 10 8 6 4 2 0
0 0
1 0
4 0
10 1
13 1
23 2
42 6
57 9
99 17
147 27
194 42
236 61
318 103
394 146
485 239
EVE+EXE PBO+EXE
No. at risk
HR = 0.45 (95% CI, 0.38-0.54) Log-rank P<.0001
Kaplan-Meier medians EVE+EXE: 7.8 months PBO+EXE: 3.2 months
Censoring times
EVE+EXE (n/N = 310/485)
PBO+EXE (n/N = 200/239)
CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free
survival
Yardley DA, et al. Adv Ther. 2013;30(10):870-884.
BOLERO-2 (39-mo): Final OS Analysis
One-sided P value was obtained from the log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasis from IXRS®.
CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; IXRS®, Interactive Voice and Web Response System;
PBO, placebo.
232
109
248
113
266
120
279
130
292
145
311
153
330
162
347
170
373
182
399
194
414
201
429
211
448
220
471
232
485
239
EVE+EXE
PBO+EXE
No. at risk
HR = 0.89 (95% CI, 0.73-1.10) Log-rank P = .14
Kaplan-Meier medians EVE+EXE: 30.98 months PBO+EXE: 26.55 months
Censoring times
11
5
23
8
39
18
58
28
91
41
118
56
154
77
196
98
216
102
0
0
1
1
• At 39 months’ median follow-up, 410 deaths had occurred (data cutoff date: 03 October 2013)
– 55% deaths (n = 267) in the EVE+EXE arm vs 60% deaths (n = 143) in the PBO+EXE arm
Piccart M, et al. Eur J Cancer. 2014;50(Suppl 1): Abstract LBA1.
BOLERO-2 (39-mo): Safety Set
34
Everolimus +
Exemestane
(n = 482a), %
Placebo +
Exemestane
(n = 238a), %
All deaths 55 60
On-treatment deathsb 5 2
Disease progression as primary cause of death 3 1
AE as primary cause of death 2 <1
Serious AEs 33 16
Suspected to be drug-related 13 2
Grade 3/4 AEs 55 29
Suspected to be drug-related 41 8
AEs leading to discontinuation 29 5
Categories are not mutually exclusive. Patients with multiple events in the same category were counted only once in that category.
Patients with events in more than 1 category were counted once in each of those categories. aSafety set.
AE, adverse events; OS, overall survival.
Piccart M, et al. Eur J Cancer. 2014;50(Suppl 1): Abstract LBA1.
Conclusion
• Sequential use of endocrine therapy is indicated for HR+ breast cancer
– Tamoxifen, fulvestrant, AI, AI+everolimus
• Fulvestrant 500 mg dose better than 250 mg
• Choice of sequence based on prior therapies as well as patient preference (side effect profile, ease of administration). No evidence to suggest one sequence better than another.
Investigational Strategies
Fibroblast Growth Factor Receptor
Histone Deacetylase
Insulin Like Growth Factor Pathway
FGFR1 Signaling
FRS2 Grb2 Sos Ras Raf
MEK
MAPK
PLC
HSPG
FGF
Gab1
PI3K
Target genes
Negative feedback
(eg, Spry/Sef/MAPKP3/MKP1)
Downstream transcription factors
(eg, Fos/Jun/Pea3)
PKC IP3
DAG
PIP2
Ca2+
SPRY CBL
SE
F
FG
FR
L1
SEF-B
SPRY
MKP3
p
p
p
p
p
p
p
p
MKP1
AKT STATs
FGFR1
• Transmembrane receptor
tyrosine kinase
• Activated by ligands (eg, FGF1,
FGF2, FGF3)
• Induces activation of MAPK
pathway and cell proliferation
DAG, diacylgycerol; FGF, fibroblast growth factor; FGFR, FGF receptor; FGFRL, FGFR-like; FRS2α, FGFR substrate 2; Grb, growth factor receptor–bound
protein; HSPG, heparan sulfate proteoglycan 2; IP3, inositol triphosphate; MAPK, mitogen-activated protein kinase; MEK, MAPK/extracellular signal-regulated
kinase kinase; MKP, MAPK phosphatase; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKCδ, protein kinase Cδ; PLCγ,
phospholipase Cγ; SEF, similar expression to FGF; SPRY, sprouty; STAT, signal transducer and activator of transcription.
Turner N, et al. Nat Rev Cancer. 2010;10(2):116–129.
FGFR1 Amplification in BC • Occurs in 8%-15% of BCs and 16%-27% of luminal B BC1
• ER+/HER2-/luminal B phenotype2
• Associated with resistance to endocrine therapy2 and
poor prognosis2,3
• Exhibits amplification of 11q12–14 (FGF3/4/19, cyclin D1)
in ~30% of samples4
• FGFR1 inhibition decreases cell viability in FGFR1
amplified cell lines2,5
• Dovitinib: Oral inhibitor of several receptor tyrosine
kinases (FGFR1, VEGFR, PDGF-B, c-KIT, FLT3)6,7
BC, breast cancer; ER, estrogen receptor; HER2, human epidermal receptor 2.
1. André F, et al. Clin Cancer Res. 2013;19(13):369-3702; 2. Turner N, et al. Cancer Res. 2010;70(5):2085-2094;
3. Elbauomy Elsheikh S, et al. Breast Cancer Res. 2007;9(2):R23; 4. Shiang CY, et al. Breast Cancer Res.
2010;123(3):747-755; 5. Kwek SS, et al. Oncogene. 2009;28(17):1892-1903; 6. Chase A, et al. Blood. 2007;110(10):3729-
3734; 7. Lee SH, et al. Clin Cancer Res. 2005;11(10):3633-3641.
Ph II Dovitinib: Efficacy Results in Patients With
Measurable Disease (N = 68)
FGFR1+/HR+
N = 20
FGFR1−/HR
+
N = 31
FGFR1−/HR
−
N = 17
Best overall RECIST response, n (%)
PR not confirmed after 4 weeks (PRnc) 3 (15) – –
SD 9 (45) 15 (48) 4 (24)
PD 5 (25) 9 (29) 6 (35)
Unknown 3 (15) 7 (23) 7 (41)
PD per clinical evaluation but not RECIST 2 1 5
Not assessable 1 6 2
Clinical benefit (CR/PR/SD ≥24 weeks) 3 (15) 1 (3) 2 (12)
PRnc and/or SD ≥24 weeks 5 (25) 1 (3) 2 (12)
PFS median by Kaplan-Meier estimates,
months [range] 3.6 [0–9.0] 3.5 [0–5.5] 2.1 [0–9.2]
André F, et al. J Clin Oncol. 2011;29(Suppl): Abstract 508.
Exploratory Analysis: Efficacy in HR+ Patients With Known Measurable Disease and FGF Status
100
80
60
40
20
0
-20
-40
-60
-80
-100
Be
st
% C
ha
ng
e F
rom
Bas
eli
ne
FGF3 amplified
FGFR1 and/or FGFR2 amplified only
FGF pathway unamplified
André F, et al. J Clin Oncol. 2011;29(Suppl): Abstract 508.
Grade 3/4 Adverse Events ≥5% (Regardless of Causality), n(%)
Grade 3 Grade 4
Asthenia 19 (24) –
ALT increased 7 (9) 1 (1)
Blood alkaline phosphatase increased 7 (9) 1 (1)
Diarrhea 7 (9) –
Fatigue 6 (7) –
Neutropenia 5 (6) –
Vomiting 5 (6) –
Dyspnea 5 (6) –
AST increased 5 (6) –
Thrombocytopenia 4 (5) 1 (1)
GGT increased 2 (2) 3 (4)
Nausea 4 (5) –
Anemia 3 (4) 1 (1)
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase.
André F, et al. J Clin Oncol. 2011;29(Suppl): Abstract 508.
Summary FGFR Inhibition
• Dovitinib phase II study was first trial of an FGFR
inhibitor in BC with biomarker-selected patients
• Although the study did not meet its primary
endpoint, dovitinib exhibited antitumor activity in
the subgroup of patients with FGFR1
amplification
• Coamplification of FGFR1 and FGF3 could define
a small group of patients with dovitinib-sensitive
disease
• Future trials (dovitinib, lucitanib, etc) are planned
Postmenopausal
women with ER-
positive advanced
breast cancer who
progressed on previous
nonsteroidal AI therapy
(N = 130)
Exemestane 25 mg/day +
Entinostat 5 mg/wk
(n = 64)
Exemestane 25 mg/day +
Placebo
(n = 66)
Treatment until disease
progression or
unacceptable toxicity
• Primary endpoint: PFS
• Secondary endpoints: ORR, CBR
ENCORE-301 Study Design Entinostat (selective HDAC inhibitor): increased expression
of ERα and aromatase in preclinical studies which sensitizes
breast cancer cells to effects of estrogen and AI therapy
Yardley DA, et al. Cancer Res. 2011;71(24 Suppl): Abstract PD01-04.
Yardley DA, et al. J Clin Oncol. 2013;31(17):2128-2135.
ENCORE-301 PFS (Left), OS (Right)
ENCORE-301 Forest Plot PFS Subgroups
Yardley DA, et al. J Clin Oncol. 2013;31(17):2128-2135.
ENCORE 301: Safety
Adverse Events, % Exemestane + Entinostat
n = 63
Exemestane + Placebo
n = 66
All Grades Grade 3/4 All Grades Grade 3/4
Fatigue 48 13 26 3
Nausea 40 5 15 2
Weight loss 19 0 18 0
Anemia 19 2 12 4
Back pain 16 0 17 2
Dyspnea 19 3 11 0
Arthralgia 11 2 17 0
Diarrhea 17 0 12 2
Constipation 10 0 15 2
Neutropenia 30 15 0 0
Peripheral edema 21 0 5 0
Vomiting 21 5 5 0
Thrombocytopenia 19 2 6 2
Pain 16 2 6 2
Yardley DA, et al. J Clin Oncol. 2013;31(17):2128-2135.
IGF-1 and Breast Cancer
• Growing evidence associates
IGF-1 system with breast cancer
establishment and progression.
• Targeting Strategies: – Mabs (mainly to IGF-1R)
- Figitumumab: preclinical activity and
mild toxicity, but negative
unpublished results
- Cixutumumab: phase I with
temsirolimus mild toxicities ER+.
Phase II (NCT00699491) ongoing
- R1507: Ph II combo with letrozole
completed, awaiting results
– Tyrosine kinase inhibitors
- NVP-ADW742 halted d/t toxicity
- Linsitinib (IGF-1R and IR) plus
endocrine therapy and erlotinib.
Stopped d/t toxicity and PD
- BMS-754807 dual RTKi in ph II with
letrozole
Christopoulos PF, et al. Mol Cancer. 2015:14(1):43.
Questions & Discussion