Cyclin CDK 4/6 inhibitors in
breast cancer treatment
Agustí Barnadas
Medical Oncology Department
Hospital Sant Pau
Barcelona
Agenda
• Cell-cycle pathway
• Cyclin CDK 4/6 inhibitors:
– Palbociclib
• Clinical efficacy
• Safety
• Clinical development
– Other inhibitors
• Conclusions
Cyclin-dependent kinase 4/6-Rb protein:
a key pathway in cell cycle progression
From Rocca A, et al. Expert Opin Pharmacother 2013
Synergy Between ER and CDK4/6: Critical for Efficacy of
Combinations in ER+ Tumours
• Cyclin D1 is a direct transcriptional
target of ER.
• Inhibition of cyclin D1 inhibits
oestrogen-induced S-phase entry.
• Endocrine resistance is associated with
persistent cyclin D1 expression and RB
phosphorylation.
• CDK4/6 inhibitors are most effective in
tumours with gene amplification and
overexpression of cyclin D1, which is
common in ER+ breast cancer.
M
B
ZR 175
75
C 30
AM
A
M -1
B
13
H
C 4
U C2
AC 0
C 2
-8
9
EF 3
M
SU 19
M
EF 19
M 0
19
M 2A
B
H -36
CC 1
1
H 50
CC 0
14
1
H 9
CC
M 38
B
M 415
C
F
U -1
AC 0A
C
H -81
CC 2
22
Z 18
M R7
D
AM 5-1
B
45
18 3
4A
1
T4
7D
M
C
F7
B
M
T
D
AM -20
B
43
B 5
T4
7
SK 4
BR
K 3
H PLCC 1
M
D 114
AM 3
B
H 23
CC 1
1
SU 39
M 5
-2
H 25
S5
78
18 T
4
U
AC B5
C
7
C 32
AL
-5
B 1
T
C 54
O
LO 9
8
D 24
U4
4
H
CC 75
1
H 18
CC 7
1
H 56
CC 9
1
H 80
CC 6
H 193
CC 7
19
5
H 4
CC
M 70
B
-4
3
M 6
M
B
15
D
AM 7
B
46
8
IC50, nM
Palbociclib Preferentially Inhibits Proliferation of Luminal Oestrogen
Receptor-Positive Human Breast Cancer Cell Lines in Vitro
1000
900
800
700
Enriched in RE+ luminal cell
600
500
400
300
200
100
0
Subtype
Luminal
HER2 amplified
Non-luminal/post EMT
Non-luminal
Immortalised
Finn RS, et al. Breast Cancer Res. 2009;11(5):R77.
ER+ breast cancer:
related sensitivity markers to palbociclib
Sensitive cell lines:
•76% luminal genes (0% in resistant cell lines)
• 0% non-luminal gene (59% in resistant cell lines)
• RB − upregulated
• cyclin D1 − upregulated
• p16 − downregulated
Molecular Mechanisms of Palbociclib Combined With ER
Antagonists in ER+ Breast Cancer
Combined inhibition of CDK4/6 and ER signalling increases senescence in ER+ breast cancer cell lines
SA**-bGal activity in T47D treated with ER antagonists and palbociclib
Normalized b-Gal Activity
2.50
2.00
*
*
1.50
1.00
0.50
0.00
*P<0.001 vs. single agents
**SA= Senescence Associated
Finn RS, et al. Breast Cancer Res. 2009;11(5):R77.
Differential response to CDK4/6 inhibition in breast cancer explants
Dean JL et al. Cell Cycle 2012; 11: 2756
CDK4/6 inhibitors in CDK4/6-dependent murine model of BC
Roberts PJ, et al. J Natl Cancer Inst 2012
Abstract S1-6
Results of a Randomized Phase 2 Study of PD 0332991,
a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor, in
Combination with Letrozole vs Letrozole Alone for FirstLine Treatment of ER+, HER2– Advanced Breast Cancer
(TRIO-18)
RS Finn,1 JP Crown,2 I Lang,3 K Boer,4 IM Bondarenko,5 SO Kulyk,6 J Ettl,7 R Patel,8 T Pinter,9 M
Schmidt,10 Y Shparyk,11 AR Thummala,12 NL Voitko,13 A Breazna,14
ST Kim,15 S Randolph,15 DJ Slamon1
1University
of California Los Angeles, Los Angeles, CA, USA; 2Irish Cooperative Oncology Research Group, Dublin, Ireland; 3Orszagos
Onkologiai Intezet, Budapest, Hungary; 4Szent Margit Korhaz, Onkologia, Budapest, Hungary; 5Dnipropetrovsk City MultipleDiscipline Clinical Hospital, Dnipropetrovsk, Ukraine; 6Municipal Treatment-and-Prophylactic Institution, Donetsk, Ukraine;
7Technical University of Munich, Munich, Germany; 8Comprehensive Blood and Cancer Center, Bakersfield, CA, USA; 9Petz Aladar
Megyei Oktato Korhaz, Gyor, Hungary; 10University Hospital Mainz, Mainz, Germany; 11Lviv State Oncologic Regional Treatment
and Diagnostic Center, Ukraine; 12Comprehensive Cancer Centers of Nevada, Henderson, NV, USA; 13Kyiv City Clinical Oncology
Center, Ukraine; 14Pfizer Oncology, New York, NY, USA; 15Pfizer Oncology, La Jolla, CA, USA
Presented at SABCS 2012; December 5, 2012; San Antonio, TX, USA
Phase 2 Design
Part 1
ER+, HER2–
BC
R
A
N
D
O
M
I
S
A
T
I
O
N
N = 66
a
Schedule 3/1.
Part 2
PD 0332991 125
mg QDa +
Letrozole
2.5 mg daily
1:1
Letrozole 2.5
mg daily
ER+, HER2– BC
with CCND1 amp
and/or loss of
p16
R
A
N
D
O
M
I
S
A
T
I
O
N
PD 0332991
125 mg QDa +
Letrozole
2.5 mg QD
1:1
Letrozole 2.5
mg QD
N = 99
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)
Best Overall Response (ITT)
PD 991 + LET
(n = 84)
LET
(n = 81)
84
81
Objective Response Rate, % (95% CI)
Complete Response, n (%)
Partial Response, n (%)
34 (24-46)
0
29 (34)
26 (17-37)
1 (1)
20 (25)
Patients with measurable disease, n (%)
64 (76)
65 (80)
Objective Response Rate, % (95% CI)
Complete Response, n (%)
Partial Response, n (%)
45 (33-58)
0
29 (45)
31 (20-43)
0
20 (31)
Stable Disease ≥24 weeks, n (%)
30 (36)
15 (18)
Clinical Benefit Rate, n (%)*
59 (70)
36 (44)
Stable Disease <24 weeks, n (%)
14 (17)
22 (27)
Progressive Disease, n (%)
3 (4)
17 (21)
Indeterminable, n (%)
8 (10)
6 (7)
All randomised patients, n
* Complete response + partial response + stable disease ≥24 weeks.
Progression-Free Survival Probability
Progression-Free Survival
LET
(n = 81)
1.0
Number of Events (%)
21 (25)
40 (49)
0.9
Median PFS, months
(95% CI)
26.1
(12.7, 26.1)
7.5
(5.6, 12.6)
0.8
Hazard Ratio
(95% CI)
0.7
P value
0.37
(0.21, 0.63)
<0.001
0.6
0.5
0.4
0.3
0.2
0.1
0
0
2
4
6
8
10
84
81
75
57
12
14
16
18
20
22
24
26
14
4
9
3
5
3
3
1
1
1
Time (Month)
Number of patients at risk
PD991+LET
LET
PD 991 + LET
(n = 84)
60
38
53
29
43
22
35
17
25
11
18
6
15
5
28
Treatment Administration (AT)
PD 991 + LET
(n = 83)
LET
(n = 77)
8.9 (<1 – 25.9)
5.1 (<1 – 29.0)
Dose Interruptions During Cycles, n (%)
59 (71)
17 (22)
Cycle Delays, n (%)
62 (75)
NA
Dose Reductions, n (%)
29 (35)
NA
Median Duration of Treatment, months
(range)
AT = as treated.
Most Common Treatment-Related
Adverse Events ≥10% (AT)
PD 991 + LET
(n = 83)
LET
(n = 77)
Grade 1/2
Grade 3
Grade 4
Grade 1/2
Grade 3
Grade 4
Neutropenia
19
46
5
1
1
0
Leukopenia
24
14
0
0
0
0
Anaemia
19
4
1
0
0
0
Fatigue
17
2
0
13
0
0
Alopecia
18
0
0
3
0
0
Hot flushes
17
0
0
10
0
0
Arthralgia
16
0
0
10
0
0
Nausea
12
2
0
1
0
0
Thrombocytopenia
11
1
0
0
0
0
Palbociclib - Predictive biomarkers
Rb nuclear score
1.00
Negative
Intermediate/equivocal
Positive
Progression-free survival
0.90
0.80
0.70
0.60
0.50
Rb Nuclear Score
Negative
Equivocal
Positive
HR (95% CI)
1
1.02 (0.34, 2.99)
0.82 (0.28, 2.43)
600
1000
0.40
0.30
0.20
0.10
0.00
0
200
400
800
Time on study (days)
Clark AS, et al. SABCS 2013
Palbociclib predictive markers
% p16 nuclear staining
positive
negative
1.00
0%
1-24%
25-75%
0.90
0.80
0.70
0.60
% p16 Nuclear Staining
0%
1-24%
25-75%
0.50
0.40
HR (95% CI)
1
0.64 (0.22, 1.83)
2.42 (0.67, 8.68)
0.30
0.20
0.10
0.00
0
200
400
600
Time on study (days)
800
1000
Clark AS, et al. SABCS 2013
Palbociclib: ongoing studies in endocrine-sensitive tumours
Phase III, PALOMA-2 (1008)
N:465
• Post-menopausal
• HR+, HER2− MBC
• No previous treatment for
advanced disease
• AI-resistant patients excluded
Primary endpoint: PFS
Secondary endpoints:
ORR
SV
Safety
Biomarkers
Palbociclib (125 mg /daily, 3/1
schedule)
+ letrozole(2.5 mg daily)
R
2:1
Placebo (3/1 schedule)
+ letrozole(2.5 mg daily)
Stratification factors
- disease site
- disease-free interval
- previous hormonal therapy
Palbociclib: ongoing studies in endocrine-resistant tumours
Phase III, PALOMA-3 (1023)
N:417
• HR+, HER2− MBC
Palbociclib (125 mg daily, 3/1
schedule)
+ Fulvestrant (500 mg IM q4wk)
• Pre-menopausal or post-menopausal
• Failure of previous hormonal treatment:
• Progressed on or ≤12 months after end of
adjuvant therapy (AI or tamoxifen)
• Progressed on or ≤1 month after end of
treatment with AI/other endocrine therapy
for advanced disease
• 1 previous chemotherapy regimen permitted
Primary endpoint: PFS
Secondary endpoints:
ORR
SV
Safety
Biomarkers
Quality of life
R
2:1
Placebo (3/1 schedule)
+ Fulvestrant (500 mg IM q 4 wk)
Stratification factors
- visceral metastases
- previous sensitivity to endocrine therapy
- menopausal status
- previous chemotherapy
Palbociclib: ongoing studies in endocrine-resistant tumours
Phase III, PEARL
N:348
• Post-menopausal
Palbociclib (125 mg daily, 3/1
schedule)
+ Exemestane (25 mg daily)
• HR+, HER2− metastatic BC
• Resistant to non-steroidal AIs:
• Recurrence on or ≤12 months after end
of adjuvant treatment with non-steroidal
AI
• Progression on or ≤1 month after end of
treatment with non-steroidal AI for
advanced disease
Primary endpoint: PFS
Secondary endpoints:
ORR
SV
Safety
Biomarkers
Quality of life
R
1:1
Capecitabine 1250 mg/m2/12 h
2/1 schedule
Stratification factors
- visceral metastases
- previous sensitivity to endocrine therapy
- menopausal status
- previous chemotherapy
- country
Phase III Study of Palbociclib in High-risk Early BC:
PENELOPE
PENELOPEa
Placebo
(3/1 schedule)
+ Standard of care
• Early ER+ BC “high risk”
(CPS-EG ≥3)
• Premenopausal/
postmenopausal
• Completed taxane-based
neoadjuvant therapy, surgery; +/−
radiotherapy
RANDOMISATION
N=800
1:1
Palbociclib
(125 mg daily,
3/1 schedule)
+ Standard of care
Non-study adjuvant endocrine therapies being taken for 5–10 years after surgery
were permitted during the study:
• tamoxifen (pre- and postmenopausal women)
• goserelin agonists (premenopausal)
• aromatase inhibitors: anastrozole, letrozole (postmenopausal)
*aIn collaboration with GBG (Germany) and GEICAM (Spain)
Primary endpoint: iDFS
Secondary endpoints: OS,
iDFS excluding second nonbreast cancer, distant
disease-free survival, local
recurrence-free survival,
iDFS by commerciallyavailable multigene assay
subtyping, safety, patientreported outcomes,
biomarkers
Stratification factors:
lymph node status, age,
biomarkers (Ki-67, pRB,
cyclin D), and region
Phase II Study of Palbociclib with Letrozole in Neoadjuvant
Treatment of Early ER+, HER2− BC: PALLET study
• Localised ER+, HER−
invasive early BC
• Suitable for neoadjuvant
therapy with letrozole
Letrozole
(2.5 mg daily)
for 2 weeks
• Post-menopausal
• N=301
Palbociclib
(125 mg daily)
for
2 weeks
Palbociclib
(125 mg daily)
+
letrozole
(2.5 mg daily)
for 2 weeks
Palbociclib
(125 mg QD,
3/1 schedule)
+
letrozole
(2.5 mg QD)
for 12 weeks
Tumour samples: biopsies taken before treatment and at 2 and 14 weeks
Surgery
Letrozole (2.5 mg QD) for 14 weeks
Primary endpoints:
• Change in the
proliferation marker
Ki67 at week 14
• Clinical response at
week 14
Secondary endpoints:
• Ki67 at 2 weeks
• ypCR after
14 weeks
Stratification factor:
Country
Other CDK 4/6 inhibitors
Other cyclin CDK 4/6 inhibitors: LEE-011
Monaleessa-1 study
LEE-011 + letrozole
600 mg/d
Early breast cancer
Size > 1.5 cm
2.5 mg/d
LEE-011 + letrozole
400 mg/d
2.5 mg/d
Letrozole
2.5 mg/d
S
U
R
G
E
R
Y
15 days
Primary objective:
Secondary objectives:
Changes in Ki67
Safety
Biological response
Other cyclin CDK 4/6 inhibitors: LEE-011
Monaleessa-2 study
LEE-011 + letrozole
600 mg/d
2.5 mg/d
Advanced disease
-RE positivity
-Postmenopausal
-1 measurable lesion
-Non-previous treatment
Letrozole
2.5 mg/d
Primary objective:
PFS
Secondary objectives: OS
Safety
ORR
CONCLUSIONS
• The cyclin D-CDK4/6-Rb pathway is an important mediator of
cell cycle regulation and is downstream of multiple mitogenic
cascades.
• It is an important target for anticancer therapy.
• Different CDK4/6 inhibitors are being studied in combination
with endocrine therapy or other targeted therapies such as
anti-HER2 agents, PI3K inhibitors or mTOR inhibitors.
• These drugs present a good opportunity to overcome
endocrine resistance.
THANK YOU !!

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