Inhibidores ciclinas: ¿son todos iguales? · 2019. 6. 28. · 1970 1980 1990 2000 2010 2019. Letrozol 1997 Exemestane 1999 Fulvestrant 250 mg 2002 Fulvestrant 500 mg 2010 Everolimus

Inhibidores ciclinas: ¿son todos iguales?

Dr. José Angel García Sá[email protected]

http://www.madrid.org/cs/Satellite?language=es&pagename=HospitalClinicoSanCarlos/Page/HCLN_home

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



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





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)





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


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


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


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


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


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


No. at risk

Ribociclib + fulvestrant


PFSc,1,2 Ribociclib + fulvestrantn=238


n=129Median PFS, months

NR 18.3

HR (95% CI) 0.58 (0.42–0.80)

PFSc,1,2Ribociclib +fulvestrant

n=236


n=109Median PFS

14.6 9.1

HR (95% CI) 0.57 (0.43–0.74)





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





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

[email protected]

Documents

Inhibidores ciclinas: ¿son todos iguales? · 2019. 6. 28. · 1970 1980 1990 2000 2010 2019. Letrozol 1997 Exemestane 1999 Fulvestrant 250 mg 2002 Fulvestrant 500 mg 2010 Everolimus