Transcript Document

Targeted therapies in lung cancer
- what are the limits?
D. Ross Camidge, MD PhD
Director, Thoracic Oncology Clinical Program
University of Colorado
Halifax, Nova Scotia, 21st October 2011
Disclosures (DRC)
•
•
Employment or leadership Position: None
Advisory Role: Ad Hoc Advisory Boards/Consultations (most recent contact last 3
years):
–
–
–
•
•
Stock Ownership: None
Honoraria: Seminar/Talks to Industry (most recent contact last 3 years).
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2011: Ariad, Array Biopharma, Pfizer
2009: Imclone, Boehringer Ingelheim,
Speakers Bureau/Talks for Industry: None
Research Funding:
–
–
•
•
2011: Ariad, Array Biopharma, AstraZeneca, Aveo, Boehringer Ingelheim, Chugai, Clovis,
Novartis, Synta
2010: Millenium, Pfizer
2009: Imclone, OSI
2010: Eli-Lilly (Translational)
2008: Onyx/Merck (IIT)
Expert Testimony: None
Other Remuneration: None
Negative phase III trials of new agents in NSCLC 2000-2010
Compound
Mechanism of action
N° trials
N
End point
Gefitinib
EGFR TKI
8
5975
OS
Erlotinib
EGFR TKI
4
3661
OS
Afatinib
EGFR/HER2 TKI
1
585
OS
Cetuximab
EGFR antibody
1
676
PFS
Prinomastat
Matrix metalloprotease inhibitor
2
1048
OS
Rebimastat
Matrix metalloprotease inhibitor
1
774
OS
PF-676
Toll-like receptor 9-activating
oligodeoxynucleotide
2
1667
OS
Aprinocarsen
Protein kinase C-alpha antisense
oligonucleotide
2
1286
OS
Bexarotene
Retinoid X receptor activator
2
1235
OS
Lonafarnib
Farnesyl-transferase inhibitor
1
675
OS
Figitumumab
IGF-1R antibody
1
681
OS
Celecoxib
Cox2 inhibitor
1
561
OS
IL-2
Cytokine
1
241
OS
27
19 065
Total
Slide courtesy of JC Soria
Targeted therapies?
NSCLC
Marker
B
NSCLC
Marker
A
Drug A
Drug B
EGFR mutant
selected
NSCLC
Spanish Lung Cancer Group
(Rosell et al, 2009):
Erlotinib in 1st/2nd line
EGFR mutant selected NSCLC
PFS: 14 months
BR.21 (Shepherd et al, 2005):
Unselected
NSCLC
Erlotinib vs. placebo in 2nd/3rd line
unselected NSCLC
PFS: 2.2 vs 1.8 Months
(.4 months difference i.e. < 2 weeks)
P<0.001
Rapid and dramatic tumor response in ALK+ NSCLC to crizotinib
Ou et al, JTO 2010
Best Percent Change from Baseline in
Target Lesions
Objective response details
(all evaluable patients)
% Decrease or increase from baseline
100
N=116
80
ORR (95% CI)
60
Median response duration
48 weeks
Median time to response
8 weeks
40
61% (52, 70)
Disease control rate at 8, 16 weeks
79%, 67%
20
0
–20
–40
–60
–80
Progressive disease
Stable disease
Partial response
–100
Complete response
Camidge et al, ASCO 2011
Potential predictive biomarkers (both
categorical and continuous variables)
• Tumor
–
–
–
–
–
Mutations
Gene rearrangements
Gene copy number
Protein expression/expression level
Transcript(s) levels
• Host
– Immune system
– Vasculature
– Endocrine environment
Personalized medicine in oncology
Unselected large
population, modest
overall benefit
Selected small
population, large benefit
From a drug-perspective, the limits
will only be partly set by the targets
Kinases
ProteinProtein
Interactions
Immune
Effectors
Nucleic
chemo
Acid Beyond
Transcriptional repressors (e.g. YM155)
SiRNA
MiRNA
Gene therapy
•Challenges set by the methods of drug delivery
•But required - given the challenge of most
oncogenic changes being loss of function …
Most of the limits are far more
immediate and more ‘obvious’
• There are no common cancers
– The practical implications of heterogeneity
– The financial consequences of heterogeneity
• Today’s miracles aren’t curing anyone
– The brain is a special place
– Addressing molecular
mechanisms of resistance
– Darwinian oncology
The elephant(s) in the room
1. There are no common cancers
516 analyzed cases: Incidence of
Oncogenic Drivers
Mutation found in 54% (280/516) of
Tumors: 97% mutually exclusive
Kris et al, ASCO 2011
1.1 The practical implications of
heterogeneity in clinical research
Have mutation, will travel
Origin of lung cancer patients (green circles) who participated in crizotinib clinical trials
at the University of Colorado (red circle) (62% from Colorado, 36% from other US
States, 2% International (Johannesburg, South Africa; not shown)).
PFS by molecular status on pemetrexed-based
therapy
Table 2: Multivariate analysis
Parameter
Molecular status
(vs. triple negative)
ALK+
EGFR mutant
KRAS mutant
Line of therapy
Age at diagnosis
Smoking status
(vs. non-smokers)
Histology
(vs. adenocarcinoma)
Adeno-squamous
Large cell
Squamous
HR
95% CI
P value
(Chi squared)
0.36
1.0
0.55
1.57
1.0
0.17-0.73
0.49-2.04
0.28-1.1
1.07-2.31
0.98-1.02
0.0051*
0.9983
0.0952
0.0221*
0.7918
1.06
0.63-1.76
0.8368
0.46
15.1
6.07
0.1-2.06
3.8-59.93
0.73-50.66
0.3093
0.0001*
0.0958
0.5
0.25-1.0
0.0494
0.85
1.59
0.44-1.63
0.96-2.64
Type of therapy
(vs. pemetrexed monotherapy)
Non-platinum combination
Platinum combination
Sex
0.6182
0.0746
* P values <0.05
Camidge et al., J Thoracic Oncol. (2011)
Ongoing randomized trials of crizotinib in
ALK+ NSCLC
PROFILE 1007 (N=318)
● ALK-FISH positive
● 1 prior chemotherapy
(platinum-based)
PROFILE 1014 (N=334)
● ALK-FISH positive, non-squamous
NSCLC
● No prior treatment for advanced
disease
R
A
N
D
O
M
I
Z
E
R
A
N
D
O
M
I
Z
E
Crizotinib 250 mg BID (n=159)
[continuous]
pemetrexed 500 mg/m2 or
docetaxel 75 mg/m2 (n=159)
infused on day 1 of a 21-day cycle
Crizotinib 250 mg BID (n=167)
[continuous]
Crossover on PD
pemetrexed/cisplatin or
pemetrexed/carboplatin (n=167)
infused on day 1 of a 21-day cycle
Tumor samples available from negative phase III trials of
chemo vs new agent or chemo +/- new agent in NSCLC?
Compound
Mechanism of action
N° trials
N
End point
Gefitinib
EGFR TKI
8
5975
OS
Erlotinib
EGFR TKI
4
3661
OS
Afatinib
EGFR/HER2 TKI
1
585
OS
Cetuximab
EGFR antibody
1
676
PFS
Prinomastat
Matrix metalloprotease inhibitor
2
1048
OS
Rebimastat
Matrix metalloprotease inhibitor
1
774
OS
PF-676
Toll-like receptor 9-activating
oligodeoxynucleotide
2
1667
OS
Aprinocarsen
Protein kinase C-alpha antisense
oligonucleotide
2
1286
OS
Bexarotene
Retinoid X receptor activator
2
1235
OS
Lonafarnib
Farnesyl-transferase inhibitor
1
675
OS
Figitumumab
IGF-1R antibody
1
681
OS
Celecoxib
Cox2 inhibitor
1
561
OS
IL-2
Cytokine
1
241
OS
27
19 065
Total
1.2 The financial consequences
of heterogeneity
Every cancer is an orphan?
Orphan disease status:
US = Prevalence <200,000
cases
EU = Prevalence <5/10,000
population
KRAS Mt
NSCLC
20% lung adenocarcinomas
< 20,000 cases/year
1% lung adenocarcinomas
<1000 cases/year
BRAF Mt
NSCLC
You can’t change
the benefit from the
drug in the marker
positive population, so
to be more cost
effective either:
$150,000
$130,000
When low biomarker frequency, cost of screening test
dominates over cost of drug in cost effectiveness analysis.
Lower screening test cost (red line ($500/person) vs blue
line ($1,500/person screened)) shifts this inflexion point
further to the left.
Cost per QALY gained
$110,000
1. Reduce cost of drug
Screening test:
$1,500; drug price
$5k/month
$90,000
Screening test:
$500; drug price
$5k/month
$70,000
2. Reduce price of
screening test per
person positive
3. Screen more
enriched populations
Screening test:
$1,500; drug price
$1k/month
$50,000
Screening test:
$500; drug price
$1k/month
$30,000
$10,000
1
-$10,000
11
21
31
41
Population prevelance rate (percentage)
Flat line if screening cost =
$0/person
Atherley and Camidge, Submitted
The ‘savings’ and ‘cost’ of enrichment
policies
Screening Criteria
Advanced NSCLC
Advanced stage
adenocarcinoma
Advanced stage
adenocarcinoma
/Never smokers
Advanced stage
adenocarcinoma
/Never smokers
/EGFR and KRAS
wildtype
Predicted
Percentage of total Predicted number Predicted number
proportion of ALK initial population
of ALK+ cases
of ALK+ cases
positives
screened
found per 1000
missed per 1000
Initial NSCLC cases Initial NSCLC cases
1.6%
100%
16
0
3.7%
39%
14
2
13.7%
5.80%
8
8
35.9%
2.00%
7
9
Atherley and Camidge, Submitted
2. Today’s miracles aren’t curing
anyone
Is there a median PFS ceiling in targeted
therapy for oncogene addicted NSCLC?
Study
PFS to specific inhibitor in marker
positive population
EGFR mutant NSCLC with EGFR
inhibitor
Spanish Lung Cancer Group (erlotinib) 14 months
EURTAC (erlotinib)
9.7 months
OPTIMAL (erlotinib)
13.1 months
IPASS (gefitinib)
9.5 months
NEJ 002 (gefitinib)
10.8 months
WJTOG 3405 (gefitinib)
9.2 months
ALK rearranged NSCLC with ALK
inhibitor
1001 (crizotinib)
10 months
Potential mechanisms of ‘acquired’
resistance:
• Fail to deliver drug to target
– E.g. Non compliance
– E.g. PK sanctuary sites (e.g. CNS)
• Alter target
– E.g. Gate-keeper or conformational change mutations
in drug target
• Bypass target
– E.g. Develop second oncogenic drivers
– E.g. Downregulate effector pathways
2.1 The brain is a special place
EGFR MT disease: CNS progression
Grommes et al, Neuro-Oncology 2011
1500 mg erlotinib weekly
(high dose intermittent)
44% ORR
Median CNS PFS 2.7 months
(range: 0.8-14.5 m)
Grommes et al, Neuro-Oncology 2011
ALK progression within brain
•29 y/o male with ALK+ NSCLC
•Systemic (body) control but
brain progression
•Blood and cerebrospinal fluid
(CSF) sampling 5 hours after taking
250mg crizotinib
•CSF:plasma ratio = 0.0026
(i.e. <0.3% gets into brain)
?too low to work on ALK
•Caveats: One patient, blood brain ‘barrierness’ may vary, ‘free’ drug may differ
Costa et al, JCO 2011
Who needs new targets? The brain in
clinical trials
Status of extra-CNS
disease
Status of CNS disease
Overall plan
Stable/responding
Progressing
Log PFS for CNS, treat with local
CNS Rx, continue drug and log
extra-CNS PFS timepoint when
occurs
Progressing
Stable/responding
Log PFS for extra-CNS, if able to
give local systemic therapy then
continue drug until CNS
progresses, if systemic therapy
has to change or stop then censor
CNS
Progressing
Progressing
Log PFS both CNS and extraCNS, no specific trial follow up,
ongoing drug at investigator
discretion
1. Only first progression considered.
2. OS follow may continue in any scenario
3. Mandates baseline and routine CNS surveillance on study
2.2 Addressing molecular
mechanisms of resistance
EGFR Mutant:
acquired resistance
mechanisms
Sequist et al,
Science Translational Medicine
2011
Natural selection of resistant clones while most disease
still controlled by crizotinib
Baseline: July 2009
April 2010: New right adrenal SBRT & crizotinib continues
Crizotinib response:Sept 2009
August 2010: New LN –
More SBRT & crizotinib
November 2009
October 2010: New LN –
More SBRT & crizotinib
Drugs for AR: Rapid Deployment
Forces vs. Armies of Occupation?
• Adding in/replacing with each new drug at time
of AR?
• Or combine up front?
• Tolerability of new drug(s)?
Afatinib + cetuximab at MTD.
Responses by mutation
Abstract 7525
ASCO 2011
N = 45
40% confirmed response rate and a clinical benefit rate of 90%
Appears independent of T790M status as assessed in study
2.3 Darwinian Oncology
Pt 9 T790M
present [low levels] in
CTCs
– still ‘responds’
to reversible TKIs
as T790M
is not an all/none
event
Turke et al, Cancer Cell 2010
Maheswaran
et al, NEJM 2008
Diversity
pre-exists
(?hardwired)
In
patients who manifested MET gene amp as mechanism of
Number of CTCs (micropost) and frequency of different alleles (L858R/Del/T790M)
acquired
resistance,
rare amplified
cells were seen pre-EGFR
relative
to control,
alters with treatment
and parallels radiographic
response
(Top panels – [X] = low frequency allele) (Bottom panels –
TKI
treatment
number of amplification cycles for detection – left to right panel at
different points in treatment)
Why is the TKI naïve molecular status as
it is?
• Why don’t T790M and MET amplified EGFR
mutants dominate prior to EGFR TKI?
– Easier to develop the basic model?
– T790M and/or MET plus EGFR MT have some
disadvantage in the absence of a specific
selection pressure?
Changes in Unidimensional CT Measurements (RECIST)
After Discontinuation and Re-Introduction of EGFR TKI
Change from baseline
50%
20%
0%
-30%
EGFR TKI
re-start
stop
3 weeks
3 weeks
Riely et al ‘07
Re-emergence of partial EGFR TKI sensitivity
during time off EGFR TKI therapy (relaxation of
specific selection pressure)
Known L858R
07/07 2nd line erlotinib (PR)
03/09 PD (new MET amp)
Sunitinib +/- pemetrexed trial
until PD in 04/2010
PD on chemo (MET amp)
04/2010 Minor response to erlotinib
rechallenge
PD in 08/2010
Minor short-lived response
to erlotinib rechallenge
CMF09048 Sample: N09-633 A2
Received – 3/12/09 Reported – 3/18/09
Mean MET= 13.07; sd= 4.51
Mean CEP7= 3.17; sd= 1.74
Ratio MET/CEP7 = 4.13
L858R EGFR mutation
05/2006
10 months off
erlotinib selection
pressure
CMF10009 Sample: S10-208 A1
Received – 1/12/10 Reported – 1/15/10
Mean MET= 9.24; sd= 5.17
Mean CEP7= 4.20; sd= 1.41
Ratio MET/CEP7 = 2.20
L858R EGFR mutation
PD pleura/lung/
bones
= 1 month
12/2010
Consolidative
Gem/Carbo SBRT
(PR)
Erlotinib
(PR)
XRT
to bone met
Pem/Sut trial
(PR)
Doc (PD)
Gem (PR)
Clinical trial
(EGFR/MET) ongoing
Biston betularia
(morpha typica)
1848 –
carbonaria
morph first
described
By 1895 – 98%
carbonaria
Natural selection, secondary to industrial soot blackening
the environment, would not have been obvious if all
local insects, rather than just the peppered moth,
had been studied together as a single group.
Changes in Unidimensional CT Measurements (RECIST)
After Discontinuation and Re-Introduction of EGFR TKI
50%
Change from baseline
Drug sensitive cells survive drug
20%
0%
-30%
EGFR TKI
re-start
stop
3 weeks
3 weeks
Riely et al ‘07
‘Sleeper’ cell?
‘Unstable
Variants’?
T
h
e
r
a
p
y
T
h
e
r
a
p
y
Relaxation of dark
blue specific
selection pressure
Relaxation of dark
blue specific
selection pressure
Sleeper cells
or unstable variants
(blue can generate
white and vice
versa)?
Stem cell?
T
h
e
r
a
p
y
Relaxation of dark
blue specific
selection pressure
Repopulation
from universal
progenitor
repeating selection
process again?
Sharma et al, Cell 2010
9 days 33 days
PC-9 EGFR exon 19 del NSCLC cell line
Sensitive to reversible EGFR TKI
0.3% of starting population survive
(drug tolerant persisters – largely
quiescent) – that can be expanded
From quiescent state over time
(drug tolerant expanded persisters).
No loss of mutation, no T790M, no
MET
Panel E: DTPs grown without erlotinib for 9 doublings
reacquire drug sensitivity
Panel F: DTEPs require ~30 passages to reacquire
same drug sensitivity
Drug tolerant persisters
Sharma et al, Cell 2010
HDACI then erlotinib did not prevent
DTEP Eemergence – HDACI must be
present at time of selection pressure
as DTPs continuously generated
Among multiple combinations with
Erlotinib, only HDAC inhibitors and
an IGF1R inhibtor (AEW541) prevented
emergence of DTEPs
Combine targeted therapy in selected population
with additional therapy directed to
purge cancer of its reservoir of resistance?
Clinical outcome:
Response duration? PFS?
(assessing pattern of failure)
The Limits:
• Making non-chemo nucleic acid targeted therapies
deliverable and addressing loss of function drivers
More immediately…
• Addressing heterogeneity:
– In trial design and interpretation
– In the financial aspects of developing new treatments
• Giving the CNS credit for being different
• Optimally monitoring, defining and treating acquired
resistance
• Addressing the existence of ‘reservoirs of resistance’
The End
of the
Beginning…
University of Colorado
Thoracic Oncology Program
Positions now available for outstanding:
Senior Clinical Fellows
Post-Doctoral Scientists
Contact: D. Ross Camidge MD, PhD
[email protected]
Acquired resistance (AR) monitoring
• Most appropriate imaging? PET or not?
• Molecular follow-up? Quantitation issues
Maheswaran et al, NEJM 2008