“Selecting the right patients for
the right trials.”
Paul Waring
Professor of Pathology
University of Melbourne
June 21, 2011
RCPA Genetics short course
Drug development challenges.
Current model of drug development is
becoming unsustainable
Data for 1991-2000 for 10 largest pharmaceutical companies
1 in 14 drugs currently entering development is approved.
Kola & Landis, Nature Reviews Drug Discovery 2004
Designer drugs
Tyrosine kinase pathways in cancer
R R
RAS RAF
SOS
K K
PI3-K pY
pY
GRB2
pY
PTEN
AKT
MEK
STAT
MAPK
Gene transcription
Cell cycle progression
P P
cyclin D1
myc
Cyclin D1
DNA
proliferation/
maturation
chemotherapy/
radiotherapy resistance
Jun Fos
Myc
metastasis
survival/anti-apoptosis
angiogenesis
Trastuzumab (HerceptinTM)
HER2 is amplified in 15-25% of breast
cancers.
Disease-free
survival probability
1.0
0.8
Not amplified
0.6
0.4
Amplified > 5 copies
0.2
0.0
0
12
24
36
48
Time (months)
Slamon et al., Science 235:177-182, 1987
60
72
84
Herceptin’s Effects Correlate with HER2 Expression
Antibody Inhibition (4D5) of Anchorage-Independent Growth
HER2 Expression Level
SK-BR-3
33
BT-474
25
MDA-MB-361
16.7
MDA-MB-453
16.7
MDA-MB-436
3.3
ZR-75-1
3.3
MDA-MB-231
1.2
MCF7
1.2
0
20
40
60
80
Growth Inhibition (%)
100
Her-2 amplified breast cancer
Clinical trial enrichment.
Negative (70%)
- 35 patients
ti t iidentified
d tifi d ffor
alternative therapy
- 3% potential responders
missed
p
- 50 unselected patients
-22% benefit from therapy
Positive (30%)
= will benefit from therapy
= will not benefit from therapy
- 15 patients
ti t selected
l t d
- 67% benefit from therapy
Herceptin®: The Power of Patient Selection
Unselected
Target prevalence
Expected survival benefit
Sample size
Study duration
Selected (HER2+)
Unselected
Selected
25%
1.25m (5.7%)
11,000
349m
100%
5m (22.7%)
1,250
52m
HercepTest® for Her2 screening
- the first FDA - approved predictive test.
Genentech approached DAKO to
co-develop a commercial IHC kit.
Validated during phase III by
demonstrating equivalence
to the clinical trial assay.
Joint approval of drug and test in
Sept 1998.
Pathologists became the decision makers for targeted therapies.
Companion Diagnostic Co-Development
Imatinib (GleevecTM)
Gastrointestinal stromal tumours
GleevecTM and GISTs
Pre
Phospho-KIT
Post (Day 7)
Signal - seeking clinical trials
Hypereosinophilia syndrome
Cyr
Cryptic PDFRA-FIP1LI
rearrangement
EGFR inhibitors
EGFR is overexpressed in many
common carcinomas.
Overexpression of EGFR protein
is rarely the result of gene
amplification (except GBM).
Target for EGFR inhibitorsSmall molecules (NSCLC):
•
Gefitinib (Iressa)
•
Erlotinib (Tarceva)
Monoclonal antibodies (CRC):
•
Cetuximab (Erbitux)
•
Panitumumab (Vetibix)
EGFR TKI in lung adenocarcinoma
Lynch et al. 2004
BR.21: Tarceva monotherapy vs. placebo in
chemotherapy-relapsed (2nd/3rd line) NSCLC
1.00
0.75
Survival rate
TARCEVA
(n=488)
Placebo
(n=243)
Median survival (months)
6.7
4.7
1 year survival rate (%)
31.2
21.5
Overall survival:
Hazard Ratio 0.73 (95% CI, 0.61-0.86)* P<0.001†
0.50
0.25
TARCEVA
Placebo
0
0
6
12
18
Months
24
30
EGFR mutations
Exons
• Activating mutations
– exon 19 deletion
EGFR
18
G719X
3.2%
P-loop
– L858R
• Overall incidence
in population
– ~10% in Western
countries
Deletion
19
48.2%
Insertion
3.7%
– ~30% in Asian
countries
DC helix
Kinase
domain
20
K
A-loop
L858R
21
42.7%
Mitsudomi T, et al. Int J Clin Oncol 2006
EGFR is a founder mutation in lung
adenocarcinoma.
Yatabe Y. Cancer Metastasis Rev 2010
BR.21: Survival and EGFR Mutations
EGFR
Mutation
H. EGFR Mutant
EGFR
Wild
G. EGFR Wild
Type Type
100
Placebo
Log-Rank: p=0.13
HR: 0.73 (0.49,1.10)
100
60
40
20
Tarceva
60
40
20
0
At Risk
Placebo
Tarceva
Placebo
Log-Rank: p=0.45
HR: 0.77 (0.40,1.50)
80
Pe r cen t age
Pe r cen t age
80
Tarceva
0
0
6
12
44
93
18
59
11
34
18
24
Time(Months)
6
9
0
1
30
0
0
Tarceva® median = 8.6 mo (n=93)
Placebo median = 3.5 mo (n=44)
Tsao M-S, NEJM 2005;353:133-44
At Risk
Placebo
Tarceva
0
6
12
19
21
10
11
5
5
18
24
Time(Months)
1
1
0
1
30
0
0
Tarceva® median = 7.4 mo (n=21)
Placebo median = 7.7 mo (n=19)
Sample attrition and assay failure
BR.21
N
%
Total patients enrolled
731
100%
IHC Analysis
325
44%
FISH Analysis
125
17%
EGFR Sequence Analysis
177
24%
Patients with EGFR mutant tumors
45*
6%
Total number of patients enrolled
1079
100%
Total number of patients participating in
optional tissue collection
710
66%
Patients with samples available for analysis
479
44%
Patients with samples suitable for sequencing
274
25%
Patients with EGFR mutant tumors
29
3%
TRIBUTE:
* in 40 patients, 24 were not previously described.
Eberhard DA, JCO 2005;23:5900-9, Tsao M-S, NEJM 2005;353:133-44
EGFR inhibitor prolongs survival in EGFR
mutant tumours
1.0
Erlotinib (n=82)
Gem/carbo (n=72)
PFS probability
0.8
HR=0.16 (0.10–0.26)
Log-rank p<0.0001
0.6
0.4
0.2
4.6
0
0
Patients at risk
Erlotinib 82
Gem/carbo
72
5
13.1
10
15
20
Time (months)
70
51
20
2
26
4
0
0
Mechanisms of acquired resistance dodging the magic bullets.
Disease
Gene
Drug
Resistance Alternate
mechanism drug
NSCLC
EGFR
Tarceva
Iressa
T790M /
D761Y
Met Ampl
XL647 /
HK1272
Met SMI
CML
ABL
Gleevec
T351I
+20 others
Dasatinib*
GIST
KIT
Gleevec
V654A
+14 others
D842V
Sutent*
Gleevec
T674I
PKC412
PDGFRD
HES
EGFR T790M
Pao W et al. PLoS Medicine 2005
PDGFRD
EGFR TKI Roller-Coaster
Tarceva
BR21
Positive
Iressa &
Tarceva
Ph II’s
Positive
Mutation
is “it”
Mutation
does not
predict
survival
in BR21.
Ph III INTACT
I/II, TALENT,
TRIBUTE
Negative
2000
2003
FISH
is “it”
PhIII
IPASS
Adjuvant positive
study in
FISH +
Commercial
concerns
over patient
selection
Ph IV
SATURN
IHC
negative
Iressa
ISEL
Negative
2004
2005
2008
Targeted therapies
The right
trial
The right
target
The right
patients
(biomarkers)
The right
drug
The right disease subset
(indication)
Break-apart FISH assay
2p23 region
t(2;5) ALK gene
breakpoint region
3’
~250 kb
5’
~300 kb
EML4-ALK frequency:
~4-10%
Primary lung adenocarcinoma
Soda et al., Nature 448: 561-566, 2007
Tumor Responses to PF-02341066 for
Evaluable NSCLC ALK Patients
Tumor Size Change and Treatment Duration (weeks)
% of best change from baseline
3 10
7
10 19 30
20 16 11
16 15 59%
6 22 2 RR
Overall
(17/29)
17 21 16
8 41 11 26 41 46 19
40
20
0
-20
-40
3 10
7
6 22 2
16 15 20
16
-60
11 10
19 30
17 21
16 8 41 11
26 41
46
-80
-100
19
Green - PR
Blue - SD
Black - PD
Two patients had clinical progression and discontinued without radiographic confirmation.
Vemurafenib inhibits BRAFV600E Kinase
RTK
RAS
40-60% of melanomas
BRAF
RAF V600E
VEMURAFENIB
ATP
MEK
ATP
ERK
Cellular
Proliferation
(PLX4032, RO5185426)
PLX4032
Progression-free survival (%)
BRIM-3 Progression-free survival
100
Hazard Ratio 0.26
90
(95% CI; 0.20 - 0.33)
Log-rank P<0.0001
Vemurafenib (N=275)
80
70
Dacarbazine
(N=274)
60
50
40
30
Median 5.3 mos
Median 1.6 mos
20
10
0
0
1
No. of patients in follow up
2
3
4
5
6
7
Months
8
9
10
11
12
BRIM -3 Overall survival
100
Vemurafenib (N=336)
Est 6 mo survival 84%
Overall survival (%)
90
80
70
Dacarbazine (N=336)
Est 6 mo survival 64%
60
50
40
30
Hazard ratio 0.37
20
(95% CI; 0.26 - 0.55)
Log-rank P<0.0001
10
0
0
1
2
3
4
5
6
7
Months
8
9
10
11
12
Cetuximab (ErbituxTM).
75% expression
10% amplified Ligand
0% mutant EGFR
Cetuximab
K K
PI3K
Grb-2
SOS
RAS
RAF
PTEN
AKT
mTOR STAT3/5
Survival
MEK
MAPK
Proliferation
Ligand
EGFR
Cetuximab
K K
PI3K
Grb-2
SOS
RAS 35% mutant
RAF
PTEN
AKT
mTOR STAT3/5
Survival
MEK
MAPK
Proliferation
Ligand
EGFR
Cetuximab
K K
15-25% mutant
PI3K
Grb-2
SOS
RAS 35% mutant
RAF 10% mutant
40% loss PTEN
AKT
mTOR STAT3/5
Survival
MEK
MAPK
Proliferation
Mutations in PTCH and SMO are found in
hereditary & sporadic basal cell carcinomas
Inactive receptor
Loss of PTCH mutations
Ligand-dependent activation
Activating SMO mutations
•PTCH/Gli1
•IGF
•Cyclin D1
•Other targets
Tumour growth
A naturally occurring inhibitor of SMO showed
that the Hedgehog pathway was drugable.
Shepherds in Idaho
in 1950s identified
cyclopic lambs.
Pregnant ewes
feeding on
corn lily plants.
The teratogen,
cyclopamine,
targets SMO.
GDC-0449
Phase 1 trial GDC-0449 in metastatic BCC
Partial response with multiple daily doses (150 mg) of GDC-0449
Baseline
After 8 weeks
After 16 weeks
8/9 patients treated so far have had benefit.
BRCA1&2 - deficient tumors are defective in
homologous recombination
PARP repairs DNA single strand breaks
Synthetic lethality
Guha M. Nature Biotechnology 2011: 29:373-374
Trade name
Target
Type
Company
TGA approved use. ( *pending)
Trastuzumab
(Herceptin®)
HER2
McAb
Genentech / Roche
Met and adjuvant HER2+ breast cancer
Metastatic HER2+ gastric cancer*
Cetuximab
(Erbitux®)
EGFR
McAb
Imclone / BMS / Merck
EGFR + KRAS wt Metastatic CRC
H & N SCC
Panitumumab
(Vectibix®)
EGFR
TK SMI
Amgen
EGFR + KRAS wt Metastatic CRC
Gefitinib
(Iresssa® )
EGFR
TK SMI
AstraZeneca
1L EGFR mut metastatic NSCLC*
Erlotinib
(Tarceva®)
EGFR
TK SMI
Genentech / OSI / Roche
2L NSCLC
1L EGFR mut metastatic NSCLC*
Crizotinib
ALK
SMI
Pfizer
EML4-ALK+ NSCLC*
Imatinib
(Gleevec®)
ABL
KIT
PDGFR
TK SMI
Novartis
CML
Adult Ph+ ALL
GIST
DFSP
Hypereosinophilia syndrome
PDGFR rearranged MDS/MPD
Systemic mastocytosis
Dasatinib
(Sprycel®)
ABL
TK SMI
BMS
Gleevec resistant CML
Gleevec resistant Adult Ph+ ALL
Sunitinib
(Sutent®)
KIT
VEGFR
TK SMI
Pfizer
Gleevec resistant GIST
Met renal cell cancer
Vemerafenib
BRAF
TK SMI
Plexikon / Roche
BRAF V600E + metastatic melanoma*
Olaparib
PARP
SMI
AstraZeneca
BRCA1 & 2 mut Breast cancer*
BRCA1 & 2 mut Ovarian cancer*
Pharmaceutical oncology pipeline
Project
Initiation
Clinical Candidate
Selection
Research
IND Filing
Phase III
Decision
Early
Development
Phase I
Phase II
Phase III
Success rate
is now 1 in 5