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
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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
● 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).
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
*
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
Palbociclib plus letrozole
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
Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.
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)