inhibidores de cdk 4/6 en cáncer de mama: datos recientes · palbociclib (pd0332991) pfizer...

Inhibidores de CDK 4/6 en

cáncer de mama: datos

recientes

Miguel Martín

Instituto de Investigación Sanitaria

Hospital Gregorio Marañón

Universidad Complutense

Madrid

[email protected]

CDK4/6 inhibitors- current status of development

Agent Company Development Status

Palbociclib

(PD0332991)

Pfizer

(Ibrance)

Approved MBC

Phase III Adjuvant

Ribociclib

(LEE011)

Novartis

(Kisqali)

Approved MBC

Phase III Adjuvant

Abemaciclib

(LY28335219)

Lilly

(Verzenio)

Approved MBC

Phase III Adjuvant

Efficacy of CDK 4/6 inhibitors (1)

• In the first-line setting, they have been examined in the PALOMA-

2 (palbociclib), MONALEESA-2 (ribociclib) and MONARCH-3

(abemaciclib) trials.

• In patients with prior Ais, they have been examined in combination

with fulvestrant in the PALOMA-3, and MONARCH-2 trials.

PALOMA 2 (2:1) MONALEESA 2 (1:1)

Median PFS

abemaciclib + NSAI: not reachedplacebo + NSAI: 14.7 m

HR (95% CI): 0.543 (0.409, 0.723) p = 0.000021

MONARCH 3 (2:1)

Median PFS

Ribociclib + NSAI: 25.3 mplacebo + NSAI: 16 m

HR (95% CI): 0.568 (0.457, 0.704) p = 0.000000096

Number of patients at risk

PCB + LET

222

171

148

131

116

98 81 54 22 12 4 2

PAL + LET

444

395

360

328

295

263

238

154

69 29 10 2

Progression-F

ree S

urvival, %

Time, months

100

90

80

70

60

50

40

30

20

10

0 0 3 6 9 12 15 18 24 27 30 33 21

Number of Events, n (%)

Median (95% CI) PFS

HR (95% CI); 1-sided P value

194 (44)

24.8 (22.1-NR)

0.58 (0.46-0.72); P<0.000001

137 (62)

14.5 (12.9-17.1)

PAL+LET (N=444)

PCB+LET

(N=222)

Median PFS

Palbociclib + NSAI: 24.8 mplacebo + NSAI: 14.5 m

HR (95% CI): 0.58 (0.46, 0.72) p =<0.000001

CDK 4/6 inhibitors in first-line, endocrine sensitive

disease

CDK 4-6 inhibitors in patients with prior AIs

MONARCH 2: PFS

abemaciclib + fulvestrant: 16.44 months (N = 446)

placebo + fulvestrant: 9.27 months (N = 223)

HR, 0.553 (95% CI, 0.449 to 0.681)p <.0000001

Efficacy of CDK 4/6 inhibitors (2)

• In subgroup analysis it does not appear to be one groupthat necessarily benefits more or less in the trials.

• A meta-analysis of the raw data from five registration trials of CDK4/6 inhibitors showed that every patient benefits about equally from the addition of CDK4/6 inhibitors1.

• Higher-risk patients with features such as liver metastasesobtain high OR rates; CDK 4/6 plus hormones is an exclentalternative to chemotherapy in these patients.

1Gao F et al, 2018 ASCO Annual Meeting

Subset AI orfulvestrant

CDK4/6 inhibitor

Placebo Hazard ratio

ITT pooled population (n = 3,002) Both 20.5 mo 11.8 mo 0.59

ITT pooled population (n = 1,817) AI 26.5 mo 15.1 mo 0.56

PR-negative (n = 490) Both 16.5 mo 7.4 mo 0.50

Lobular cancer (n = 264) Both 16.1 mo 9.2 mo 0.58

Bone-only metastases (n = 875) Both 27.9 mo 15.5 mo 0.55

De novo metastatic (n = 617) AI 27.8 mo 16.8 mo 0.59

Disease-free > 12 months (n = 929) AI 25.7 mo 14.2 mo 0.55

CDK4/6 Inhibitors in Advanced Breast Cancer: Median PFS by Disease

Subset- Pooled data of first-line CDK 4/6 inhibitor trials

Toxicity of CDK 4/6 inhibitors

Palbociclib phase III studies

Trial N

pts

Design Population Primary

Endpoint

Status

PALOMA-2 (TRIO) 450 Palbo+LET vs

Pbo+LET

1L MBC PFS Final results on PFS

reported

PALOMA-3 417 Palbo+FULV vs

Pbo+FULV

after ED failure

MBC

PFS Final results on PFS and OS

reported

PEARL (GEICAM) 597 Palbo+EXE/FULV

vs

Capecitabine

MBC with

resistance to

NSAIs

PFS Enrollment ended

Efficacy analysis planned for

QI 2019

PENELOPE-B

(GBG)

1250 Palbo+ED vs

Pbo+ED

after NACT

(residual disease

high risk CPS-EG

score)

iDFS Enrollment ended

Efficacy interim analysis

planned for QII 2019

PALLAS (BIG) 5600 Palbo+ED vs

Pbo+ED

adjuvant

(moderate to

high risk)

iDFS Enrollment ended

Turner et al, NEJM 2015

Turner et al, SABCS 2016

PALOMA 3: Post- Progression Therapies

Turner et al, NEJM 2015

PALOMA 3

Overall Survival with Palbociclib and Fulvestrant

in Advanced Breast Cancer (PALOMA 3 trial)

• OS was secondary endpoint

• Study not powered to show clinically meaningful

differences in OS

• OS in subgroups unplanned

Overall Survival with Palbociclib and Fulvestrant in

Advanced Breast Cancer (PALOMA 3 trial)

The median overall survival was 34.9 months (95% CI, 28.8 to 40.0) in the palbociclib group

and 28.0 months (95% CI, 23.6 to 34.6) in the placebo group (hazard ratio for death, 0.81;

95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months).

Turner N et al, N Engl J Med 2018;379:1926.

Overall Survival with Palbociclib and Fulvestrant

in Advanced Breast Cancer (PALOMA 3 trial)


Among 410 patients with sensitivity to previousendocrine therapy*, the median overall survival was39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months).

*Relapse after at least 2 years of endocrine therapy or progression after

at least 24 weeks on endocrine therapy for metastatic disease

PALOMA-3 PRO Analysis: Global QoL results

Harbeck N at al, Annals of Oncology 27: 1047–1054, 2016

Biomarkers of palbociclib efficacy

Finn R et al. Presented at: 40th San Antonio Breast Cancer Symposium (SABCS); December 5-9, 2017; San Antonio, TX. Abstract P2-09-10

Ribociclib phase III studies

Trial N Design Population Primary

Endpoint

Status

MONALEESA-2 668 Ribo+LET vs

Pbo+LET

1L MBC postmen. PFS Final results on PFS

reported

MONALEESA-3 726 Ribo+FULV vs

Pbo+FULV

1L, 2L MBC

postmen.

PFS Final results on PFS

reported

MONALEESA-7 672 Ribo+TAM or AI +

Goserelin vs

TAM or AI plus

Goserelin

MBC with

resistance to NSAIs

Pre/perimen.

PFS Efficacy analysis on PFS

reported

NATALEE (TRIO) 5250 Ribo+ED vs

Pbo+ED

adjuvant,

moderate to high-

risk patients

iDFS Enrollment just started

Dennis J. Slamon, M.D., Ph.D.

Ribociclib + fulvestrant in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from MONALEESA-3

Dennis J. Slamon,1, Patrick Neven,2 Stephen Chia,3 Seock-Ah lm,4 Peter A. Fasching,5

Michelino De Laurentiis,6 Katarina Petrakova,7 Giulia Val Bianchi,8 Francisco J. Esteva,9

Miguel Martín,10 Xavier Pivot,11 Gena Vidam,12 Yingbo Wang,13 Karen Rodriguez Lorenc,12

Michelle Miller,12 Tetiana Taran,12 Guy Jerusalem14

1UCLA Medical Center, Santa Monica, CA; 2Multidisciplinary Breast Centre, Universitair Ziekenhuis Leuven, Leuven, Belgium; 3BC Cancer Agency, Vancouver, BC, Canada; 4Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; 5University Hospital Erlangen, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; 6Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples, Italy; 7Masaryk Memorial Cancer Institute, Brno, Czech Republic; 8Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 9NYU Langone Health, New York, NY; 10Instituto de Investigacion Sanitaria Gregorio Marañon, Centro de Investigación Biomédica en Red de Cáncer, Grupo Español de Investigación en Cáncer de Mama, Universidad Complutense, Madrid, Spain; 11Institut Régional du Cancer, Strasbourg, France; 12Novartis Pharmaceuticals Corporation, East Hanover, NJ; 13Novartis Pharma AG, Basel, Switzerland; 14CHU Liege and Liege University, Liège, Belgium

Dennis J. Slamon, M.D., Ph.D.25


Introduction

• In the Phase III MONALEESA-2 and MONALEESA-7 trials, addition of ribociclib to endocrine therapy significantly improved PFS vs placebo plus endocrine therapyin pre-, peri-, and postmenopausal women with HR+/HER2– ABC1,2

• CDK4/6 inhibitor and fulvestrant combinations have demonstrated efficacy in patients with HR+ breast cancer that has progressed on prior endocrine therapy3,4

• No study has evaluated CDK4/6 inhibitor + fulvestrant combinations in patients withde novo HR+/HER2– ABC, or in patients who have relapsed >12 months after priorendocrine therapy with no subsequent treatment for advanced disease

• MONALEESA-3 is investigating ribociclib with fulvestrant in postmenopausal women with HR+/HER2– ABC who were treatment-naive or had received up to 1 line of prior endocrine therapy in the advanced setting

ABC, advanced breast cancer; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; PFS, progression-free survival.Advanced breast cancer refers to locoregionally recurrent or metastatic disease.

1. Hortobagyi GN, et al. N Engl J Med 2016;375:1738–1748; 2. Tripathy D, et al. SABCS 2017;abstract GS2-05; 3. Cristofanilli M, et al. Lancet Oncol 2016;17:425–439; 4. Sledge GW, et al. J Clin Oncol 2017;35:2875–2884.

26


MONALEESA-3: Phase III placebo-controlled study of ribociclib + fulvestrant

• Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter

• 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

ECOG PS, Eastern Cooperative Oncology Group performance status; RECIST, Response Evaluation Criteria In Solid Tumors.*Fulvestrant administered intramuscularly on Cycle 1 Day 1, Cycle 1 Day 15, and Day 1 of every 28-day cycle thereafter.

Stratified by:

• Presence/absence of liver/lung

metastases

• Prior endocrine therapy

Primary endpoint

• PFS (locally assessed per RECIST v1.1)

Secondary endpoints

• Overall survival

• Overall response rate

• Clinical benefit rate

• Time to response

• Duration of response

• Time to definitive deterioration of ECOG PS

• 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

Randomization (2:1)

Ribociclib (600 mg/day orally;

3-weeks-on/1-week-off)

+

fulvestrant(500 mg)*

n=484

Placebo+

fulvestrant(500 mg)*

n=242

27


Key enrollment criteria

QTcF, Fridericia's corrected QT interval.

• Prior treatment with chemotherapy for ABC

• Inflammatory breast cancer

• Clinically significant cardiac arrhythmias and/or uncontrolledheart disease, including QTcF >450 ms

• Ineligible for endocrine therapy dueto disease burden

Key exclusion criteria

• Postmenopausal women and men

• ≥1 measurable lesion (RECIST 1.1) or ≥1 predominantly lytic bone lesion

• No or ≤1 line of prior endocrine therapy for ABC

• ECOG PS of ≤1

Key inclusion criteria

28


Prior endocrine therapy status criteria

29

First line(i.e. treatment-naive for ABC)

Second line + early relapsers(i.e. received up to 1 line of prior endocrine therapy for ABC)

• Relapse >12 months after completion of (neo)adjuvant endocrine therapy

OR

• De novo advanced/metastatic disease (no prior exposure to endocrine therapy)

• Early relapse on or ≤12 months from completion of (neo)adjuvant endocrine therapy

OR

• Relapse >12 months from completion of (neo)adjuvant endocrine therapy with subsequent progression after 1 line of endocrine therapy (antiestrogen/AI) for ABC

OR

• ABC at diagnosis that progressed after 1 line of endocrine therapy (antiestrogen/AI) for ABC


Patient demographics and baseline characteristics

Characteristic*Ribociclib + fulvestrant

n=484Placebo + fulvestrant

n=242

Median age, years (range) 63 (31–89) 63 (34–86)Race

Caucasian 406 (83.9) 213 (88.0)Asian 45 (9.3) 18 (7.4)Other‡ 33 (6.8) 11 (4.5)

ECOG PS§

0 310 (64.0) 158 (65.3)1 173 (35.7) 83 (34.3)

Metastatic sitesVisceral disease 293 (60.5) 146 (60.3)Bone-only disease 103 (21.3) 51 (21.1)

Prior endocrine therapy statusǁ

First line¶ 238 (49.2) 129 (53.3)Second line + early relapsers** 236 (48.8) 109 (45.0)

Prior endocrine therapy setting(Neo)adjuvant 289 (59.7) 142 (58.7)Advanced 110 (22.7) 40 (16.5)

Prior (neo)adjuvant chemotherapy 261 (53.9) 126 (52.1)

*All values are n (%), unless stated otherwise; ‡‘Other’ includes Black, Native American, other, and unknown; race unknown for 15 (3.1%) patients in the ribociclib arm and 5 (2.1%) patients in the placebo arm;

§ECOG PS missing for 1 (0.2%) patient in the ribociclib arm and 1 (0.4%) patient in the placebo arm; ǁ14 patients were not included in the prior endocrine therapy status subgroup due to missing data or criteria not being met;

¶Treatment naive for ABC; **Received up to 1 line of prior endocrine therapy for ABC.

30


Primary endpoint: PFS (investigator-assessed)

• The hazard ratio of 0.593 corresponds to a 41% reduction in risk of progression in the ribociclib vs placebo arm

No. at risk

Ribociclib + fulvestrant

Placebo + fulvestrant

484

242

403

195

365

168

347

156

324

144

305

134

282

116

259

106

235

95

155

53

78

27

52

14

13

4

0

0

PFS (investigator assessment)

Ribociclib +fulvestrant

n=484


n=242

Events, n (%) 210 (43.4) 151 (62.4)

Median PFS, months (95% CI)

20.5(18.5–23.5)

12.8(10.9–16.3)

Hazard ratio (95% CI) 0.593 (0.480–0.732)

One-sided p value 0.00000041

Time (months)

Pro

babilit

y o

f PFS (

%)

100

80

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

CI, confidence interval.


SubgroupEvents, n/n Favors ribociclib Favors placebo Hazard

ratio95% CI

Ribociclib + fulvestrant Placebo + fulvestrant

All patients 210/484 151/242 0.593 0.480–0.732

Prior endocrine therapy*

First line‡ 76/238 66/129 0.577 0.415–0.802

Second line + early relapsers§ 131/236 84/109 0.565 0.428–0.744

Liver or lung involvement

Yes 116/242 77/121 0.645 0.483–0.861

No 94/242 74/120 0.563 0.415–0.764Bone lesion only Yes 36/103 35/51 0.379 0.234–0.613

No 174/381 116/190 0.658 0.519–0.833Age <65 years 115/258 81/129 0.607 0.454–0.810

≥65 years 95/226 70/113 0.597 0.436–0.818Race Asian 22/45 7/18 1.353 0.574–3.186

Caucasian 174/406 136/213 0.562 0.448–0.704

Other 8/18 3/6 0.881 0.199–3.907ECOG PS 0 126/310 95/158 0.559 0.427–0.733

1 83/173 56/83 0.633 0.450–0.890Number ofmetastatic sites

<3 126/309 92/149 0.586 0.447–0.768

≥3 84/175 59/92 0.621 0.441–0.874Prior tamoxifen Yes 79/193 63/104 0.620 0.443–0.866

No 131/291 88/137 0.562 0.428–0.738Prior AI Yes 135/257 80/118 0.670 0.507–0.886

No 75/227 71/123 0.481 0.345–0.669

32

0.125 0.25 0.5 1 2 4 8

Hazard ratio (95% CI)

PFS subgroup analysis

*14 patients were not included in the prior endocrine therapy subgroup analysis due to missing data or criteria not being met; ‡Treatment naive for ABC; §Received up to 1 line of prior endocrine therapy for ABC.

Hazard ratios were estimated based on stratified Cox proportional hazards model except in the subgroups related to the stratificationfactors (presence or absence of lung or liver metastases and prior endocrine therapy), where an unstratified analysis was used.


Pro

babilit

y o

f PFS (

%)

26222016121086420 1814 24

0

20

40

60

80

100

Time (months)

Pro

babilit

y o

f PFS (

%)

26181614121086420 20 22 24

0

20

40

60

80

100

Time (months)

PFS by prior endocrine therapy status

33

First line* Second line + early relapsers‡



n=236


n=109

Events, n (%) 131 (55.5) 84 (77.1)

Median PFS, months

14.6 9.1


0.565 (0.428–0.744)



n=238


n=129

Events, n (%) 76 (31.9) 66 (51.2)

Median PFS, months

NR 18.3


0.577 (0.415–0.802)

No. at risk



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

No. at risk



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

*Treatment naive for ABC; ‡Received up to 1 line of prior endocrine therapy for ABC.


Secondary endpoints: ORR and CBR

• In all patients, the CBR was 70.2% for ribociclib + fulvestrant vs 62.8% for placebo + fulvestrant (p=0.020)

• In patients with measurable disease, the CBR was 69.4% for ribociclib + fulvestrant vs 59.7% for placebo + fulvestrant (p=0.015)

CBR, clinical benefit rate; ORR, overall response rate.Overall response rate = complete response + partial response.

Clinical benefit rate = complete response + partial response + (stable disease + non-complete response/non-progressive disease ≥24 weeks) in all patients and complete response + partial response + (stable disease ≥24 weeks) in patients with measurable disease.

0

20

40

60

80

100

Rate

(%

)

ORR

p=0.003

Patients with measurable disease

0

20

40

60

80

100

Rate

(%

)

ORR

p=0.000912

All patients

Ribociclib + fulvestrantPlacebo + fulvestrant

32.4

21.5

40.9

28.7

34


Conclusions

• Patients receiving ribociclib + fulvestrant had a statistically significant and clinically meaningful improvement in PFS vs placebo + fulvestrant

• Hazard ratio: 0.593; p=0.00000041; 41% reduction in risk of disease progression vs placebo

• Ribociclib treatment benefit was consistent across patient subgroups

• Prolonged PFS was observed with first-line ribociclib + fulvestrant (hazard ratio: 0.577; 95% CI: 0.415–0.802)

• Benefit was also observed in patients who received treatment in the second-line setting (hazard ratio: 0.565; 95% CI: 0.428–0.744)

• Ribociclib + fulvestrant demonstrated a manageable safety profile, consistent with previous Phase III ribociclib studies

• Ribociclib combined with fulvestrant may be a new first- or second-line treatment option for postmenopausal women with HR+/HER2– ABC

• This is the first study to show that CDK4/6 inhibitor + fulvestrant combinations are efficacious in patients with de novo ABC and patients with disease that relapsed >12 months after completion of prior (neo)adjuvant endocrine therapy

35

Abemaciclib studies

Trial N Design Population Primary

Endpoint

Status

MONARCH-1 132 Abemaciclib 200

mg

pretreated MBC

postmen.

PFS Final results on PFS/OS/RR

reported

nextMONARCH 234 abema 150 vs

abema 200 vs

abema 150 +

tamoxifen

Pretreated MBC

Postmen.

PFS Final results to be reported

at SABCS 2018

MONARCH-2 463 Abema + FULV vs

Placebo + FULV

1L postmen. PFS Final results on PFS already

reported

MONARCH-3 493 Anbema+ AI vs

Plac + AI

Final results on PFS

reportedrecently

neoMONARCH 597 Abema +

anastrozol

Early bteast cancer PFS Final results reported

MONARCH-E 4080

+1000

Abema+ED vs

ED

adjuvant,

moderate to high-

risk patients

iDFS Enrollment ongoing

MONARCH 1• 200 mg of single agent abemacivlib was administered orally on a continuous

schedule every 12 hours until disease progression or unacceptable toxicity.

• The primary objective of MONARCH 1 was investigator-assessed objectiveresponse rate (ORR).

• Patients (n = 132) had a median of 3 (range, 1-8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastaticsites

• ORR of 19.7% (95% CI: 13.3, 27.5; 15% not excluded)

• Median DoR of 8.6 mos

• CBR of 42.4%

• median PFS of 6.0 mos

• median OS of 17.7 mos

• Safety and toxicity profile of twice daily continuous administration was consistent with previous experience

• Few patients (7.6%) discontinued treatment due to adverse events

Dickler M, et al, Clin Cancer Res. 2017 Sep 1;23(17):5218-5224.

nextMONARCH 1: Phase 2 study of abemaciclib plus tamoxifen or

abemaciclib alone in HR+, HER2-advanced breast cancer

Erika Hamilton1, Javier Cortes2,3, Veronique Dieras4, Ozgur Ozyilkan5,

Shin-Cheh Chen6, Katarina Petrakova7, Aleksey Manikhas8,

Guy Jerusalem9, Roberto Hegg10, Yi Lu11, Melissa M. Bear11,

Erica L. Johnston11, Miguel Martin12

1Sarah Cannon Research Institute, Tennessee Oncology PLLC, Nashville, TN, USA; 2Ramon y Cajal University Hospital, Madrid, Spain; 3Vall d'Hebron Institute of Oncology, Barcelona, Spain;

4Centre Eugene Marquis UNICANCER, Rennes Cedex, France; 5Baskent University Department of Medical Oncology, Adana, Turkey; 6Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan; 7Masarykuv Onkologický Ustav,

Brno, Czech Republic; 8City Clinical Oncology Dispensary, St. Petersburg, Russia; 9Centre Hospitalier Universitaire,Liege, Belgium; 10Hospital Pérola Byington/FMUSP, Centro de Referência da Saúde da Mulher, São Paulo, Brazil;

11Eli Lilly and Company, Indianapolis, IN, USA; 12Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, CIBERONC, Madrid, Spain

PD1-11

OBJECTIVES

♦ Primary objective: investigator-assessed Progression-free Survival (PFS)

♦ Key secondary objectives: Overall Response Rate (ORR), Clinical Benefit Rate

(CBR), Overall Survival (OS) and safety

METHODS - Study Design

a during cycle 2 and beyond, loperamide was administered at investigator’s discretion

Statistics: PFS analysis tested superiority of Arm A to C at ~110 events across the 2 arms assuming a hazard ratio (HR) of .667 to achieve ~80% power. Arm B would be considered non-inferior to Arm C if the observed PFS HR was <1.2

Enrollment: From September 2016 to June 2017, patients were enrolled in 60 sites in 14 countries

Inclusion criteria

• HR+, HER2- MBC

• Progression on or after prior ET• Prior treatment with ≥2

chemotherapy regimens− 1-2 prior chemotherapies

in metastatic setting• Measurable disease• ECOG PS ≤ 1

abemaciclib: 150 mg Q12H (continuous schedule)

tamoxifen: 20 mg QD

Random

ization

1:1:1

abemaciclib: 150 mg Q12H

(continuous schedule)

abemaciclib: 200 mg Q12H (continuous schedule)

prophylactic loperamide: 2 mg QD (during cycle 1)a

A

B

CSame population as MONARCH 1 without prior taxane mandation

N = 234

Stratification factors

• Presence of liver metastases at baseline (yes or no)• Prior tamoxifen in the advanced/metastatic setting (yes or no)

MONARCH 3: Abemaciclib as initial therapy for patients with HR+, HER2- advanced breast cancer –

Results from the preplanned final PFS analysis

Matthew P. Goetz1, Miguel Martin2, Angelo Di Leo3, Seock-Ah Im4, Ahmad Awada5, Tammy Forrester6, Martin Frenzel6, Joanne Cox7,

Susana Barriga8, Masakazu Toi9, Hiroji Iwata10, Stephen Johnston11

1Mayo Clinic, Rochester, MN; 2Instituto De Investigacion Sanitaria Gregorio Marañon, Ciberonc, Geicam; Universidad Complutense, Madrid, Spain; 3Hospital of Prato, Prato, Italy; 4Seoul National University College of Medicine, Seoul, South

Korea; 5Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium; 6Eli Lilly and Company, Indianapolis, IN; 7Eli Lilly and Company, Windlesham, UK; 8Eli Lilly and Company, Madrid, Spain; 9Kyoto University, Kyoto, Japan; 10Aichi Cancer

Center Hospital, Nagoya, Japan; 11The Royal Marsden NHS Foundation Trust, London, UK

MONARCH 3: Study Design

♦Statistics: 240 PFS events for 80% power at one-sided α of .025 assuming a hazard ratio of .67

Enrollment: From November 2014 to November 2015 patients enrolled in 158 centers from 22 countries

Median follow-up: 26.7 months (final analysis)

Overall Survival: OS immature at this time

• HR+, HER2- ABC

• Postmenopausal

• Metastatic or locoregionally recurrent disease with no prior systemic therapy in this setting

• If (neo)adjuvant ET administered, a disease free interval of >12 months since completion of ET

• ECOG PS ≤1

abemaciclib: 150 mg BID

(continuous schedule) plus

anastrozole: 1 mg or a

letrozole: 2.5 mg QD until PD

placebo: BID (continuous

schedule) plus

anastrozole: 1 mg or a

letrozole: 2.5 mg QD until PD

a per physician’s choice: 79.1 % received letrozole, 19.9 % received anastrozole

Ra

nd

om

iza

tion

2 :1

N = 493

Abbreviations: AI, aromatase inhibitor; ABC, advanced breast cancer; BID, twice daily dose; ECOG PS, Eastern Cooperative Oncology Group Performance Status; ET, endocrine therapy; HER2-, human epidermal growth factor receptor 2-; HR+, hormone receptor-positive; PD, progressive disease; PFS, progression-free survival; QD, daily; OS, overall survival

Primary endpoint:

Investigator-assessed PFS

Secondary endpoint:

OS, Response rates, Safety

Stratification factors:

- Metastatic site (visceral, bone only, or other)- Prior ET (AI, no ET, or other)

Patient and Disease Characteristics (ITT)

Median age (range) 63 (38 – 87) 63 (32 – 88)

Race a

Caucasian 186 (56.7) 102 (61.8)

Asian 103 (31.4) 45 (27.3)

Other 11 (3.4) 7 (4.2)

Measurable diseaseYes 267 (81.4) 132 (80.0)

No 61 (18.6) 33 (20.0)

Disease settingb

Locoregionally recurrent 11 (3.4) 5 (3.0)

Metastatic recurrent 182 (55.5) 99 (60.0)

De novo metastatic 135 (41.2) 61 (37.0)

Metastatic siteb

Visceral 173 (52.7) 89 (53.9)

Bone-only 69 (21.0) 40 (24.2)

Other 86 (26.2) 36 (21.8)

Prior (neo)adjuvant chemotherapy

Yes 125 (38.1) 66 (40.0)

No 203 (61.9) 99 (60.0)

Prior (neo)adjuvantendocrine therapy

No endocrine therapy 177 (54.0) 85 (51.5)

Aromatase inhibitor therapy 85 (25.9) 50 (30.3)

Other endocrine therapy 66 (20.1) 30 (18.2)

Treatment free interval b,c

<36 months 44/151 (29.1) 32/80 (40.0)

≥36 months 95/151 (62.9) 40/80 (50.0)

Unknown 12/151 (7.9) 8/80 (10.0)

placebo + NSAIn = 165

abemaciclib + NSAIn = 328

a 28 patients in abemaciclib arm and 11 in placebo arm were not identified by race due to country law; bPercentage does not equal 100% as the result of

rounding; cTreatment-free interval calculated only for patients with prior endocrine therapy

Investigator-assessed PFS

PFS benefit confirmed by blinded independent central review: HR (95% CI): 0.465 (0.339-0.636); p <0.000001

PFS: Pre-specified Subgroup Analysis (ITT)placebo + NSAI

abemaciclib + NSAI

Change in Tumor Size and Response Rate

placebo + NSAI

abemaciclib + NSAI

Abbreviations: CBR, clinical benefit rate; CR, complete response; ITT, intent-to-treat; ORR, objective response rate

Change in Tumor Size by Cycle and Duration of Response

aInvestigator assessment

♦ Duration of responsea was measured from the time of initial response (time = 0) to progression

♦ Median time to response was 3.6 months in abemaciclib arm and 3.7 months in the placebo arm

Treatment-Emergent Adverse Events

≥ 20% occurrence in abemaciclib arm, n (%) All Grade 3 Grade 4 All Grade 3 Grade 4

Any adverse event 323 (98.8) 169 (51.7) 22 (6.7) 152 (94.4) 36 (22.4) 4 (2.5)

Diarrhea 269 (82.3) 31 (9.5) 0 52 (32.3) 2 (1.2) 0

Neutropenia 143 (43.7) 72 (22.0) 6 (1.8) 3 (1.9) 1 (0.6) 1 (0.6)

Fatigue 135 (41.3) 6 (1.8) - 54 (33.5) 0 -

Nausea 135 (41.3) 4 (1.2) - 33 (20.5) 2 (1.2) -

Anemia 103 (31.5) 23 (7.0) 0 13 (8.1) 2 (1.2) 0

Abdominal pain 102 (31.2) 6 (1.8) - 21 (13.0) 2 (1.2) -

Vomiting 99 (30.3) 5 (1.5) 0 21 (13.0) 4 (2.5) 0

Alopecia 90 (27.5) - - 18 (11.2) - -

Decreased appetite 86 (26.3) 5 (1.5) 0 17 (10.6) 1 (0.6) 0

Leukopenia 72 (22.0) 27 (8.3) 1 (0.3) 4 (2.5) 0 1 (0.6)

Blood creatinine increased 67 (20.5) 6 (1.8) 1 (0.3) 7 (4.3) 0 0

Note: An imbalance of venous thromboembolic events was observed between the abemaciclib arm (all Grade, n = 20 [6.1%]; Grade 3+, n = 10 [3.1%]) and the placebo arm

(all Grade: n = 1 [0.6%]; Grade 3+, n = 1 [0.6%]

Deaths due to AEs:

• abemaciclib arm: 11 (lung infection [4], embolism [2], respiratory failure [2], cerebral ischemia [1], cerebrovascular accident [1], pneumonitis [1]);

• placebo arm: 2 (general physical health deterioration [1], sudden death [1])

placebo + NSAIn = 161

abemaciclib + NSAIn = 327

Relationship Between Early Toxicity and PFS

abemaciclib + NSAI vs placebo + NSAI, median PFSabemaciclib arm with diarrhea: 28.2 monthsabemaciclib arm without diarrhea: 29.1 monthsplacebo arm: 14.8 months

HR = 0.49 (95% CI, 0.35-0.67)HR = 0.58 (95% CI, 0.43-0.78)

CONCLUSIONS

♦ Abemaciclib plus NSAI significantly improved PFS and ORR as initial therapy of HR+, HER2- advanced breast cancer in postmenopausal patients

♦ Benefit from abemaciclib plus NSAI was consistent across preplanned subgroups, including patients with concerning clinical characteristicsa

♦ Responses observed in patients who received abemaciclib generally occurred early, were maintained over time, and led to substantial tumor shrinkage

♦ Abemaciclib in combination with NSAI was generally well-tolerated and the safety profile was consistent with other abemaciclib studies

aAbstract CT099: The benefit of abemaciclib in prognostic subgroups: An update to the pooled analysis of MONARCH 2 and 3;

Poster will be presented on Monday April 16th, 1:00 PM - 5:00 PM at McCormick Place South, Hall A, Poster Section 42; Poster Board # 20

Final results of neoMONARCH: A phase 2 neoadjuvant study of abemaciclib in

postmenopausal women with hormone receptor positive, HER2 negative breast

cancer

Miguel Martin1, Sara Hurvitz2, David Chan3, María Fernandez-Abad4, Edgar Petru5, Regan Rostorfer6, Valentina Guarneri7, Chiun-Sheng Huang8, Michael F. Press9, and Dennis Slamon2

1Hospital General Universitario Gregorio Marañón, Madrid, España; 2University of California, Los Angeles, CA, Estados Unidos; 3Cancer Care Associates, Redondo Beach, CA, Estados Unidos; 4Hospital Universitario Ramón y Cajal, Madrid, España; 5Medical University Graz, Graz, Austria; 6UF Health Cancer Center at Orlando Health, Orlando, FL, Estados Unidos; 7University of Padova, Istituto Oncologico Veneto IRCCS, Padova, Italia; 8National Taiwan University Hospital, Taipei, Taiwan; 9University of Southern California, Los Angeles, CA, Estados Unidos; 10Eli Lilly and Company, Indianapolis, IN, Estados Unidos; 11Eli Lilly and Company, Madrid, España.

Sociedad Española de Oncología Médica (SEOM); Madrid, España; 25 al 28 de septiembre de 2018

O5

METHODSFigure 2. NeoMONARCH study design, and consort diagram

Patients: ♦ Post-menopausal women with HR+, HER2-−

breast cancer stage: I (T ≥ 1 cm), II, IIIA, or IIIB suitable for neoadjuvant endocrine therapy

Primary objective: ♦ Compare the change from baseline in Ki67

expression after 2 weeks of therapy

Secondary objectives (after week 16): ♦ Safety and tolerability♦ Clinical, radiological and pathological

response

♦ Pharmacokinetics of abemaciclib and anastrozole

Exploratory objectives:♦ Association between biomarkers and clinical

outcomes

♦ Relationship between abemaciclib exposure and response variables (i.e. Ki67, change in tumor size, and clinical response)

Statistical design:♦ 220 randomized patients required to achieve

50 evaluable patients in each arm♦ 80% power at 1-sided alpha of 0.1, assuming:

• mean reduction of 85 % for anastrozole

alone and 91% for combination

aStratified for PR status, tumor sizeb2 mg loperamide was administered prophylactically with each abemaciclib dose for the

first 28 days and then at the investigator’s discretioncParticipants who experience benefit following 14 weeks may remain on neoadjuvant

therapy for up to 8 additional weeksAbbreviations: QD=every day; Q12H=every 12 hours

223 Patients treated

224 Patients randomizeda

(Core biopsy at baseline)

Randomized but never treated, n = 1

167 Patients evaluable for Ki67 at Week 2

(Core biopsy after 2 weeks of treatment; Primary Endpoint)

Patients on abemaciclib 150 mg Q12H + anastrozole 1 mg QD until Week 16c

(Core biopsy after 14 weeks of treatment c; 138 Patients evaluable for Ki67 at Week 16; Secondary endpoints)

Surgery (optional)

Patients not evaluable:

Discontinued prior to Day 14, n = 6Baseline Ki67 positive <5%, n = 14Baseline and/or Week 2 notavailable at time of analysis, n = 36

Abemaciclibb 150 mg Q12H

n = 75

Anastrozole 1 mg QD

n = 74

Abemaciclib b 150 mg Q12H + Anastrozole 1 mg QD

n = 74

RESULTSFigure 3. Update of primary endpoint: percent change in Ki67 from baseline to week 2

© 2016 Eli Lilly and Company53

a Geometric Mean Ratio (GMR), 2-sided 90 % confidence interval (CI), p-value. p-values are based on a one-sided hypothesis test from a linear model with treatment progesterone receptor status (positive versus negative/unknown) and tumor size (<2 cm versus ≥2 cm and <5 cm versus ≥ 5 cm) as fixed effectsbA responder is identified as a patient with a ln(Ki67) value of less than 1. Odds ratio (OR), 2-sided 90 % CI, p value. p value is calculated by Fisher's Exact test of a one-sided hypothesis. Abbreviations: ANZ, anastrozole

Geometric Mean Change(Primary Endpoint of Study)

GMRa =

Me

an

Ch

an

ge

in

Ki6

7 (

%)

0

-20

-40

-60

-80

-100

0.19 (0.13, 0.28)

p<0.001a0.25 (0.17, 0.38)

p<0.001a

n = 59 n = 52 n = 56

- 92.86 - 90.52 - 62.78

8.2 (3.4, 20.0)

p<0.001b

Complete Cell Cycle Arrest

(Ki67 index <2.7% at 2 weeks)

OR =

Re

sp

on

se

Ra

te (

%)

100

80

40

60

20

0

Responders b: 40 30 8

67.8 57.7 14.3

12.6 (5.3, 30.7)

p<0.001b

Abemaciclib + ANZ

ANZ

Abemaciclib

♦ 167/223 treated patients were evaluable for primary objective. 78 patients achieved complete cell cycle

arrest (Ki67 <2.7%) with 40/59 patients treated with abemaciclib + ANZ, 30/52 patients treated with

abemaciclib and 8/56 patients treated with ANZ

RESULTS (continued)Figure 7. Analysis of PIK3CA and ESR1 mutation status on Ki67 expression change from baseline to 2 weeks

♦ PIK3CA mutation status had no effect on Ki67 expression change from baseline to 2 weeks

in response to combination or abemaciclib, compared to ANZ

♦ No analysis was performed on ESR1 mutation status for the outcome of Ki67 change due to

the small number of mutation positive patients

Mutation Status:

PIK

3C

AE

SR

1

+-

+-

+-

+-+-

+-

0 40 60 80 10020

n= 14n= 20

n= 8n= 19

n= 11n= 22

n= 2n= 33

n= 1n= 28

n= 4n= 29

PIK3CA and ESR1 mutation status per patient by arm (%)

Abemaciclib + ANZ vs ANZ

GMR = 0.166, p<.001

PIK3CA

Mutant:

Mean

Ch

an

ge in

Ki6

7 (

%)

0

-20

-40

-60

-80

-100

n = 14 n = 11 n = 20 n = 22+ + - -

P= 0.441

0.267, p=.001

Interaction mutation

vs Ki67 outcome

-92.5 -54.9 -92.5 -71.9

Abemaciclib vs ANZ

PIK3CA

Mutant:

Mean

Ch

an

ge in

Ki6

7 (

%)

0

-20

-40

-60

-80

-100

n =8 n = 11 n = 19 n = 22+ + - -

GMR = 0.136, p=.001

P= 0.445

0.230, p<.001

Interaction mutation

vs Ki67 outcome

-93.9 -54.9 -93.5 -71.9

Geometric Mean Change

Abemaciclib + ANZ (N = 39a,d) Anastrozole (N = 36c,f)Abemaciclib (N = 34b,e) Mutant gene + Wild type gene-a,b,cPIK3CA mutation status was undetermined in 5 patients in the abemaciclib + ANZ arm, 7 patients in the abemaciclib arm, and 3 patients in the ANZ armd,e,fESR1 mutation status was undetermined in 4 patients in the abemaciclib + ANZ arm, 5 patients in the abemaciclib arm, and 3 patients in the ANZ arm

RESULTS (continued)Figure 6. Caliper, radiological, and pathological responses at the completion of study treatment (16 weeks)

Note: pCR is defined as absence of invasive disease in breast and sampled

axillary lymph nodes. pCR rate is reported as the percentage of randomized

patients with a pCR. aconfidence interval (CI) was based on the exact test for

the binomial. bP-value was calculated by 1-sided right tailed binomial exact

test. cOnly 190 patients underwent surgery

C. Pathological response (pCR)n = 190c

ORR (CR/PR)n (%) 95% CIa

120 (53.6) 46.8 – 60.2

A. Caliper response n = 224

17 (7.6)CR

103 (45.9)PR

36 (16.1)SD2 (0.9)PD

66 (29.5)*NE

Patients, n (%)

11 (4.9)CR

93 (41.5)PR

68 (30.4)SD5 (2.2)PD

47 (21.0)*NE

Patients, n (%)

B. Radiological response n = 224

ORR (CR/PR)n (%) 95% CIa

104 (46.4) 39.8 - 53.2

Note: Caliper and radiological

response were evaluated by

RECIST1.1. *The elevated %

of NE patients was due to the

absence of assessment at

the end of treatment

Abbreviations:

CR, complete response; PR,

partial response;

SD, stable disease;

PD, progressive disease; NE,

not evaluable;

ORR, overall response rate. aconfidence interval (CI) was

based on the exact test for

the binomial

n % 90% CIa P-valueb

pCR 7 3.7 2.1, 100.0 0.842

♦ The majority of patients showed tumor shrinkage, and 7 (3.7%) patients achieved pCR

RESULTS (continued)Table 1. Treatment-emergent adverse events at the end of treatment (16 weeks)

© 2016 Eli Lilly and Company56

Investigator assessed TEAEs ≥ 10% (N=223)

CTCAE Grade, n (%)

Grade 1 Grade 2 Grade 3 Grade 4 All Grades

Pts ≥ 1 TEAE 44 (19.7) 87 (39.0) 80 (35.9) 4 (1.8) 215 (96.4)

Diarrhea 92 (41.3) 34 (15.2) 11 (4.9) 0 137 (61.4)

Constipationa 72 (32.3) 21 (9.4) 4 (1.8) 0 97 (43.5)

Nausea 66 (29.6) 22 (9.9) 5 (2.2) - 93 (41.7)

Fatigue 57 (25.6) 25 (11.2) 6 (2.7) - 88 (39.5)

Abdominal pain 35 (15.7) 7 (3.1) 8 (3.6) - 50 (22.4)

Decreased appetite 32 (14.3) 12 (5.4) 4 (1.8) 0 48 (21.5)

Neutropenia 6 (2.7) 19 (8.5) 21 (9.4) 0 46 (20.6)

ALT increased 13 (5.8) 3 (1.3) 12 (5.4) 3 (1.3) 31 (13.9)

Vomiting 21 (9.4) 8 (3.6) 2 (0.9) 0 31 (13.9)

Anemia 13 (5.8) 14 (6.3) 2 (0.9) 0 29 (13.0)

Hot flush 24 (10.8) 5 (2.2) 0 - 29 (13.0)

Dysgeusia 18 (8.1) 7 (3.1) - - 25 (11.2)

Rash 14 (6.3) 7 (3.1) 3 (1.3) 0 24 (10.8)

AST increased 8 (3.6) 9 (4.0) 5 (2.2) 1 (0.4) 23 (10.3)

Headache 20 (9.0) 2 (0.9) 1 (0.4) - 23 (10.3)

Leukopenia 14 (6.3) 7 (3.1) 1(0.4) 1(0.4) 23 (10.3)a2 mg loperamide was administered prophylactically with each abemaciclib dose for the first 28 days and then at the investigator’s discretionNote: No Grade 5 was observed

Abbreviations: ALT, alanine aminotransferase, AST , aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events v4.0;

EOT, end of treatment

Markers of response to CDK4 & 6 inhibition from neoMONARCH: a phase II

neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive, HER2 negative breast

cancerSara Hurvitz1, Miguel Martin2, Sameera Wijayawardana3, Manisha Brahmachary3, Philip J Ebert3, Suzanne Young3, Valerie Jansen3,

Dennis Slamon1

1University of California, Los Angeles, CA; 2Instituto de Investigacion Sanitaria Gregorio Marañon, Universidad Complutense, Ciberonc, Madrid, Spain; 3Eli Lilly and Company,

Indianapolis, IN

P3-10-08

RESULTSFigure 4. Addition of abemaciclib to ANZ therapy led to complete cell cycle arrest in majority of ANZ-resistant tumors

♦ Data from 19 tumors with available Ki67 IHC at all 3 timepoints that were treated with ANZ (n = 5, ANZ-sensitive tumors; n = 14, ANZ-resistant tumors) for 2 weeks followed by 14 weeks of abemaciclib and ANZ.

♦ Ki67 IHC expression in tumor specimens was measured at baseline, 2 weeks after initial treatment with ANZ alone, and EOT after 14 weeks of combination therapy. All patients received abemaciclib + ANZ after 2 weeks of initial treatment.

♦ ANZ-sensitive tumors (n = 5) were defined by an expression of Ki67 ≤ 2.7% at 2 weeks

♦ ANZ-resistant/abemaciclib+ANZ-sensitive tumors (n= 9) were defined by Ki67 >7.4% at 2 weeks, and Ki67 ≤ 2.7% at EOT

♦ ANZ-resistant/abemaciclib+ANZ-resistant tumors (n= 5) had an expression of Ki67>2.7% at 2 weeks, and Ki67 >7.4% at EOT

Note: Numbers represent the patient 1-6 who have IHC staining shown in Figure 5Abbreviations: ANZ, anastrozole; EOT, end of treatment

Figure 11. Differential baseline gene expression in intrinsically resistant subgroup from RNAseq analysis

♦ Intrinsically resistant tumors displayed higher expression (relative to sensitive tumors) of

genes in pathways involved in cell cycle and immune response and lower expression of

genes in pathways involved with estrogen signaling and metabolism

♦ These results suggest baseline gene expression analysis might be used to predict

response to abemaciclib plus endocrine therapy

(A) GSEA of resistant versus sensitive subgroups at baseline for the top downregulated and upregulated pathways (FDR cutoff at 0.05). (B) Heatmap of the top differentiated genes between resistant and sensitive groups at baseline. Patient tumors were categorized by the post-treatment Ki67 expression as either sensitive (Ki67 ≤2.7 at 2 and 16 weeks) or intrinsically resistant (Ki67 ≥7.4 at 2 and 16 weeks)

Cell cycle

Estrogen signaling

Immune response

CONCLUSIONS

♦ Both MODAplex and RNAseq analyses revealed differential gene expression between

resistant and sensitive early-stage HR+, HER2- BC tumors from patients treated on the

neoMONARCH study

♦ High RB1 mRNA and low Rb-loss-of-function gene expression signature were associated

with sensitivity to abemaciclib monotherapy, based on this small subset of tumors from

neoMONARCH

♦ Gene expression analysis revealed that tumors intrinsically resistant to any therapy

displayed higher levels of cell cycle and immune related genes at baseline compared to

sensitive tumors

♦ Together, these data suggest that the early changes in CCAG gene expression and baseline gene expression pathways might be used to predict response to abemaciclib and endocrine therapy in early-stage HR+, HER2- breast cancer

Conclusiones

• Los inhibidores de CDK 4/6 en combinación con hormonas aumentan de

forma estadísticamente significativa y clínicamente relevante el PFS en

mujeres metastásicas con tumores HR+/HER2-.

• No existe ningún subgrupo de enfermas que no se beneficie de la

combinación en primera o segunda línea

• Es muy probable que el beneficio se traslade a un aumento de

supervivencia, aunque de menor magnitud

• La mayoría de las enfermas HR+/HER2- metastásicas deberían recibir

inhibidores de CDK 4/6 en primera o segunda línea.

• No hay evidencias de que un fármaco sea superior a otro(s) dentro del

grupo.

• Estos fármacos se están actualmente desarrollando en adyuvancia.

Table 2. Prior Therapies

Endocrine Therapy for

ABC (# of regimens), n (%)a

1 21 (26.9) 24 (30.4) 26 (33.8)

2 23 (29.5) 26 (32.9) 16 (20.8)

>3 16 (20.5) 16 (20.3) 15 (19.5)

Chemotherapy

by setting, n (%)

1 regimen for ABC 43 (55.1) 36 (45.6) 40 (51.9)

2 regimens for ABC 30 (38.5) 39 (49.4) 33 (42.9)

3 regimens for ABC 3 (3.8) 0 0

Chemotherapy

in any setting, n (%)

Taxanes 68 (87.2) 71 (89.9) 66 (85.7)

Capecitabine 30 (38.5) 43 (54.4) 27 (35.1)

aprior fulvestrant in metastatic setting: 22 (28.2%) in arm A; 20 (25.3%) in arm B; 18 (23.4%) in arm C

abemaciclib 150 mg + tamoxifen

N = 78

abemaciclib 150 mgN = 79

abemaciclib 200 mg N = 77

Figure 1. Primary Endpoint: Investigator-assessed Progression-free Survival

HRa 95% CI p value

A vs Cb .815 .556, 1.193 .293

B vs C 1.045 .711, 1.535 .811

A vs B .805 .551, 1.177 .256

astratified HRbprimary endpoint was A vs C

Median PFS

Arm A (abemaciclib 150 mg + tamoxifen): 9.1 monthsArm B (abemaciclib 150 mg): 6.5 monthsArm C (abemaciclib 200 mg): 7.4 months

Figure 2. Change in Tumor Size from BaselineC

hange f

rom

Baselin

e (

%)

20% Increase

30% Decrease

20% Increase

30% Decrease

20% Increase

30% Decrease

ARM A

ARM C

ARM B

N = 78 ORRa CBRa

Investigator-assessed 34.6% 61.5%

Confirmed 25.6% 57.7%

N= 77 ORRa CBRa



N= 79 ORRa CBRa



aORR and CBR were not statistically significant between any arm

Table 4. Treatment-emergent Adverse Events(Safety Population)

Grade (≥15 % occurrence in any arm), n (%)

Any Grade 3 Any Grade 3 Any Grade 3

Any Adverse Event 73 (93.6)a 33 (42.3) 77 (97.5)d 34 (43.0) 76 (98.7)h 46 (59.7)

Diarrhea 42 (53.8) 1 (1.3) 53 (67.1) 3 (3.8) 48 (62.3) 6 (7.8)

Neutropenia 32 (41.0)b 14 (17.9) 40 (50.6)e 21 (26.6) 40 (51.9)i 26 (33.8)

Anemia 31 (39.7) 9 (11.5) 25 (31.6) 6 (7.6) 32 (41.6) 8 (10.4)

Nausea 24 (30.8) 2 (2.6) 26 (32.9)f 2 (2.5) 33 (42.9) 2 (2.6)

Leukopenia 21 (26.9) 8 (10.3) 27 (34.2) 10 (12.7) 21 (27.3) 9 (11.7)

Fatigue 23 (29.5) 3 (3.8) 20 (25.3) 2 (2.5) 22 (28.6) 5 (6.5)

Abdominal Pain 21 (26.9) 0 17 (21.5) 1 (1.3) 25 (32.5) 0

Thrombocytopenia 15 (19.2)c 2 (2.6) 12 (15.2)g 3 (3.8) 27 (35.1)j 2 (2.6)

Vomiting 14 (17.9) 2 (2.6) 20 (25.3) 3 (3.8) 20 (26.0) 4 (5.2)

Decreased Appetite 20 (25.6) 4 (5.1) 12 (15.2) 1 (1.3) 17 (22.1) 2 (2.6)

Constipation 10 (12.8) 0 9 (11.4) 0 25 (32.5) 1 (1.3)

Muscular Weakness 14 (17.9) 2 (2.6) 12 (15.2) 1 (1.3) 7 (9.1) 2 (2.6)

Blood Creatinine Increased 14 (17.9) 1 (1.3) 8 (10.1) 0 8 (10.4) 0

Dyspnea 9 (11.5) 2 (2.6) 13 (16.5) 3 (3.8) 5 (6.5) 0

abemaciclib 150 mg+ tamoxifen

N = 78



Grade 4 events, n (%): a 6 (7.7)b 2 (2.6)c 1 (1.3)

d 4 (5.1)e 1 (1.3)f 1 (1.3)g1 (1.3)

h 8 (10.4)i 3 (3.9)j 3 (3.9)

Table 5. Overview of Treatment-emergent Diarrhea (Safety Population)

Median Time to First Onset, days (range) 14.0 (1-219) 11.0 (1-596) 10.5 (2-351)

Duration of Grade 2/3 Diarrhea, daysa

4.5/3.0 7.0/4.0 3.5/4.5

Patients with ≥1 Diarrhea Event, n 42 53 48

Use of Antidiarrheal Medication, n (%)b

Loperamide 20 (47.6) 30 (56.6) 15 (31.3)c

Other 9 (21.4) 8 (15.1) 8 (16.7)

Dose Omission of abemaciclib, n (%)b

2 (4.8) 6 (11.3) 6 (12.5)

Dose Reduction of abemaciclib, n (%)b

1 (2.4) 4 (7.5) 7 (14.6)

a1 patient across study arms discontinued study treatment due to diarrheabpercentage was calculated based on the number of patients with ≥1 diarrhea eventcloperamide was administered as supportive therapy and does not include prophylactic doses administered during cycle 1


N = 78



Table 6. Occurrence of Venous Thromboembolism

Preferred terma

Total, n (%) 7 (9.0) 4 (5.1) 3 (3.9)

Venous

DVT, n (%) 3 (3.8) 2 (2.5) 1 (1.3)

PE, n (%) 4 (5.1) 2 (2.5) 2 (2.6)b

Death 0 0 0

Discontinued Treatment 0 0 0

SAE, n (%) 3 (3.8) 2 (2.5) 1 (1.3)

amapped from AE verbatim (i.e. reported term)b1 DVT and 1 PE event occurred in the same patient on the same day; reported here as PE

1 patient in each arm had an arterial thromboembolism event


N = 78



Conclusions

68

♦ nextMONARCH 1 confirmed the single-agent activity of abemaciclib in HR+,

HER2- MBC patients who experienced progression after prior chemotherapy and

ET

♦ Combining tamoxifen with abemaciclib resulted in numerically higher PFS but did

not demonstrate a statistically significant improvement in PFS compared to

abemaciclib 200 mg monotherapy. Efficacy of abemaciclib monotherapy was

similar at both 150 mg and 200 mg dose levels

♦ Addition of prophylactic loperamide to abemaciclib 200 mg resulted in treatment-

emergent diarrhea similar to abemaciclib 150 mg without prophylaxis

♦ Compared to the MONARCH 1 study, rates of grade 2 and 3 diarrhea were lower

across all arms. Early onset of treatment-emergent diarrhea is dose-dependent

and best managed with antidiarrheal medication and dose omissions/reductions

References

69

Abbreviations: ABC, advanced breast cancer; AEs, adverse events; CBR,

clinical benefit rate; CDK, cyclin-dependent kinase; CI, confidence interval;

DVT; deep vein thrombosis; ECOG PS, Eastern Cooperative Oncology

Group performance status; ET, endocrine therapy; HER2-, human

epidermal growth factor receptor 2 negative; HR, hazard ratio; HR+,

hormone receptor-positive; MBC, metastatic breast cancer; ORR, objective

response rate; OS, overall survival; PE, pulmonary embolism; PFS,

progression-free survival; PgR, progesterone receptor; QD, every day;

Q12H, every 12 hours; SAEs, serious adverse events; TAM, tamoxifen

1. Cardoso F, et al. Breast 2017;31:244-59

2. Cardoso F, et al. Ann Oncol 2017;28(1):16-333. Milani A, et al. World J Clin Oncol 2014;5(5):990-10014. Dickler MN, et al. Clin Cancer Res 2017;23(17):5218-245. Sledge GW Jr, et al. J Clin Oncol 2017;35(25):2875-846. Goetz MP, et al. J Clin Oncol 2017 Nov 10;35(32):3638-467. Cristofanilli M, et al. Eur J Cancer 2018;104:21-318. Slamon DJ, et al. J Clin Oncol 2018;36(24):2465-729. Patnaik A, et al. Cancer Discov 2016;6(7):740-53

MONARCH ·: ORR and CBR

All patients, n 328 165

Objective Response Rate, % (95% CI) 48.2 (42.8, 53.6) 34.5 (27.3, 41.8) 0.002

Complete Response, n (%) 5 (1.5) 0

Clinical Benefit Rate, % (95% CI) 78.0 (73.6, 82.5) 71.5 (64.6, 78.4) 0.101

Patients with measurable disease at baseline, n

267 130

Objective Response Rate, % (95% CI) 59.2 (53.3, 65.1) 43.8 (35.3, 52.4) 0.004

Complete Response, n (%) 5 (1.9) 0

Clinical Benefit Rate, % (95% CI) 79.4 (74.5, 84.3) 69.2 (61.3, 77.2) 0.024

p valueplacebo + NSAIabemaciclib + NSAIResponse

MONARCH 3: side effects

Phase III study in women with HR+, HER2– with locally advanced or mBC1

• Postmenopausal

women with HR+,

HER2–

locoregionally

recurrent or

metastatic BC

• No prior systemic

therapy for

advanced disease

Placebo +anastrozole or letrozole*

Abemaciclib + anastrozole or letrozole*

Ran

do

miz

ati

on

2:1

Primary endpoint PFS

Secondary endpoints OS

ORR

DCR

DOR

CBR

QoL

PK

MONARCH-3

Abemaciclib in combination with NSAIs in HR+, HER2– mBC

1. NCT02246621. Clinicaltrials.gov: http://www.clinicaltrials.gov. Accessed May 2015.

*150 mg of oral abemaciclib or matching placebo given once every 12 hours in 28 day cycles. 1 mg anastrozole given once daily in 28-day cycles.

2.5 mg letrozole given once daily in 28-day cycles.

BC, breast cancer; CBR, clinical benefit rate; DCR, disease control rate; DOR, duration of response;

HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; NSAI, non-steroidal aromatase inhibitor;

ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; QoL, quality of life.

Abemaciclib Phase III trials

Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer (PALOMA 3 trial)



Turner N et al,

Among 521 patients who underwent randomization, the median overall survival

was 34.9 months (95% confidence interval [CI], 28.8 to 40.0) in the palbociclib–

fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulves-

trant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P=0.09; absolute

difference, 6.9 months).

LEE011 development in BC

Specifically inhibits CDK4 and 6 in tumors with full functional pRb (intact total pRbby IHC)

Phase I recommended dose 600 mg/d 21-of-28 day dosing schedule

AEs: neutropenia (19%), leukopenia (12%) and lymphopenia (14%)

Infante et al AACR 2012 & O'Brien et al AACR 2014

Trial Phase(N)

Design Population PrimaryEndpoint

MONALEESA-1 II(120)

LEE011+LET (400

mg or 600 mg) vs LETNA (resectable BC)

Cell-cycleRR (Ki 67)

MONALEESA-2 III(550)

LEE011600 mg+LETvs Pbo+LET

1L MBC PFS

* Other combinations with EVE+EXE, BYL719+LET or FULV+BYL719 or BKM120 being tested in phase I CTs (preclinical in vivo/in vitro evidence of potential efficacy of triple-combination)

LY2835219 development in BCSpecifically inhibits CDK4 and 6

Recommended dose 200 mg /12 h in 28d cycles

Phase I trial:AEs: diarrhea (5% G3-4), nausea (3% G3-4), fatigue (2%

G3-4) and neutropenia (11% G3-4)

MBC cohort (N=47) median 7 prior regimens (highly pre-treated)

ORR 25% in HR+ confirmed BC and 56% SD rate

Disease control rate: 70% all MBC and 81% HR+ MBC

Median PFS: 5.8 mo all MBC and 9.1 mo HR+ MBC

NCT02107703

Infante et al AACR 2012 & Patniak et al AACR 2014

Trial Phase(N)

Design Population PrimaryEndpoint

NCT02057133 I(81)

LY2835219+HT(LET, ANA, TAM, EXE or EXE+EVE)

MBC Drug-related AEs

NCT02102490 II(128)

LY2835219 200mg/12hx28d

MBC ORR

NCT02107703 III(550)

LY2835219+FULvs Pbo+FUL

MBC PFS

P276-00Selectively inhibits CDK4/cyclin D1, CDK1/cyclin B and CDK9/cyclin T1

Preclinical data: induces G1-G2 arrest and shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models

Phase I/II in TN-MBC pts testing GEM 1000 mg/m2 + CARBO AUC2 d1, 8 q 21d vs P276-00 100mg starting dose d1-5 with CT

Joshi et al Mol Cancer Ther 2007

Other CDK/cyclin inhibitors in BC

Dinaciclib (SCH 727965)

• Selectively inhibits CDK1, CDK2, CDK5 and CDK9

• Preclinical data: inhibition of CDK1 and CDK2 may result in cell cycle repression and tumor cell apoptosis

• Phase I in TN-MBC pts testing dinaciclib + epirubicin

MONALEESA 2

• Postmenopausal

women with

HR+/HER2–

advanced breast

cancer

• No prior therapy

for advanced

disease

• N=668

(1:1)

RANDOMIZATION

Stratified by the

presence/absence

of liver and/or lung

metastases

Ribociclib (600 mg/day)3-weeks-on/1-week-off

+Letrozole (2.5 mg/day)

n=334

Placebo+

Letrozole (2.5 mg/day)n=334

Primary endpoint

• PFS (locally assessed

per RECIST v1.1)*

Secondary endpoints

• OS (key)

• ORR

• CBR

• Safety

Hortobagyi G et al, NEJM 2017

MONALEESA 2: PFS


MONALEESA 2: ORR and CBR


MONALEESA 2: Side effects

0

Median TTP/PFS (months)

12 246 18

Evolution of therapy for endocrine sensitive metastatic breast cancer

PFS, progression-free survival; TTP, time-to-progression1.Ellis M, et al. ESMO 2016, LBA14_PR; 2. Finn RS, et al. N Engl J Med 2016;375:1925–36; 3.Hortobagyi G, et al. N Engl J Med 2016;375:1738–48

Letrozole + palbociclib or ribociclib or abemaciclib24.8 months7

Fulvestrant 500 mg16.6 months1

Aromatase inhibitors13–15 months1-3

HR+/HER2- MBC: Objective Response Rate to First Line withDifferent Therapies

0 10 20 30 40 50 60

AROMATASE INHIBITORS*

FULVESTRANT 500MG (1)

AI PLUS RIBOCICLIB (2)

AI PLUS PALBOCICLIB (3)

AI PLUS ABEMACICLIB (4)

%ORR

39%

48.2%

42.1%

34.8%

40.7%

Data from: 1) Robertson JFR et al. Lancet 2016; 2) Hortobagyi G et al, NEJM 2017; 3) Finn R et al, NEJM 2016; 4). Goetz MP et al, J Clin Oncol. 2017; * pooled data

of the control arm of the trials

AE, %

First-Line (grade 3-4)

Palbo + AI1 Ribo + AI2 Abema + AI3

Neutropenia 56 + 10 50 + 10 20 + 2

Diarrhea 1 + 0 1 + 0 9 + 0

Liver enzymes* <1* 16* 13*

QTc prol NR <1 NR

TEP/VE NR + <1 <1 + <1 5 (grade?)

4Turner NC, et al. N Engl J Med 2015; 5Cristofanilli M, et al. Lancet Oncol 2016; 6Sledge G, et al. J Clin Oncol 2017

1Finn RS, et al. N Engl J Med 2016; 2Hortobagyi G, et al. N Engl J Med 2016; 3di Leo A, et al. J Clin Oncol 2017

Main toxicities of CDK 4-6 inhibitors

*all grades

CDK 4-6 inhibitors in patients with prior AIs

MONARCH 2 Median PFS 1

abemaciclib + fulvestrant: 16.44 months (N = 446)placebo + fulvestrant: 9.27 months (N = 223)

HR, 0.553 (95% CI, 0.449 to 0.681)

p <.0000001

0

PFS (months)

12 246 18

Sequence of therapies in hormone-sensitibe MBC

PFS, progression-free survival; TTP, time-to-progression1.Ellis M, et al. ESMO 2016, LBA14_PR; 2. Finn RS, et al. N Engl J Med 2016;375:1925–36; 3.Hortobagyi G, et al. N Engl J Med 2016;375:1738–48

Letrozole plus palbociclib or ribociclib or abemaciclib

24.8 months7

Fulvestrant 500 mg16.6 months1

Aromatase inhibitors13–15 months1-3

30 36 42

Fulvestrant plus abemaciclib

16.5 mo

Fulvestrant 500 mg4-9 mo

Aromatase inhibitors

plus CDK 4-6 inh

?

Combination Trials

inhibidores de cdk 4/6 en cáncer de mama: datos recientes · palbociclib (pd0332991) pfizer...

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