Inhibidores ciclinas: ¿son todos iguales?
Dr. José Angel García Sá[email protected]
Disclosures
• Consultancy/speaker fees from Novartis, Celgene, Eli Lilly, EISAI
• Institution research funding from Astrazeneca
• Travel support from Novartis, Roche, Pfizer
Cyclin-dependent
kinase inhibitors
Hananan. Cell. 2011
Evolution of ER+ Breast Cancer
Tamoxifen1977
Anastrozol1995
1970 1980 1990 2000 2010 2019
Letrozol1997
Exemestane1999
Fulvestrant250 mg
2002
Fulvestrant500 mg
2010
Everolimus2012
Palbociclib2015
Ribociclib2017
Abemaciclib2017 (*)
Alpelisib2019
Activation of signaling pathways
Alteration of survival and cell cycle pathways
ESR1 activation mutations
Mechanisms of endocrine therapy resistance
CDK4/6-inhibitors. Mechanism of Action
Tonaley. ASCO 2015
CDK-i
▪ Interpretación clínica de MOA diferencial
▪ Datos de eficacia en cáncer de mama
▪ Poblaciones diferenciales. Supervivencia
▪ Biomarcadores. Toxicidad diferencial
Lallena MJ et al. Cancer Research 2015
Ribociclib has high CDK4-specific Inhibitory Activity
8
1,3
5,5
0
2
4
6
8
10
Ribociclib Palbociclib Abemaciclib
Fold
Dif
fere
nce
Fold Difference of Activity in CDK4-Dependent Cell Lines Compared With
CDK6-Dependent Cell Lines1
Fold
Dif
fere
nce
Kim S. Oncotarget 2018. Sammons SL. Curr Cancer Drug Targets 2107. Chen P. 2016
TREEspot view of KINOME scan
TREEspot view of a KINOMEscan. Kinases that bind are marked with red circles if <35% of the recombinant kinase remained captured on the immobilized ligand in the presence of the indicated concentration of CDK4/6 inhibitor relative to the DMSO control
The specific safety profile of abemaciclib may be influenced by off-target effects
ATYPICAL MUTANT
OTHER
CMGC
CAMK
AGC OTHER
CK1
STE
TKL
TK
Ribociclib1 µM
Palbociclib1 µM
TK
TKL
STE
CK1
AGC
ATYPICAL MUTANT
CAMK
CMGC
ATYPICAL MUTANT
CAMK
CMGC
OTHER
TK
TKL
STE
CK1
Percent of control(captured)
Kim S. Oncotarget 2018.. Chen P. 2016
MC
F-7
Bre
ast
Can
cer
Cel
ls Gro
wt
h
Sen
esce
nce
Ap
op
tosi
s
7 days 10 days4 days2 days
7 days 10 days4 days2 days
7 days 10 days4 days2 days
Torres-Guzman et al.
Oncotarget 2017
Abemaciclib. CNS Response for ER+/HER2-
Tonaley. ASCO 2017
Cplasma
(nM)
10 100 1000 10000
Bra
in/P
lasm
a R
atio
(K
p,b
rain)
0
1
2
3
4LY2835219 total
PD0332991 total
LY2835219 unbound
PD0332991 unbound
AbemaPalbo
Abemaciclib. JPBOCNS Response for ER+/HER2-
Anders C. ASCO19
Change in Tumor Size and Best Overall Response
Overall Intracraneal RR
All (58) Eval (52)
(3) 5% (3) 6%
MONARCH 1: Phase 2 Abemaciclib in previously treated ER2+/HER2- MBC
HR+/HER2(-) ABC with PD
following prior hormonal
therapy and chemotherapy
200 mg abemaciclib Q12H
Primary endpoint:
objective response rate
Dickler MN. Clin Cancer Res 2017
n: 132
The study was powered
assuming a null
hypothesis ORR of 15%
vs the alternative
hypothesis ORR of 25%
Ch
ang
e F
rom
Bas
elin
e (%
)
Investigator Assessed Response,a %
Abemaciclib
200 mg (N=132)
Confirmed ORR(95 % CI) 19.7 (13.3,
27.5)CR
PR
0
19.7
Stable Disease ≥ 6 months 22.7
Clinical Benefit Rate (CBR = ORR +SD ≥ 6
mos)42.4
mPFS 6m
mOS 22.3m
▪ Interpretación clínica de MOA diferencial
▪ Datos de eficacia en cáncer de mama
▪ Poblaciones diferenciales. Supervivencia
▪ Biomarcadores. Toxicidad diferencial
First line setting
Study/Arms N Median FUMedian PFS (months) HR
(95% CI)Plac CDK4/6i
PALOMA-2 Letrozol +/- Palbociclib
666 37.6 14.5 27.60.56
(0.46-0.69)
MONALEESA-2Letrozole +/- Ribociclib
668 26.4 16.0 25.30.57
(0.46-0.70)
MONALEESA-7Letrozole +/- Ribociclib
672 13.0 23.80.55
(0.44-0.69)
MONARCH-3 Letrozole +/- Abemaciclib
493 26.7 14.7 28.10.54
(0.42-0.69)
MONALEESA-3Fulvestrant +/- Ribociclib
367 20.4 18.3 NR0.58
(0.42-0.80)
Messina C et al. Breast Cancer Res Treat 2018
Laderiana B & Fojoa T. Sem Oncol 2017
Comparision of eficacy PFS, ORR CBR
Progression after endocrine therapy
Study/Arms N Median FUMedian PFS (months) HR
(95% CI)Plac CDK4/6i
PALOMA-3 Fulvestrant +/- Palbociclib
521 15 4.6 11.20.50
(0.40-0.62)
MONARCH-2Fulvestrant +/- Abemaciclib
669 19.5 9.3 16.40.55
(0.45-0.68)
MONALEESA-3Fulvestrant +/- Ribociclib
345 20.4 9.1 14.60.57
(0.42-0.74)
▪ Interpretación clínica de MOA diferencial
▪ Datos de eficacia en cáncer de mama
▪ Poblaciones diferenciales. Supervivencia
▪ Biomarcadores. Toxicidad diferencial
Klijn GM et al. JNCI 2000El Alamo III. GEICAM 2014
In postmenopausal Ribociclib +
letrozol increase PFS
Hortobagyi. Ann Oncol 2018
Young vs Older women with ABC
have a distinct tumor biology
experience more aggressive disease
are more likely to die from their cancer
Zaidi S.2017; Anders CK. 2009
Unmet need in premenopausal patients with ER+/HER2- ABC
MONALEESA-7: Phase III placebo-controlled study of ribociclib and tamoxifen/NSAI + goserelin
• Primary analysis planned after ~329 PFS events
– 95% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5%, corresponding to an increase in median PFS to 13.4 months (median PFS of 9 months for the placebo arm1,2), and a sample size of 660 patients
– Data cut-off date: August 20, 2017 (318 events)
Stratified by:
• Presence/absence of liver/lung metastases
• Prior chemotherapy for ABC
• Endocrine therapy partner (tamoxifen vs NSAI)
Primary endpoint
•PFS (locally assessed per RECIST v1.1)‡
Secondary endpoints
•Overall survival (key)
•Overall response rate
•Clinical benefit rate
•Safety
•PRO
•Pre/perimenopausal women with HR+, HER2– ABC
•No prior endocrine therapy for ABC
•≤1 line chemo for ABC
•N=672
Randomization (1:1)
Ribociclib(600 mg/day; 3-weeks-
on/1-week-off)
+ tamoxifen/NSAI + goserelin*
n=335
Placebo+ tamoxifen/NSAI +
goserelin* n=337
Tripathy D. Lancet Oncol 2018
Tripathy D. Lancet Oncol 2018
Pro
bab
ility
of
PF
S (
%)
Time (months)No. at risk
Ribociclib + tamoxifen/NSAI 335 301 284 264 245 235 219 178 136 90 54 40 20 3 1 0
Placebo + tamoxifen/NSAI 337 273 248 230 207 183 165 124 94 62 31 24 13 3 1 0
PFS (investigator assessment)
Ribociclib + tamoxifen/NSAI n=335
Placebo + tamoxifen/NSAI n=337
Number of events, n (%) 131 (39.1) 187 (55.5)
Median PFS, months (95% CI)
23.8(19.2–NR)
13.0(11.0–16.4)
Hazard ratio (95% CI) 0.553 (0.441–0.694)
One-sided p value 0.0000000983
1086420
100
80
60
40
20
0
30282624222018161412
10
30
50
70
90
Primary endpoint: PFS (investigator-assessed)
PFS by endocrine therapy partner
PFS (investigator assessment)
Tamoxifen NSAI
Ribociclib armn=87
Placebo armn=90
Ribociclib armn=248
Placebo armn=247
mPFS, months (95% CI)
22.1 (16.6–24.7)
11.0 (9.1–16.4)
27.5 (19.1–NR)
13.8 (12.6–17.4)
Hazard ratio (95% CI) 0.585 (0.387–0.884) 0.569 (0.436–0.743)
Subgroup n (%) Favors ribociclib Favors placebo Hazard ratio 95% CI
All patients 672 (100) 0.553 0.441–0.694
Endocrine therapy partnerTamoxifen
NSAI177 (26)495 (74)
0.5850.569
0.387–0.8840.436–0.743
Age<40 years ≥40 years
186 (28)486 (72)
0.4430.590
0.293–0.6710.449–0.777
Race‡ AsianNon-Asian
198 (29)413 (61)
0.4010.657
0.258–0.6250.492–0.877
ECOG performance status§ 0≥1
500 (74)166 (25)
0.5490.495
0.417–0.7210.320–0.765
ER/PgR statusER+ and PgR+
Other572 (85)100 (15)
0.5740.444
0.446–0.7390.258–0.765
Liver and/or lung involvementNoYes
329 (49)343 (51)
0.6420.503
0.454–0.9070.375–0.677
Bone-only diseaseNoYes
513 (76)159 (24)
0.5330.703
0.415–0.6860.414–1.194
Prior chemotherapy for advanced diseaseNoYes
578 (86)94 (14)
0.5660.547
0.443–0.7240.314–0.954
Disease-free interval≤12 m>12 m
De novo
36 (5)366 (54)270 (40)
0.5600.6150.428
0.210–1.4900.455–0.8320.287–0.640
0.125 0.25 0.5 1 2 4
Hazard ratio (95% CI)8
PFS subgroup analysis
Overall Survival
Overall Survival
Hurvitz S. ASCO 2019
Tripathy D. Lancet Oncol 2018
Secondary endpoints
Ribociclib + tamoxifen/NSAI
Placebo + tamoxifen/NSAI
• The CBR in patients with measurable disease was 79.9% for ribociclib + tamoxifen/NSAI vs 67.3% for
placebo + tamoxifen/NSAI (p=0.000340)
• Overall survival data were immature at the cut-off date
All patients
Rat
e (%
)
Patients with measurable disease
Rat
e (%
)
p=0.00098p=0.000317
Patient-reported outcomes (EORTC QLQ-C30 – global health status)
Harbeck N. ESMO 2018
Ribociclib +tamoxifen/NSAI
n=335
Placebo + tamoxifen/NSAI
n=337
Number of events, n (%) 102 (30.4) 115 (34.1)
Median, months (95% CI)
NR(22.2–NR)
21.2(15.4–23.0)
Hazard ratio (95% CI) 0.699 (0.533–0.916)
Log-rank test p value 0.004
Time to deterioration (months)
80
9
0
60
50
70
40
30
20
10
0
100
1086420 282624222018161412
Ribociclib + tamoxifen/NSAI
Placebo + tamoxifen/NSAI
No. at risk
335 282 256 236 218 201
337 260 218 198 178 158
188
132 97
145 112
67
69
38
43
18
41
17
15
6
3
1
0
0
Eve
nt-
free
pro
bab
ility
(%
)
A clinically meaningful (>5 points) improvement from baseline in pain score was observed as early as 8 weeks in the ribociclib arm, and was sustained
Summary ML7
Ribociclib plus endocrine therapy in patients with premenopausal, HR(+)/HER2(-) ABC:
✓ improved PFS (23.8 months vs 13.0 months; HR 0.553)
✓ improved OS (41 months vs NR; HR 0.7)
✓ had predictable and manageable safety profile.
✓ achieves clinically meaningful improvement QoL
✓ represents a new 1st line treatment option
MONALEESA3 BackgroundRibociclib increases PFS when added to 1st-line letrozole in
premenopausal MONALEESA7
Palbociclib increases PFS when added to 2nd-line letrozole in
PALOMA3
Abemaciclib increases PFS when added to 2nd-line letrozole
in MONARCH2
Tripathy D. Lancet Oncol 2018
Turner NC. NEJM 2015 Sledge. JCO 2017
MONALEESA-3: Phase III placebo-controlled study of ribociclib + fulvestrant
Slamon D. JCO 2018
Primary analysis planned after ~364 PFS events
– 95% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5%, corresponding to an increase in median PFS to 13.4 months (median PFS of 9 months for the placebo arm), and a sample size of 660 patients
– Data cut-off date: Nov 3 2017 (361 events)
Stratified by:
• Presence/absence of liver/lung metastases
• Prior endocrine therapy
Primary endpoint
PFS (locally assessed per RECIST v1.1)
Secondary endpointsOverall survival
Overall response rate
Clinical benefit rate
Time to response
Duration of response
Time to definitive deterioration
Patient-reported outcomes
Safety
Pharmacokinetics
•Postmenopausal women and men with HR+/HER2– ABC
•No or ≤1 line of prior endocrine therapy for advanced disease
•N=726
Ribociclib (600 mg/day orally;
3-weeks-on/1-week-off)
+ Fulvestrantn=484
Placebo + fulvestrant
n=242
Randomization (2:1)
Primary endpoint: PFS (investigator-assessed)
Slamon D. JCO 2018
First line Second line + early relapse
238
129
205
109
189
99
180
91
173
88
166
85
159
78
149
75
141
68
97
40
49
18
31
10
7
4
0
0
236
109
188
83
167
67
159
63
143
54
132
47
117
36
104
29
91
25
55
12
28
8
20
4
5
0
0
0
Pro
bab
ility
of
PFS
(%
)
26181614121086420 20 22 24
0
20
40
60
80
100
Time (months)
Pro
bab
ility
of
PFS
(%
)
26222016121086420 1814 24
0
20
40
60
80
100
Time (months)No. at risk
Ribociclib + fulvestrant
Placebo + fulvestrant
No. at risk
Ribociclib + fulvestrant
Placebo + fulvestrant
PFSc,1,2 Ribociclib + fulvestrantn=238
Placebo + fulvestrant
n=129Median PFS, months
NR 18.3
HR (95% CI) 0.58 (0.42–0.80)
PFSc,1,2Ribociclib +fulvestrant
n=236
Placebo + fulvestrant
n=109Median PFS
14.6 9.1
HR (95% CI) 0.57 (0.43–0.74)
▪ Interpretación clínica de MOA diferencial
▪ Datos de eficacia en cáncer de mama
▪ Poblaciones diferenciales. Supervivencia
▪ Biomarcadores. Toxicidad diferencial
OS Endpoint Not met in PALOMA-1
PALOMA 1Randomized phase II
N: 165
PFS HR 0.49 (0.32-0.75)OS HR 0.89 (0.62-1,39)
Phase III trials notpowered for overall
survival
Finn R. ASCO 2017
OS Endpoint Not Significant Met in PALOMA-3
Turner N. NEJM 2018
Overall Survival
Hurvitz S. ASCO 2019
OS Endpoint significant met in MonaLEEsa7
▪ Interpretación clínica de MOA diferencial
▪ Datos de eficacia en cáncer de mama
▪ Poblaciones diferenciales. Supervivencia
▪ Biomarcadores. Toxicidad diferencial
Biomarkers that have NOT identified responders:
Finn, Lancet Oncol, 2015; Cristofanilli, Lancet Oncol 2016; Fribbens, JCO 2016Finn, ESMO 2016, Hortobagyi ASCO 2018 DeMichele ASCO 2018
• Cyclin D amplification (CCDN1)
• Loss of p16 (INK4A or CDKN2A)
• Protein levels of cyclin D/CDK4-6/RB pathway
• Expression level of ER and/or PgR
• PIK3CA mutations (cfDNA)
• ESR1 mutations (cfDNA)
Turner NC. JCO 2019
Cyclin E1 Expression and Palbociclib Efficacy in Previously Treated HR+ MBC
Grades 3-4 of CDK4/6-i
Grade 3-4 toxicities
Neutropenia
FebrilNeutropenia
AnemiaTransa-minitis
QTc(f) Asthenia DVT-PTE Diarrea
Palbociclib +++ +/- + + - + - -
Ribociclib +++ +/- + ++ + + - -
Abemaciclib ++ +/- ++ + - ++ ++ +++
Permanent discontinuation as a result AEs
Letrozol + CDK4/6-i
Letrozol + Placebo
PALOMA 2 Palbociclib 9.7% 5.9%
MONALEESA 2 Ribociclib 7.5% 2.1%
MONARCH 3 Abemaciclib 19.6% 2.5%
MONALEESA 7 Ribociclib 3,6% 3%
PALOMA 3 Palbociclib 2,6% 1,7%
MONALEESA 3 Ribociclib 8,5% 4,1%
MONARCH 2 Abemaciclib 15,9% 4,1%
Palbo + NSAI Ribo + NSAI
Palbo + FUL Ribo+ FUL
Abema + NSAIRibo + NSAIGosereline
Abema + FUL
Summary CDK4/6-i
✓ Consistent, clinically-meaningful improvements in PFS and OR
✓ OS improvement in premenopausal women with Ribociclib
✓ Regardless of endocrine sensitivity, endocrine therapy
partner, menopausal status
✓ Predictive, tolerable and manageable side effect profile
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