¿podemos seleccionar un perfil de pacientes óptimo para … · 2019-04-16 · 1. dickler mn et...

¿Podemos seleccionar un perfil de pacientes

óptimo para abemaciclib?

Javier Cortes,

IOB Institute of Oncology, Madrid & Barcelona

Vall d´Hebron Institute of Oncology (VHIO),

Medica Scientia Innovation Research (MedSIR)

Barcelona, Spain

CDK4 & 6 in HR+ Breast Cancer

D-type cyclins activate CDK4 & 6,

which phosphorylate Rb, resulting in

G1 to S progression1

Estrogen stimulates cyclin D1 in HR+

breast cancer2

Short-term inhibition of CDK4 & 6 leads to

G1 arrest with rebound of Rb

phosphorylation and cell cycle progression

upon withdrawal1

Continuous inhibition leads to prolonged

cell cycle arrest with initiation of apoptosis

or senescence3

Cyclin D

CDK4Cyclin D

CDK6

Rb

Proliferation

PO4

PO4

PO4

RbG2

M

S

G1

Rb=retinoblastoma. PO4=phosphate ion.

1. Gelbert LM, et al. Invest New Drugs. 2014;32:825-837. 2. Altucci L, et al. Oncogene.1996;12:2315-2324. 3. Torres-Guzman R, et al. Oncotarget. 2017;8:69493-69507.

Chemical Structures of CDK4 & 6 Inhibitors

1. Abemaciclib [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018. 2. Palbociclib [prescribing information]. New York, NY: Pfizer Inc.; 2015. 3. Ribociclib [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2017.

Palbociclib RibociclibAbemaciclib

TargetAbemaciclib

IC50 (µM)

Palbociclib

IC50 (µM)

Ribociclib

IC50 (µM)

CDK4/Ciclin D1 0.002 0.011 0.010

CDK6/Ciclin D2 D3 0.010 0.009 – 0.015 0.039

CDK1/Ciclin B 1,627 > 10 113

CDK2/Ciclin A 0.5 > 10 76

Abemaciclib is Associated with Senescence and Apoptosis in a

Time-dependent Manner

Torres-Guzmán R, et al. Oncotarget 2017;8:69493–507.

MCF-7

Sustained Target Inhibition Contributes to Higher Levels of Senescence and

Apoptosis

Growth

Ce

ll N

um

be

r

4500

4000

3500

3000

2500

2000

1500

1000

500

01DT 2DT 3.5DT 5DT

Treatment duration

Senescence

β-g

al P

osit

ive

Ce

lls

(%

)

30

25

20

15

10

5

01DT 2DT 3.5DT 5DT

Treatment duration

Apoptosis

TU

NE

L P

osit

ive

Ce

lls

(%

)

40

35

30

25

20

15

10

5

01DT 2DT 3.5DT 5DT

Treatment duration

DMSO 0.125 µM abemaciclib 0.5 µM abemaciclib

In vitro, continuous exposure to Abemaciclib inhibited Rb phosphorylation and blocked progression from G1

to S phase of the cell cycle, resulting in senescence and apoptosis (cell death)1

Abemaciclib Effectively Distributes to CNS

Abemaciclib Prolongs Survival in an

Intracranial U87MG GBM Model

Treatment Median Survival (days) SE

Vehicle 25.14 2.82

20 mg/kg 29.83 0.70

40 mg/kg 33.50* 1.32

80 mg/kg 36.86* 1.28

♦ Functional evidence for CNS penetration by abemaciclib1

♦ Abemaciclib is a potent and selective oral CDK4 and CDK6

inhibitor that crosses the blood-brain barrier and inhibits the

growth of intracranial human brain tumour xenografts2*p<0.05

1. Beckmann R, et al. Presented at AACR Annual Meeting; New Orleans, April 16–20 2016;

2. Gelbert LM, et al. Invest New Drugs 2014:32;825–37.

Abemaciclib Clinical Trial Program

Abemaciclib Clinical Trial Program Overview

*Numbers in parentheses indicate percentage of patients; 〒The majority of patients (89%) received 2 or more systemic

therapies for metastatic disease prior to study entry7.

1. Abemaciclib [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018; 2. Dickler MN, et al. Clin Cancer Res

2017;23:5218–24; 3. Cardoso F, et al. Ann Oncol 2018; 4. Sledge GW Jr, et al. J Clin Oncol 2017;35:2875–84; 5. Rugo

HS, et al. J Clin Oncol 2016;34:3069–103; 6. Goetz MP, et al. J Clin Oncol 2017;35:3638–46;

MONARCH 1

Abemaciclib as a single agent1

ET-refractory disease2

• ET and chemotherapy in the metastatic setting (100%)1

Later lines〒

MONARCH 2

Abemaciclib in combination with fulvestrant1

ET-resistant disease3,4

• (Neo)adjuvant chemotherapy (60%)4

• Most recent ET4

• (Neo)adjuvant (59%)• Metastatic (38%)• Unknown (3%)

First or second

MONARCH 3

Abemaciclib in combination with an AI1

ET-responsive disease5,6

• (Neo)adjuvant chemotherapy (38%)6

ET (46%)6

• Systemic treatment in the metastatic setting (0%)6

First

Setting

Prior therapy

Line of therapy

Lilly does not, nor does it intend to sell products prior to regulatory approval or promote products inconsistent with label, nor does Lilly intend to promote or proactively engage in the discussion of

competitive products. Any current external or promotional activities must be consistent with the approved label and carried out in compliance with all company policies and applicable laws.

MONARCH 1: Study Design

Dickler M, et al. Clin Cancer Res 2017;23:5218–24.

♦ Phase 2, single arm, open-label study

♦ Overall, this patient population was heavily pre-treated and had a poor prognosis

♦ Study population at baseline:• 100% of women received ET and 1–2 chemotherapy regimens in the metastatic setting

• Majority (90%) of patients with visceral disease

• Liver (71%) and bone were most common metastatic sites

• 51% of women had 3 or more metastatic sites

• Median of 3 (range 1–8) lines of systemic therapy

• Median of 1 (range 1–3) lines of chemotherapy

• Median of 2 (range 1–6) lines of ET

♦ ER+ (ER and/or PR+), HER2- MBC

♦ Measurable disease

♦ ECOG PS 0/1

♦ Progressed on or after prior ET

♦ Prior treatment with 1 or 2 chemotherapy

regimens in MBC

♦ Included treatment with taxane in adjuvant or

metastatic setting

Abemaciclib 200 mg

PO Q12H

Primary Endpoint:

ORR

Inclusion Criteria

N=132

Lilly does not, nor does it intend to sell products prior to regulatory approval or promote products inconsistent with label, nor does Lilly intend to promote or proactively engage in the discussion

of competitive products. Any current external or promotional activities must be consistent with the approved label and carried out in compliance with all company policies and applicable laws.

MONARCH 1 (JPBN): 12-Month Response Summary1

Dickler M et al. Clin Cancer Res 2017;23:5218–24.

1. Dickler MN et al. Presented at ASCO 2016. Abstract #510

Investigator Assessed Response,a %

Abemaciclib

200 mg (N=132)

Confirmed Objective Response Rate (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

a Assessments based on independent review were comparable

Median time to response = 3.7 months

Median DoR = 8.9 monthsa

100

50

20

0

-30

-50

-100

Ch

an

ge F

rom

Ba

se

lin

e (

%)

20% Increase

Progressive disease (31)

Stable disease (63)

Partial response (26)

Condensing bone lesion

30% Decrease

♦ Abemaciclib, a CDK4/6 inhibitor, demonstrates single agent activity in heavily

pre-treated patients with HR+/HER2- MBC; at 18 months:

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

• Median DoR of 8.9 months

• CBR of 42.4%, median PFS of 6.0 months; median OS of 22.3 months

MONARCH 1: 18-Month Conclusions

Lilly does not, nor does it intend to sell products prior to regulatory approval or promote products inconsistent with label, nor does Lilly intend to promote or proactively engage in the discussion of competitive products. Any current external

or promotional activities must be consistent with the approved label and carried out in compliance with all company policies and applicable laws.

Rugo HS, et al. Cancer Res 2017;77(suppl 13):Abstract CT044.


a Required to receive GnRH agonist; b Dose reduced by protocol amendment in all new and ongoing patients from 200 mg to 150 mg twice daily after 178 patients enrolled; 121 were randomized to abemaciclib at the 200 mg starting dose

and 57 to matching placebo3; c Fulvestrant administered per label.

1. Sledge GW, et al. J Clin Oncol 2017;35(suppl):Abstract 1000; 2. Cardoso F, et al. Breast 2014;6:489–502;

3. Cardoso F, et al. Ann Oncol 2014;25:1871–88.

Primary endpoint:

Investigator-assessed PFS

Secondary endpoints:

OS, response, clinical benefit rate,

safety

Stratification factors:

♦ Metastatic site

♦ ET resistance

(primary vs secondary) 2,3

Placebo twice daily

(continuous schedule)

Fulvestrant 500 mg c

Abemaciclib

150 mg b twice daily

(continuous schedule)

Fulvestrant 500 mg c

♦ ER+/HER2- MBC

♦ Pre/peria or postmenopausal

♦ ET resistant:

• Relapsed on neoadjuvant or

on/within 1 yr of adjuvant ET

• Progressed on first-line ET

♦ No chemo for MBC

♦ No more than 1 ET for MBC

♦ ECOG PS ≤1

RandomiZatIon

2 :1

N = 669

Study Population at Baseline1:

♦ Bone-only disease – 27%

♦ Visceral disease – 56%

♦ Primary ET resistance – 25%

♦ De novo metastatic – 20%

Inclusion Criteria

MONARCH 2: Baseline Characteristics

a Data not available for all patients; b 401 (59.9%) had chemotherapy in neoadjuvant or adjuvant setting.

Sledge GW Jr, et al. J Clin Oncol 2017;35:2875–84.

Characteristic, n (%)Abemaciclib + fulvestrant

(N=446)

Placebo + fulvestrant

(N=223)

Median age, years (range) 59 (32–91) 62 (32–87)

ET resistance a Primary 111 (24.9) 58 (26.0)

Secondary 326 (73.1) 163 (73.1)

Most recent ET a Neoadjuvant or adjuvant 263 (59.0) 133 (59.6)

Metastatic 171 (38.3) 85 (38.1)

Prior AIYes 316 (70.9) 149 (66.8)

No 130 (29.1) 74 (33.2)

PR status a Positive 339 (76.0) 171 (76.7)

Negative 96 (21.5) 44 (19.7)

Metastatic site a

Visceral 245 (54.9) 128 (57.4)

Bone only 123 (27.6) 57 (25.6)

Other (non-visceral soft tissue) 75 (16.8) 38 (17.0)

Measurable diseaseYes 318 (71.3) 164 (73.5)No 128 (28.7) 59 (26.5)

Racea

Asian 149 (33.4) 65 (29.1)

Caucasian 237 (53.1) 136 (61.0)

Other 29 (6.5) 13 (5.8)

ECOG PSa 0 264 (59.2) 136 (61.0)

1 176 (39.5) 87 (39.0)

Prior chemotherapy for neo-

or adjuvant treatment

Yes 267 (59.9) 134 (60.1)

No 179 (40.1) 89 (39.9)

Menopausal status a Pre/peri 72 (16.1) 42 (18.8)

Post 371 (83.2) 180 (80.7)

MONARCH 2: Primary Endpoint, PFS (ITT)


Median PFS

Abemaciclib + fulvestrant: 16.4 months

Placebo + fulvestrant: 9.3 months

HR 0.553 (95%CI 0.449, 0.681)

p<0.0000001

PFS benefit confirmed by blinded independent central review [HR 0.460 (95% CI 0.363, 0.584) p < 0.000001]

Time (months)

Pro

gre

ssio

n-f

ree

su

rviv

al (%

)

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30

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Patients at risk:abemaciclib 446 367 314 281 234 171 101 65 32 2 0

placebo 223 165 123 103 80 61 32 13 4 1 0

MONARCH 2: PFS Patient Subgroup Analysis (ITT)


Overall

ET resistance

PR status

Metastatic site

Measurable disease

Age group (years)

Geographical region

Race

ECOG PS

Menopausal status

ITT

Primary

Secondary

Negative

Positive

Visceral

Bone only

Other

Yes

No

<65

≥65

N. America

Europe

Asia

Caucasian

Asian

Other

0

1

Pre/peri

Post

HR (95% CI)

0.553 (0.449, 0.681)

0.454 (0.306, 0.674)

0.591 (0.464, 0.754)

0.509 (0.325, 0.797)

0.586 (0.463, 0.743)

0.481 (0.369, 0.627)

0.543 (0.355, 0.833)

0.837 (0.501, 1.398)

0.523 (0.412, 0.664)

0.622 (0.413, 0.936)

0.523 (0.402, 0.681)

0.620 (0.447, 0.860)

0.486 (0.325, 0.726)

0.617 (0.449, 0.848)

0.520 (0.362, 0.747)

0.620 (0.474, 0.811)

0.515 (0.359, 0.740)

0.305 (0.116, 0.804)

0.489 (0.373, 0.641)

0.657 (0.478, 0.904)

0.415 (0.246, 0.698)

0.580 (0.463, 0.726)

0.2 0.6 0.8 1

Pinteraction

0.263

0.583

0.171

0.474

0.427

0.618

0.322

0.166

0.246

N

669

169

489

140

510

373

180

113

482

184

424

245

178

279

212

373

214

42

400

263

114

551

0 1.40.4

Favours placebo armFavours abemaciclib arm


Statistics: 240 PFS events for 80% power at one-sided a of 0.025 assuming a hazard ratio of 0.67

Enrolment: From November 2014 to November 2015 patients enrolled in 158 centres from 22 countries

Median follow-up: 26.7 months (final analysis)

Overall Survival (OS): Immature at this time

♦ ER+, HER2- MBC

♦ 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 = 493Primary 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)

Goetz MP, et al. Cancer Res 2018;78(suppl 13):Abstract CT040; Goetz MP, et al. J Clin Oncol 2017;35:3638–46.

MONARCH 3: Patient Baseline Characteristics

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.;Goetz MP, et al. Cancer Res 2018;78(suppl 13):Abstract CT040.

Abemaciclib + NSAI(N=328)

Placebo + NSAI(N=165)

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

Racea

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 setting b

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)adjuvant endocrine

therapy

No endocrine therapy 177 (54.0) 85 (51.5)

Aromatase inhibitor

therapy85 (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)

MONARCH 3: Investigator-Assessed PFS

Goetz MP, et al. Cancer Res 2018;78(suppl 13):Abstract CT040.

Pro

gre

ssio

n-f

ree s

urv

iva

l (%

)

0 8 24

0

40

80

36

60

20

4 2016 3212 28

100

Time (months)

Median PFS

Abemaciclib + NSAI: 28.18 months

Placebo + NSAI: 14.76 months

HR 0.540 (95% CI 0.418, 0.698)

p=0.000002

MONARCH 3: PFS in Pre-specified Subgroup Analysis (ITT)


0.25

Placebo + NSAIAbemaciclib + NSAISubgroups

All patients

Metastatic site

Visceral

Bone-only

Other

Endocrine therapy

Prior aromatase inhibitor therapy

Other prior endocrine therapy

No prior endocrine therapy

Disease setting

De novo metastatic

Metastatic recurrent

Measurable disease

Yes

No

Age group

<65 years

≥65 years

Geographical region

North America

Europe

Asia

Progesterone receptor status

Negative

Positive

ECOG PS

1

0

328

173

69

86

85

66

177

135

182

267

61

180

148

60

166

102

70

255

136

192

165

89

40

36

50

30

85

61

99

132

33

91

74

30

93

42

36

127

61

104

HR (95% CI)

0.540 (0.418, 0.698)

0.567 (0.407, 0.789)

0.565 (0.306, 1.044)

0.368 (0.219, 0.619)

0.428 (0.260, 0.705)

0.806 (0.473, 1.375)

0.503 (0.352, 0.717)

0.471 (0.312, 0.712)

0.579 (0.416, 0.805)

0.517 (0.392, 0.681)

0.519 (0.267, 1.009)

0.481 (0.346, 0.667)

0.616 (0.413, 0.918)

0.763 (0.422, 1.381)

0.636 (0.451, 0.896)

0.326 (0.200, 0.531)

0.410 (0.246, 0.685)

0.589 (0.440, 0.789)

0.528 (0.353, 0.790)

0.538 (0.389, 0.746)

Favours abemaciclib Favours placebo

0.5 1 2

Safety and Administration

MONARCH 1: 18-Month Most Common Adverse Events

Lilly does not, nor does it intend to sell products prior to regulatory approval or promote products inconsistent with label, nor does Lilly intend to promote or proactively engage in the discussion of competitive products. Any current external

or promotional activities must be consistent with the approved label and carried out in compliance with all company policies and applicable laws.

a NCI-CTCAE Version 4.03; bN=130 for lab abnormalities listed, except platelet count decreased (N=128); cAbemaciclib is a competitive inhibitor of OCT2, MATE1 and MATE2-K,

efflux transporters of creatinine; cystatin C calculated GFR was not raised; dOne patient who received cytotoxic chemotherapy within the 30-day follow-up window experienced febrile

neutropenia.

Rugo HS, et al. Cancer Res 2017;77(suppl 13):Abstract CT044.

Investigator Assessed TEAEsa >20% (N=132), % Grade 1 Grade 2 Grade 3 Grade 4 All Grades

Diarrhea 41.7 28.8 19.7 0 90.2

Nausea 39.4 21.2 4.5 0 65.2

Fatigue 20.5 30.3 13.6 0 64.4

Decreased appetite 28.0 14.4 3.0 0 45.5

Abdominal pain 22.0 14.4 2.3 0 38.6

Vomiting 23.5 10.6 1.5 0 35.6

Headache 13.6 6.8 0 0 20.5

Pain 12.1 6.8 1.5 0 20.5

Lab abnormalitiesb TEAEsa >40%

Creatinine increasedc 46.9 50.8 0.8 0 98.5

White blood cell decreased 20.0 44.6 27.7 0 92.3

Neutrophil count decreased 16.9 43.8 22.3 4.6 87.7d

Anaemia 30.0 39.2 0 0 69.2

Lymphocyte count decreased 4.6 23.1 13.8 0.8 42.3

Platelet count decreased 28.9 10.2 2.3 0 41.4

Abemaciclib + fulvestrant

(n=441)Placebo + fulvestrant

(n=223)

20 % in either arm, n (%) All Grade 3 Grade 4 All Grade 3 Grade 4

Any 435 (98.6) 241 (54.6) 26 (5.9) 199 (89.2) 46 (20.6) 5 (2.2)

Diarrhea a

381 (86.4) 59 (13.4) 0 55 (24.7) 1 (0.4) 0

Neutropenia b

203 (46.0) 104 (23.6) 13 (2.9) 9 (4.0) 3 (1.3) 1 (0.4)

Nausea 199 (45.1) 12 (2.7) - 51 (22.9) 2 (0.9) -

Fatigue 176 (39.9) 12 (2.7) - 60 (26.9) 1 (0.4) -

Abdominal pain 156 (35.4) 11 (2.5) - 35 (15.7) 2 (0.9) -

Anemia 128 (29.0) 31 (7.0) 1 (0.2) 8 (3.6) 2 (0.9) 0

Leukopenia 125 (28.3) 38 (8.6) 1 (0.2) 4 (1.8) 0 0

Decreased appetite 117 (26.5) 5 (1.1) 0 27 (12.1) 1 (0.4) 0

Vomiting 114 (25.9) 4 (0.9) 0 23 (10.3) 4 (1.8) 0

Headache 89 (20.2) 3 (0.7) - 34 (15.2) 1 (0.4) -

MONARCH 2: Treatment-Emergent Adverse Events in ≥20 % in Either

Treatment Arm (Safety Population)1,2

aGrade 2 diarrhea: abemaciclib + fulvestrant n=140 (31.7%); placebo + fulvestrant n=11 (4.9%)2

bFebrile neutropenia was uncommon [6 patients in the abemaciclib arm (1 incorrectly coded; 1 post-chemotherapy)] and was not associated with severe infection2

1. Sledge GW et al. J Clin Oncol 2017;(Ahead of print)

2. Sledge GW et al. Presented at ASCO 2017. Abstract 1000© 2017 Eli Lilly and Company

MONARCH 3: Treatment-Emergent Adverse Events


Abemaciclib + NSAI

(N=327)

Placebo + NSAI

(N=161)

≥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) -

Anaemia 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 ischaemia [1], cerebrovascular accident [1], pneumonitis [1]); placebo arm: 2 (general physical health

deterioration [1], sudden death [1])

In practice, What does abemaciclib offer compared to

other CDK4/6 inhibitors?

Agent Median PFS PFS HR p CBR ORR

Palbociclib 27.6 months (a) 0.58 <0.0001 85% 55% (Δ 10%)

Ribociclib 25.3 months (b) 0.56 <0.0001 80% 53% (Δ 15%)

Abemaciclib 28.2 months (c) 0.54 <0.0001 78% 59% (Δ 15%)

First Line – Endocrine Sensitive

CDK4/6 & aromatase Inhibitors

Finn RS, et al. N Engl J Med 2016;375:1925–36; (b) Hortobagyi GN et al. ASCO Annual Meeting; 2017; Poster 1038.; Goetz MP, et al. J Clin Oncol 2017;35:3638–46.

(a)ASCO 2017 (c) Verzenio spc 2018

ER[+] HER2[-] MBC : Scenarios where I will consider abemaciclib:

1.- Single agent in heavily pretreated

Monarch 1: Abemaciclib is the only CDK4/6 inhibitor to provide relevant single agent activity

Heavily but not CDK4/6 pretreated ER[+]/HER2[-] MBC: Abemaciclib single agent looks at least

similar in terms of activity to standard chemotherapy (capecitabine, Eribulin or vinorelbine)

Agent Trial N

Prior CT

lines

mBC

ORR, %Median PFS,

months

Median OS,

monthsInvestigator

assessed

Central

review

Abemaciclib Phase II 132 1–2 19.7 17.4 5.9 17.7

Capecitabine Phase III 546 0–2 19.9 11.5 4.2 14.5

Eribulin Phase III 544 0–2 16.1 11.0 4.1 15.9

Dickler MN, et al. Clin Cancer Res 2017;23:5218–24; Kaufman PA, et al. J Clin Oncol 2015;33:594–601.

Variables identified as prognostic

(P<.05)

Univariate Cox model stratified by

treatment arm and study

Variables confirmed as independently

prognostic (P<.05)

Multivariate Cox model stratified by

treatment arm and study

1. Identify prognostic factors common

to MONARCH 2 and MONARCH 3

PFS

2. Describe efficacy for patients by

subgroups of prognostic factors

ORR

Starting Variables

Age Race ECOG PS

Bone-only Metastases

Liver Metastases

Prior Chemotherapy

Lung Metastases

# Organs Involved

Pleural Metastases

PgR Status (local)Tumor Grade (local)

Any Visceral Metastases

Variables identified as prognostic (p<.05) by univariate analysis of PFS, based on a univariate Cox model stratified by treatment arm and study

Bone-only MetastasesLiver Metastases

Race ECOG PS PgR Status (local)Tumor Grade (local)# Organs Involved

Any Visceral Metastases

Variables identified as prognostic (p<.05) were selected in a stepwise a fashion based on a multivariate Cox model stratified by treatment arm and study

ECOG PS

Bone-only MetastasesLiver Metastases

PgR Status (local)Tumor Grade (local)

Company Confidential © 2018 Eli Lilly and Company

Goetz MP et al. Presented at SABCS 2017. Abstract GS06-02

O’Shaughnessy J et al. Presented at AACR 2018. Abstract CT099

Identifying Prognostic Variables – Pooled MBC

MONARCH 3: Treatment-free Interval

aInteraction for treatment-free interval has been adjusted for removal of patients with de novo disease.

O’Shaughnessy J, et al. Cancer Res 2018;78(suppl 13):Abstract CT099.

Pint=0.156a

Abemaciclib

+ NSAI

Placebo +

NSAI HR/

Change in ORRn estimate n estimate

PFS (ITT) 95 27.1 m 40 20.9 m HR 0.780

ORR (MD) 73 56.2% 31 51.6% +4.6%

Abemaciclib

+ NSAI

Placebo +

NSAI HR/

Change in ORRn estimate n estimate

PFS (ITT) 44 29.5 m 32 9.0 m HR 0.441

ORR (MD) 31 54.8% 22 22.7% +32.1%

27

PF

S (

%)

0 4 8 12 32

0

PF

S (

%)

100

0 8 24 32

0

Abemaciclib + NSAI

Placebo + NSAI

Time (months) Time (months)

20 4 12 2016 28

Abemaciclib + NSAI

Placebo + NSAI

20

80

60

40

TFI <36 months TFI ≥36 months

2824

100

20

80

60

40

16

Effect of Abemaciclib Across Prognostic Subgroups (1 of 2)

.55.37 .83

Liver

Mets

No

Liver

Mets

Liver

Mets

No

Liver

Mets

High

GradeL/I

Grade

High

GradeL/I

GradePR- PR+

PR- PR+

*No apparent difference for ECOG 0 [M2: .49, M3: .54] vs ECOG 1 [M2: .66, M3: .53].

Short

TFILong

TFI

Bone

Only Y/N

Bone

only

Not

Bone

Only

.45 .68

Hazard Ratio

Effect of Abemaciclib Across Prognostic Subgroups (2 of 2)

MONARCH 2

placebo

arm (%)

abemaciclib

arm (%)delta

(%)

PgR - Negative 9.68 43.94 34.26

Liver Metastases - Yes 15.25 48.65 33.39

High Grade 20.83 51.32 30.48

Bone-only Disease - No 21.79 49.50 27.70

Low/intermediate Grade 19.51 47.06 27.55

ECOG PS - 0 20.59 47.47 26.89

ECOG PS - 1 22.58 49.17 26.59

PgR - Positive 25.40 50.00 24.60

Liver Metastases - No 24.76 47.83 23.06

Note: Response rates are not reported for bone-only disease since the majority of lesions were not measurable

MONARCH 3

placebo

arm (%)

abemaciclib

arm (%)

delta

(%)

Liver Metastases - Yes 20.00 54.45 33.39

PgR - Negative 27.59 60.66 33.07

High Grade 39.29 67.86 28.57

ECOG PS - 1 44.00 66.96 22.96

Bone-only Disease - No 44.26 61.81 17.55

Low/intermediate Grade 48.00 65.47 17.47

PgR - Positive 50.49 61.27 10.78

ECOG PS - 0 46.34 56.77 10.43

Liver Metastases - No 52.94 61.82 8.88

♦ Liver metastases, bone-only disease, progesterone receptor status, tumor grade,

performance status, and treatment-free interval were identified as significant and

independent prognostic characteristics in the MONARCH 2 and 3 trials

♦ While all subgroups benefited from the addition of abemaciclib, patients with more

concerning clinical characteristics received the greatest benefit from the addition of

abemaciclib to endocrine therapy in the MONARCH 2 and 3 trials

♦ These data are hypothesis generating, and will need to be evaluated in the context of

prospective clinical trials in consideration with other determinants of abemaciclib response

(both pathological and molecular). They may also provide insight into the development of

personalized therapy for women with HR+, HER2- breast cancer

CONCLUSIONS

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