Inhibidores de CDK 4/6 en cáncer de mama€¦ · Inhibidores de CDK 4/6 en cáncer de mama Prof....

Inhibidores de CDK 4/6 en cáncer de

mama

Prof. Miguel Martín

Instituto de Investigación Sanitaria

Hospital Gregorio Marañón

Universidad Complutense

Madrid

[email protected]

Hanahan & Weinberg, Cell 2011

Cell Cycle deregulation: a Hallmark of cancer

Cell Cyle regulation

Malumbres M, CNIO 2014

Regulation of the G1/S Checkpoint in Breast Cancer

Lange et al. Endocrine-Related Cancer 2011;18:C19–C24; 1Caldon CE, et al. J Cell Biochem 2006;97:261–274; 2Buckley MF, et al. Oncogene 1993;8:2127–2133; 3Dickson C, et al. Cancer Lett 1995;90:43–50; 4Finn RS, et al. Breast Cancer Res 2009;11:R77

G2 S

M

G1

G0

D-type cyclins regulated in

response to mitogenic stimuli,

including activation of RTKs and

steroid hormone receptors1

• Cyclin D1 is amplified in

15–20% of breast

cancers2,3

• Human ER+ breast

cancer cell lines (including

those with HER2

amplification) sensitive to

G0/G1 arrest4



RB

RB

Gene

transcription G2 S

M

G1

G0

P P P

P

Inactive

Active tumor

suppressor

E2F

E2F

R






15–20% of breast

cancers2,3



those with HER2


G0/G1 arrest4



RB

RB

Gene

transcription G2 S

M

G1

G0

P P P

P

Inactive

Active tumor

suppressor

E2F

E2F

R

CDK4/6 Cyclin D






15–20% of breast

cancers2,3



those with HER2


G0/G1 arrest4



RB

RB

Gene

transcription G2 S

M

G1

G0

P P P

P

Inactive

Active tumor

suppressor

E2F

E2F

R

CDK4/6 Cyclin D

Pl3K/Akt

STATs MAPKs

ER/PR/AR Wnt/β-catenin

NF-κB D-type cyclins regulated in





15–20% of breast

cancers2,3



those with HER2


G0/G1 arrest4



RB

RB

Gene

transcription G2 S

M

G1

G0

P P P

P

Inactive

Active tumor

suppressor

E2F

E2F

R

CDK4/6 Cyclin D

Pl3K/Akt

STATs MAPKs

ER/PR/AR Wnt/β-catenin

NF-κB

p16

p21

p53 D-type cyclins regulated in





15–20% of breast

cancers2,3



those with HER2


G0/G1 arrest4

Paloma 1/TRIO 018: Phase 2 Design

N = 66

1:1

Part 1

ER+, HER2–

BC

R

A

N

D

O

M

I

Z

A

T

I

O

N

PD 0332991

125 mg QDa +

Letrozole

2.5 mg QD

Letrozole

2.5 mg QD

Part 2

N = 99

1:1

ER+, HER2–

BC with

CCND1 amp

and/or

loss of p16

R

A

N

D

O

M

I

Z

A

T

I

O

N

PD 0332991

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) a Schedule 3/1.

• Post-menopausal women, ER+/Her2 negative, RECIST measureable or bone only

• Primary endpoint: PFS (powered for 50% improvement; 9 > 13.5 months

• Analyses presented: IMPAKT 2012, SABCS 2012, AACR 2014 (Final)

Clintrial.gov; Finn RS, et al SABCS 2012, Abstract S1-6

PALOMA 1-TRIO 018. Results: Final Analysis. PFS (ITT)

Finn et al AACR 2014

PALOMA 1-TRIO 018. Results: Final Analysis. OS (ITT)

Finn et al AACR 2014

Most Common Treatment-Related AEs ≥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

Anemia 19 4 1 0 0 0

Fatigue 17 2 0 13 0 0

Alopecia 18 0 0 3 0 0

Hot flush 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

CDK4/6 inhibitors currently in development

Agent Company Development

Status

Palbociclib

(PD0332991)

Pfizer Phase III

Ribociclib (LEE011) Novartis Phase III

Abemaciclib

(LY28335219)

Lilly Phase III

Palbociclib in HR+/HER2– BC: Phase 3 Studies

Metastatic breast cancer Post-

neoadjuvant

Study 1008 (PALOMA-2) 1023 (PALOMA-3) PEARL PENELOPE

Setting Endocrine

sensitive

Endocrine

resistant

Endocrine

resistant High risk

Menopausal status Post-menopausal Pre-menopausal +

post-menopausal Post-menopausal

Pre-menopausal +

post-menopausal

No. patients 650 521 348 800

Treatment arms

Palbociclib +

letrozole

vs. placebo +

letrozole

Palbociclib +

fulvestrant

vs. placebo +

fulvestrant

Palbociclib +

exemestane

vs. capecitabine

Palbociclib

vs. placebo

Primary endpoint PFS PFS PFS iDFS

FFPV, first patient first visit; iDFS, invasive disease-free survival; PFS, progression-free survival

Abstract LBA502

A Double Blind Phase 3 Trial of Fulvestrant With or Without

Palbociclib in Pre- and Post-menopausal Women With

Hormone Receptor-positive, HER2-negative Advanced Breast

Cancer That Progressed on Prior Endocrine Therapy

(PALOMA3 Study)

Nicholas Turner,1 Jungsil Ro,2 Fabrice André,3 Sherene Loi,4 Sunil Verma,5 Hiroji Iwata,6 Nadia Harbeck,7 Sibylle Loibl,8 Cynthia Huang Bartlett,9 Ke Zhang,10

Carla Giorgetti,11 Sophia Randolph,10 Maria Koehler,9 Massimo Cristofanilli12

1Royal Marsden Hospital, London, UK; 2National Cancer Center, Goyang-si, Korea; 3Institut Gustave Roussy, Villejuif, France; 4Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; 5Sunnybrook Odette Cancer Centre,

Toronto, Canada; 6Aichi Cancer Center Hospital, Nagoya, Japan; 7Brustzentrum der Universität München, München, Germany; 8German Breast Group Forschungs GmbH, Neu-Isenburg, Germany; 9Pfizer Inc, New York City, USA; 10 Pfizer

La Jolla, USA; 11Pfizer Milan, Italy, 12Thomas Jefferson University, Philadelphia, PA, USA

Presented at ASCO 2015; June 1, 2015; Chicago, IL, USA

PALOMA3 Study Design

Placebo

(3 wks on/ 1wk off)

+

Fulvestrant†

(500 mg IM q4w)

Palbociclib

(125 mg QD;

3 wks on/1 wk off)

+

Fulvestrant† (500 mg IM q4w)

†administered on Days 1 and 15 of Cycle 1.

● Visceral metastases

● Sensitivity to prior

hormonal therapy

● Pre-/peri- vs Post-

menopausal

Clinicaltrials.gov NCT01942135

2:1 Randomization

N=521

Stratification:

• Post-menopausal patients must have progressed on prior aromatase inhibitor therapy.

n=347

n=174

• HR+, HER2– ABC

• Pre-/peri-* or post-menopausal

• Progressed on prior endocrine

therapy:

– On or within 12 mo adjuvant

– On therapy for ABC

• ≤1 prior chemotherapy regimen

for advanced cancer

*All received goserelin.

Study Endpoints

● Primary Endpoint

– Progression-free survival (PFS) by investigator assessment

● Secondary Endpoints

– Objective response and clinical benefit rate

– Overall survival

– Safety

– Biomarkers

– Patient-reported outcomes

Statistical Design

● PFS by investigator assessment

– Median PFS from 6 to 9.38 months (HR: 0.64; 90% power, 1-sided =2.5%)*

– Planned 417 patients randomized and 238 PFS events

● Interim Analysis (IA) for PFS

– Planned after approximately 60% (143) of PFS events

– Pre-specified Haybittle-Peto efficacy boundary (1-sided =0.00135)

● Blinded independent central review (BICR)1

– Randomly selected subgroup (approximately 40%)

1. Zhang JJ et al. Clin Cancer Res. 2013;19:2637-45. *2-sided P values are presented.

Demographics and Baseline Tumor Characteristics

Characteristic Palbociclib +

Fulvestrant

(n=347)

Placebo +

Fulvestrant

(n=174)

Median age (range), years 57 (30−88) 56 (29−80)

Receptor status, %

ER+ PR+ 69 64

ER+ PR– 26 28

ECOG performance status, %

0 60 66

1 40 34

Menopausal status,a %

Pre-/peri 21 21

Post 79 79

Visceral metastases,b % 59 60

Number of disease sites, %

1 32 35

2 29 29

3 39 36 aBased on randomization; blung, liver, brain, pleural, and peritoneal involvement.

Tumor Characteristics and Prior Treatment

Characteristic

Palbociclib +

Fulvestrant

(n=347)

Placebo +

Fulvestrant

(n=174)

Documented sensitivity to prior hormonal

therapy,a %

Yes 79 78

No 21 22

Prior aromatase inhibitor +/- GnRH,b % 85 87

Prior tamoxifen +/- GnRH,b % 61 60

Prior chemotherapy in advanced setting,

% 31 36

Prior lines of therapy in advanced setting,

%

0 24 26

1 38 40

2 26 25

≥3 12 9 aRelapsed after 24 months of adjuvant endocrine therapy or had clinical benefit to prior therapy in the advanced setting. bAny prior endocrine therapy anytime before study entry.

GnRH=gonatotropin-releasing hormone.

Tumor Characteristics and Prior Treatment

Characteristic Palbociclib +

Fulvestrant

(n=347)

Placebo +

Fulvestrant

(n=174)

Documented sensitivity to prior hormonal

therapy,a %

Yes 79 78

No 21 22

Prior aromatase inhibitor +/- GnRH,b % 85 87

Prior tamoxifen +/- GnRH,b % 61 60

Prior chemotherapy in advanced setting,

% 31 36

Prior lines of therapy in advanced setting,

%

0 24 26

1 38 40

2 26 25

≥3 12 9 aRelapsed after 24 months of adjuvant endocrine therapy or had clinical benefit to prior therapy in the advanced setting. bAny prior endocrine therapy anytime before study entry.

GnRH=gonatotropin-releasing hormone.

● Neutropenia was the most common AE leading to dose reductions (21%) and interruptions (45%)

Treatment Summary

*ITT population.

AE=adverse event; AT=as treated.

Treatment Summary (AT population)

Palbociclib

+

Fulvestrant

(n=345)

Placebo +

Fulvestrant

(n=172)

Relative fulvestrant dose intensity (%),

median 99.7 100

Relative palbociclib/placebo dose

intensity (%), median 91.7 100

Dose interruptions due to AEs, % 54 4

Cycle delays due to AEs, % 22 1

Dose reductions due to AEs, % 32 2

Discontinuations due to AEs, %* 2.6 1.7

Adverse Events—All Cause

AE, % Palbociclib + Fulvestrant

(n=345)

Placebo + Fulvestrant

(n=172)

Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4

Any AE 98 59 11 89 16 2

Neutropenia 79 53 9 3 0 1

Leukopenia 46 25 1 4 0 1

Anemia 26 3 0 10 2 0

Thrombocytopenia 19 2 1 0 0 0

Fatigue 38 2 0 27 1 0

Nausea 29 0 0 26 1 0

Headache 21 <1 0 17 0 0

Upper respiratory infectiona 19 <1 0 16 0 0

Diarrhea 19 0 0 17 1 0

Constipation 17 0 0 14 0 0

Alopecia 15 0 0 6 0 0

AE=adverse event. AEs with ≥15% incidence in the palbociclib + fulvestrant group reported. aUpper respiratory infection includes influenza, influenza-like illness, laryngitis, nasopharyngitis or pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection.

Summary of Adverse Events

● In patients receiving palbociclib + fulvestrant vs placebo + fulvestrant:

– Overall incidence of SAEs was similar (9.6% vs 14.0%)

– Incidence of febrile neutropenia was the same (0.6% vs 0.6%)

– Infections (any grade) were more common (34.2% vs 24.4%)

• The vast majority were of grade 1 or 2 (32.5% vs 22.7%)

● There were no deaths due to AEs/toxicity

AE=adverse event; SAE=serious adverse event.

0 2 4 6 8 10 12

Time (Month)

0

10

20

30

40

50

60

70

80

90

100

PF

S P

rob

ab

ilit

y (

%)

347 279 132 59 16 6 PAL+FUL

174 109 42 16 6 1 PCB+FUL

Number of patients at risk

Primary Endpoint: PFS (ITT Population)

CI=confidence interval; HR=hazard ratio; ITT=intent-to-treat; NE=not estimable; PFS=progression-free survival.

Palbociclib

+

Fulvestrant

n=347

Placebo +

Fulvestrant

n=174

Median PFS,

months

(95% CI)

9.2

(7.5, NE)

3.8

(3.5, 5.5)

HR (95% CI) 0.422 (0.318, 0.560)

2-sided P value <0.000001

PAL+FUL

147

118 53 24 7 2

PCB+FUL 64 37 12 4 1 1

12

PF

S P

rob

ab

ilit

y (

%)

0 2

Number of patients at risk

4 6

Time (Month)

8 10

CI=confidence interval; NE=not estimable; PFS=progression-free survival.

PFS: Central Blinded Review Audit (n=211)

Palbociclib

+

Fulvestrant

n=147

Placebo +

Fulvestrant

n=64

Median PFS,

months

(95% CI)

NE 3.7

(3.4, 7.2)

HR (95% CI) 0.268 (0.158, 0.455)

2-sided P value <0.000001

0

10

20

30

40

50

60

70

80

90

100

PFS: Patient Subgroup Analysis

ER=estrogen receptor; PgR=progesterone receptor. aRace was unspecified in 2 patients (1 in each treatment group).

Subgroup Hazard Ratio and 95% CI

All randomized patients (ITT) Age

Racea

Menopausal status at study entry

<65 Years 65 Years

White Asian Black and other

Pre/Peri Post

Site of metastatic disease Visceral Non visceral

Sensitivity to prior hormonal therapy Yes No

Receptor status ER+/PgR+ ER+/PgR-

Disease-free interval 24 months

>24 months Prior chemotherapy

(Neo)adjuvant only Metastatic +/- (neo)adjuvant No prior chemotherapy

Prior lines of therapy in advanced setting 0 1 2 3+

In favor of Placebo + Fulvestrant In favor of Palbociclib + Fulvestrant

n (%)

521 (100) 392 (75.2) 129 (24.8) 385 (73.9) 105 (20.2)

29 (5.6) 108 (20.7) 413 (79.3) 311 (59.7) 210 (40.3) 410 (78.7) 111 (21.3) 349 (67.0) 139 (26.7)

65 (12.5) 281(53.9) 219 (42.0) 170 (32.6) 132 (25.3) 129 (24.8) 202 (38.8) 133 (25.5) 57 (10.9)

P value for Interaction

0.480

0.412

0.940

0.624

0.302

0.883

0.149

0.427

0.684

0.125 0.25 0.5 1 2 8

Summary of Key Secondary Efficacy Endpoints

CBR=clinical benefit rate (CR+PR+SD ≥24 wk); CR=complete response; ORR=objective response (CR+PR); OS=overall survival; PR=partial response;

SD=stable disease.

* CBR is underestimated.

36% of palbociclib and 24% of placebo pts remain on study treatment with <24 weeks of follow up.

At the time of the interim analysis, OS data was immature with 28 deaths.

Palbociclib +

Fulvestrant

(n=347),

% of patients

Placebo +

Fulvestrant

(n=174),

% of patients

P value

ORR 10.4 6.3 0.1582

CBR* 34.0 19.0 0.0004

Conclusions

● Palbociclib combined with fulvestrant improved PFS compared to

placebo and fulvestrant in women with HR+/HER2– advanced breast

cancer whose disease had progressed on prior endocrine therapy.

– HR = 0.422 (95% CI, 0.318 to 0.560; P<0.000001)

● Benefit from palbociclib was also demonstrated across pre-specified

subgroups.

● Palbociclib was well tolerated.

● Palbociclib in combination with fulvestrant is an effective treatment

option for women whose cancer progressed on prior endocrine

therapy.

Inhibidores de CDK 4/6 en cáncer de mama€¦ · Inhibidores de CDK 4/6 en cáncer de mama Prof....

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