ncpf: assessing early signals of efficacy to guide

NCPF: Assessing Early Signals of

Efficacy to Guide Clinical Development

Richard S. Finn, MD

Associate Professor of Medicine

Division of Hematology/Oncology

Co-director Signal Transduction and Therapeutics Program

Jonsson Comprehensive Cancer Center

Geffen School of Medicine at UCLA

Gefitinib: EGFR TKI

non-small cell lung cancer response

Nucleus

AngiogenesisMitogenesisInhibition of ApoptosisCytoskeleton changes

DNA

Transcription

Factors

COOH

ATP Activated RTK

Cell membrane

Differentiation

PI3-KPO-

AKT -OP

SHC

Grb2

SOS RAS

RAF

MEK

MAPK

PO-PLCγ

PKC

Epidermal Growth Factor Receptor (EGFR)

Human Protein Reference Database (www.hprd.org)450 genes

Herbst RS, et al. JCO 2004

Lynch etal NEJM 2004

Maemondo NEJM 2010

Molecularly Characterized Human Cancer Cell Lines

and Tissue Xenografts

Molecular CharacterizationDefine “target driven” disease

Target Expression

Target “activation”

Global expression profile

Biologic CharacterizationProliferation

Cell Cycle

Apoptosis

Novel Combinations

Correlate

Identify predictive markers for response/resistance

Downstream effects of agent

Identify non-empiric combinations for further

clinical development

Discovery

Early Clinical

Development

Phase II

Science 2014

10

Palbociclib: an Oral Selective

CDK 4/6 Kinase Inhibitor

• Inhibits cell proliferation and cellular DNA synthesis by preventing cell-cycle progression from G1 to S phase

• In vitro activity in retinoblastoma-positive tumor cell lines and primary

tumors

• Low nanomolar concentrations block Rb phosphorylation, inducing G1

arrest in sensitive cell lines

• Specific cell cycle arrest in G1 phase

Fry DW, et al. Mol Cancer Ther 2004;3:1427-38

Menu E, et al. Cancer Res 2008;68:5519-23

Sutherland RL, Musgrove EA. Breast Cancer Res 2009;11:112Palbociclib (PD-0332991)

N

N

N

HN

N+

H2

O

ON

N

CDK (partner) IC50 (mM)

CDK4 (cyclin D1) 0.011



CDK2 (cyclin A) >10

CDK1 (cyclin B) >10

CDK5 (p25) >10

Trastuzumab

Chemotherapy

Anti-estrogens

15%

ER,PR,

HER2–

60%

ER+25%

HER2+

Sörlie T, et al. PNAS. 2001;98:10869-74

0

100

200

300

400

500

600

700

800

900

1000

MB-175

ZR75

-30

CAMA-1

MB13

4

HCC20

2

UACC-893

EFM

19

SUM19

0

EFM

192A

MB-361

HCC15

00

HCC14

19

HCC38

MB-415

MCF-

10A

UACC-812

HCC22

18

ZR75

-1

MDAMB45

3

184A

1

T47D

MCF7

BT-

20

MDAMB43

5

BT4

74

SKBR3

KPL-

1

HCC11

43

MDAMB23

1

HCC13

95

SUM-225

HS57

8T

184B

5

UACC73

2

CAL-51

BT5

49

COLO

824

DU44

75

HCC11

87

HCC15

69

HCC18

06

HCC19

37

HCC19

54

HCC70

MB-436

MB15

7

MDAMB46

8

Subtype

Luminal Non-luminal/post EMT

HER2 amplified Non-luminal

Immortalized

Palbociclib: CDK 4/6 Inhibitor – Breast Panel

Finn RS, et al. Breast Cancer Res. 2009;11(5):R77.

14

Palbociclib Acts Synergistically with

Tamoxifen in ER+ Breast Cancer Cell Lines

Tamoxifen 10000 5000 2500 1250 625 312

Palbociclib 100 50 25 12.5 6.25 3.125

100

80

60

40

20

0

Inh

ibitio

n (

%)

Concentration nM

Tamoxifen 5000 2500 1250 625 312

Palbociclib 50 25 12.5 6.25 3.125

100

80

60

40

20

0

Inh

ibitio

n (

%)

Concentration nM

Tamoxifen 5000 2500 1250 625 312

Palbociclib 50 25 12.5 6.25 3.125

100

80

60

40

20

0

Inh

ibitio

n (

%)

Concentration nM

MCF7CIm = 0.37±0.04

EFM19CIm = 0.45±0.09

T47D

CIm = 0.1±0.01

Palbociclib alone Tamoxifen alone Palbociclib/Tamoxifen combination

Finn RS, et al. Breast Cancer Res. 2009;11(5):R77

● Mean combination index (CIm) <1 indicates synergy for the combinations

PALOMA-1/TRIO-18 Study Design (NCT00721409)

• Randomized phase II open-label trial involving 50 centers in 12 countries

• Key eligibility criteria: inoperable ER+/HER2– locally recurrent disease, postmenopausal status, no prior therapy for advanced breast cancer, no prior CDK inhibitors, no letrozole within 12 months, no prior/current brain metastases, measurable disease (RECIST 1.0) or bone-only disease, ECOG performance status ≤1, adequate bone marrow and renal function

Palbociclib

125 mg/d† +

Letrozole

2.5 mg/d

Letrozole

2.5 mg/d

ER+/HER2−

advanced

breast cancer

*Randomization stratified by disease site and disease-free interval.† Palbociclib schedule 3/1 (28-day cycles).

Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.

1:1

R

A

N

D

O

M

I

Z

A

T

I

O

N

*

n=150

PALOMA-1/TRIO-18 Study Design (NCT00721409)

• Randomized phase II open-label trial involving 50 centers in 12 countries

• Key eligibility criteria: inoperable ER+/HER2– locally recurrent disease, postmenopausal status, no prior therapy for advanced breast cancer, no prior CDK inhibitors, no letrozole within 12 months, no prior/current brain metastases, measurable disease (RECIST 1.0) or bone-only disease, ECOG performance status ≤1, adequate bone marrow and renal function

Palbociclib

125 mg/d† +

Letrozole

2.5 mg/d

Letrozole

2.5 mg/d

ER+/HER2−

advanced

breast cancer

*Randomization stratified by disease site and disease-free interval.† Palbociclib schedule 3/1 (28-day cycles).


1:1

R

A

N

D

O

M

I

Z

A

T

I

O

N

*

Palbociclib

125 mg/d† +

Letrozole

2.5 mg/d

Letrozole

2.5 mg/d

ER+/HER2−

advanced breast

cancer with

CCND1

amplification

and/or loss of

p16

1:1

n=66 n=99

R

A

N

D

O

M

I

Z

A

T

I

O

N

*

Cohort 1 Cohort 2

PFIZER CONFIDENTIAL

Progression-Free Survival

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

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

gre

ss

ion

-Fre

e S

urv

ival

Pro

bab

ilit

y

PD 0332991 + LET (N = 34),

Median PFS = 18.2 mo (CI, 12.6-)

LET (N = 32),

Median PFS = 5.7 mo (CI, 2.8-12.9)

Hazard ratio = 0.35

95% CI, 0.17-0.72

P = 0.006

34 30 27 25 24 21 17 13 10 6 2PD 0332991 + LET

32 22 15 11 9 8 8 7 5 3 3 1 1LET

Number of subjects at risk

Finn RS et al IMPAKT 2012

Progression-Free Survival

by Biomarker Status*

Population Comparison

Number

of

Patients

HR (95% CI) /

P value

Biomarker PositivePD 0332991 + Letrozole

vs. Letrozole

12

9

0.37 (0.10, 1.40) /

0.13

Biomarker NegativePD 0332991 + Letrozole

vs. Letrozole

10

15

0.19 (0.05, 0.67) /

<0.01

Biomarker Status

Unknown

PD 0332991 + Letrozole

vs. Letrozole

12

8

0.59 (0.11, 3.08) /

0.53

PD 0332991 + LetrozoleBiomarker Positive

vs. Biomarker Negative

12

10

1.42 (0.31, 6.43) /

0.65

LetrozoleBiomarker Positive

vs. Biomarker Negative

9

15

0.68 (0.24, 1.94) /

0.47

* CCND1 amplification and/or loss of p16.

18Finn RS et al IMPAKT 2012

PALOMA-1/TRIO-18: PFS (ITT Population)

0

10

20

30

40

50

60

70

80

90

100

Number at risk

Palbociclib plus letrozole

Letrozole

5

1

8

3

28

14

21

6

47

28

36

19

84

81

13

3

67

48

60

36

1


Letrozole

HR 0.488 (95% CI 0.319–0.748; one-sided P = .0004)

Pro

gre

ssio

n-f

ree

surv

ival

, %

0 4 8 12 16 20 24 28 32 36 40

Time, months


PALOMA-1/TRIO-18: PFS (Cohorts)

Cohort 1 Cohort 2

0

10

20

30

40

50

60

70

80

90

100

Pro

gre

ssio

n-f

ree

surv

ival

, %

Number at riskPalbociclib plus letrozole

Letrozole

5

1

8

3

13

4

11

4

18

8

15

5

34

32

8

3

26

15

23

10

1

HR 0.299 (95% CI 0.156–0.572; one-sided P = .0001)

Time, monthsTime, months

0

10

20

30

40

50

60

70

80

90

100

HR 0.508 (95% CI 0.303–0.853; one-sided P = .0046)

15

10

10

2

29

20

21

14

50

49

541

33

37

26


Letrozole

0 4 8 12 16 20 24 28 32 36 40 0 4 8 12 16 20 24 28 32 36 40


February 3rd 2015

• U.S. Food and Drug Administration (FDA) granted

accelerated approval of palbociclib (IBRANCE®)

• Indicated in combination with letrozole, for the treatment of

postmenopausal women with ER+/ HER2- advanced breast

cancer as initial endocrine-based therapy

• This indication is approved under accelerated approval based

on progression-free survival (PFS). Continued approval for

this indication may be contingent upon verification and

description of clinical benefit in a confirmatory trial

(PALOMA-2)

August 2007: in lab

Nov 2007: data shared

September 2008: Phase I open

November 2009: Phase II open

Development of Palbociclib:

First Approved CDK 4/6 Inhibitor

FDA Approved February 2015

Global Approval 2016

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1609709

DOI: 10.1056/NEJMoa1609709

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1609709

Kinase IC50 (nM)*

hCDK4 / cyclinD1 2.0

hCDK6 / cyclinD1 9.9

hCDK1 / cyclinB1 1627.0

hCDK9 / cyclinT1 57.0

hPIM1 50.0

*Abemaciclib mesylate

Abemaciclib (LY2835219)

Change in Tumor Size

(Part D, Abemaciclib)

NCT01394016

a3 non-evaluable patients are not shown. All patients in Part D were

required to have measurable disease. † Patient progressing on endocrine therapy before study entry and continued on that specific therapy

* Indicates HER2+ Tolaney et al. SABCS 2014

October 8th 2015

• U.S. Food and Drug Administration (FDA) granted

“Breakthrough Therapy Designation” as monotherapy for heavily

pre-treaetd patients with refractory hormone-receptor-positive

advanced breast cancer

Genomic Data by Breast Subtype

TCGA Nature 2012

Conclusions:

• The greatest advances in patient outcomes

have come from integrating biology into

clinical care

• Critical use of pre-clinical models can help

guide this process

• Generate hypothesis driven phase 1/2

studies

Canada

P Desjardins, H Lim

France

F Priou, P Soulie

Germany

W Abenhardt, M Clemens, J Ettl, C

Hanusch, A Kirsch, M Schmidt, V

Schulz, C Thomssen

Italy

D Amadori

Ukraine

I Bondarenko, S

Kulyk, Y Shparyk,

N Voytko

Russia

M Kopp, O Lipatov,

S Tjulandin, V

Vladimirov

Spain

M Ruiz Borrego, EM

Ciruelos Gil, JM Gil Gil, MJ

Vidal Losada, M Ramos

Vazquez

Hungary

K Boer, J Erfan, L

Landherr, I Lang, T

Pinter, A Weber, M

Wenczl

US

J Blum, D Chan, R

Dichmann, R Finn,

E Hu, W Lawler, A

Montero, R Patel, N

Robert, A Thummala

South Africa

M Coccia-Portugal

South Korea

SA Im, JS Ro

Ireland

J Crown, M Kennedy,

J McCaffrey, C

Murphy

This study is sponsored and funded by Pfizer Inc.

Acknowledgements

Acknowledgements

Canada

P Desjardins, H Lim

France

F Priou, P Soulie

Germany

W Abenhardt, M Clemens, J Ettl, C

Hanusch, A Kirsch, M Schmidt, V

Schulz, C Thomssen

Italy

D Amadori

Ukraine

I Bondarenko, S

Kulyk, Y Shparyk,

N Voytko

Russia

M Kopp, O Lipatov,

S Tjulandin, V

Vladimirov

Spain

M Ruiz Borrego, EM

Ciruelos Gil, JM Gil Gil, MJ

Vidal Losada, M Ramos

Vazquez

Hungary

K Boer, J Erfan, L

Landherr, I Lang, T

Pinter, A Weber, M

Wenczl

US

J Blum, D Chan, R

Dichmann, R Finn,

E Hu, W Lawler, A

Montero, R Patel, N

Robert, A Thummala

South Africa

M Coccia-Portugal

South Korea

SA Im, JS Ro

Ireland

J Crown, M Kennedy,

J McCaffrey, C

Murphy

The Patients and

Their Families

Network of

Investigators and

Study StaffRevlon-UCLA Women's

Cancer Research Program

Department of Defense

Innovator Award

This study is sponsored and funded by Pfizer Inc.

UCLA

Dylan Conklin

Andrew Kalous

Judy Dering

Sara Hurvitz

Meghan Brennan

Dennis Slamon

TRIO

Mary-Ann Lindsay

Matthieu Rupin

Valerie Bee

Pfizer

Sindy Kim

Sophia Randolph

Camilla Fowst

Eric Kowak

Eric Gauthier

Yuqiu (John) Jiang

Cynthia Huang

Maria Koehler

Mace Rothenberg

Gary Nichols

Acknowledgements

ncpf: assessing early signals of efficacy to guide

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