2009_-_KRAS_et_thÚranostiques.pptx

PERSONALIZED MEDICINE
THERAPY
THERA
DIAGNOSTIC
NOSTIC
LABYT Charlotte, MAHIEU Aymeric, PECHON Philippe
THERANOSTIC
TARGETED THERAPY
•
Trastuzumab (Herceptin®)
 breast cancer
•
Cetuximab (Erbitux®)
Panitumumab (Vectibix®)
 colorectal cancer
TARGETED THERAPY : HERCEPTIN®
OVER-EXPRESSED IN 25%
OF THE TUMORS
MONOCLONAL
ANTIBODY
HER2
Owen MA, Horten BC, Da Silva MM (2004) HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry. Clin breast
cancer 5:63-69
TARGETED THERAPY : HERCEPTIN®
Clinical trials on « HER2 + » population
Herceptest®
FDA/EMEA Approval:
Herceptin’s labelling includes pathology test
 THERANOSTIC
PERSONALIZED MEDICINE
Colorectal cancer
COLORECTAL CANCER
The fourth largest cause of cancer deaths
worldwide
The third most common cancer in developed
countries
370,000 people in Europe/year
Five-year survival rates: as low as 5%
COLORECTAL CANCER
Before targeted therapies:
First line regimens:
 5FU/LV : Fluorouracil + levofolinate
 FOLFIRI : Irinotecan + 5FU/LV
Second line regimens:
 FOLFOX : Oxaliplatin + 5FU/LV
COLORECTAL CANCER
new opportunities
Monoclonal antibody : Anti-EGFR
Over-expressed in 80%
of the colorectal tumors
COLORECTAL CANCER
Clinical trials : population EGFR+
EGFR test : ICH
COLORECTAL CANCER
Anti-EGFR :
Cetuximab ERBITUX®
Panitumumab VECTIBIX®
ImClone/BMS/Merck
Amgen
COLORECTAL CANCER : ERBITUX®
Second line treatment:
Patients with EGFR-expressing cancer:
- FDA + EMEA : In combination with irinotecan  refractory
to irinotecan
- FDA : As a single agent  intolerant to irinotecan
COLORECTAL CANCER : VECTIBIX®
FDA : SECOND LINE
Patients with EGFR-expressing cancer:
- In combination with irinotecan  refractory to
irinotecan
- As a single agent  intolerant to irinotecan
EMEA : NOT APPROVED !!
COLORECTAL CANCER
Discovery of New Factors
affecting Erbitux/Vectibix
response
COLORECTAL CANCER
•
Clinical trials:
: response to erbitux  22,9% maximal
response rate
 EGFR+
•
Mutation in Kras protein
J Clin Oncol 23:1803-1810
Cancer Res 2006;66: (8). April 15, 2006
COLORECTAL CANCER
KRAS MUTATION
KRAS
EGFR activated  Kras activated
EGFR non activated  Kras non activated
Kras is mutated in
35% of the
colorectal tumors
KRAS
mKRAS
Kras wild type
Kras mutated
KRAS
K-RAS mutation involvement in
the clinical response to AntiEGFR
Market share
First line treatment ?
KRAS & ERBITUX
Progression free survival
27,3%
7,2 %
Mutated Kras
The new england journal of medicine october 23, 2008 vol. 359 no. 17
Wild-type Kras
KRAS & VECTIBIX
Progression free survival
38,7 %
6,6 %
Mutated KRAS
EMEA:Annex 1 summary of product characteristics Vectibix panitumumab AMGEN
Wild-type KRAS
KRAS TEST
KRAS TEST
Many tests available, unknown quality
Homebrew tests
Commercial tests
DxS Dakocytomotion
CE mark in EU (not regulated by EMEA)
FDA does not regulate KRAS tests yet
Knowledge of KRAS statut benefit ?
For patients
For payers
For patients
PFS :
The length of time during and after treatment in
which a patient is living with a disease that does
not get worse.
Side-effects
For patients
2 cases :
KRAS Wild-type
FOLFIRI*
FOLFIRI* + Cetuximab
KRAS Mutant
In combination
FOLFIRI*
FOLFIRI* + Cetuximab
* FOLFIRI = Irinotecan + 5FU/LV
++ 1,2
months
For patients
KRAS Wild-type :
PFS : increase with
addition of Cetuximab
= 1,2 months (p=0,017)
Side effects : increase
with addition of
Cetuximab : Acne like
rash, diarrhea
KRAS mutant
PFS: decrease with
addition of Cetuximab
= 0,5 months not
significant (p=0,47)
Side effects : increase
with addition of
Cetuximab : Acne like
rash, diarrhea
For patients
QALY : quality-adjusted life year
A year in perfect health is considered equal to 1.0
QALY
For example, a year bedridden might have a value
equal to 0.5 QALY
For patients
With addition of Cetuximab you live longer
but with worst quality of life
For payers
Incremental
costs principally
due to the cost
of Cetuximab =
19 473 £
For Payers
Cetuximab is very expensive in term of QALY
(NICE generally accepts 30 000 £ per QALY)
LY = Life Year
Interest of KRAS test for payers
65% of patients are KRAS Wild Type
35% of patients are KRAS mutant
Save money for 35% of patients who will
not profit of cetuximab
Low over cost of the test price 300 £ to
compare to 19 000 £ of a treatment
Nice for the first line treatment of metastasic colorectal cancer
Key opinion leader Advice
“ Treatment with
cetuximab, which is
relatively expensive, would
be most cost-effective if it
were given to patients with
the highest chance of
benefiting from it "
(The new england journal of medicine)
ERBITUX® & VECTIBIX®
EMEA
 FIRST LINE treatment of patients with EGFR-expressing, KRAS
wild-type metastatic colorectal cancer
o

In combination with chemotherapy
Second line
o Single agent in patients refractory/intolerant to irinotecan
FDA
Did not change its position !
FDA vs EMEA
Why are EMEA and FDA looking at
the same data and coming to
different conclusions?
Chronology
Feb 04:
FDA
approved
Erbitux
June 04:
EMEA
approved
Erbitux
Sept 06:
FDA
approved
Vectibix
May 07:
EMEA
rejected
Vectibix
Biocentury, The case for retrospection, december 22, 2008
Biocentury, The jury is no longer out, june 9, 2008
Dec 07:
EMEA
approved
Vectibix
for mCRC
WT KRAS
June 08:
EMEA
approved
Erbitux
for mCRC
WT KRAS
Dec 08:
FDA
accepted
retrospective
analysis
mCRC: Metastatic ColoRectal Cancer
WT: Wild-Type = non mutated
Issue
FDA approved Vectibix in september 2006
EMEA rejected Vectibix in may 2007
EMEA approved Vectibix for KRAS WT in december
2007
FDA not eager to update Vectibix’s label
Why are the FDA and EMEA looking at the same data
and coming to different conclusions?
The case for Vectibix
Feb 04:
June 04:
Sept 06:
FDA approved
Erbitux
EMEA approved
Erbitux
FDA approved
Vectibix
Equivocal clinical data:
8% of mCRC patients response
Survival prolonged by only a few weeks
Failed to improve overall survival vs. BSC
FDA granted approval
results « clinically modest,
but highly significant »
EMEA more
skeptical
BSC: Best Supportive Care
Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008
EMEA’s opinion on Vectibix
Feb 04:
June 04:
Sept 06:
May 07:
FDA approved
Erbitux
EMEA approved
Erbitux
FDA approved
Vectibix
EMEA rejected
Vectibix
Concerns about trial design
Pivotal trial designed in collaboration with FDA
Poor efficacy
Highly toxic (89% dermatologic toxicity)
AMGEN forced to discontinue a late-stage trial
High price
EMEA more cost-sensitive than FDA
 Benefits did not outweigh risks (and costs…)
Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008
Therapeuticsdaily.com
Rejected
by EMEA
Seeing the light at the end of the tunnel?
Feb 04:
June 04:
Sept 06:
May 07:
FDA approved
Erbitux
EMEA approved
Erbitux
FDA approved
Vectibix
EMEA rejected
Vectibix
Vectibix left as a second-line (if not third-line) treatment in
the US
Not marketed in Europe
KRAS mutated patients known to be resistant to Erbitux
(another EGFR inhibitor)
Then, AMGEN retrospectively genotyped patients’ tumors
Retrospective analysis showed difference in response rate
Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008
KRAS & VECTIBIX
Progression free survival
38,7 %
6,6 %
Mutated KRAS
EMEA:Annex 1 summary of product characteristics Vectibix panitumumab AMGEN
Wild-type KRAS
EMEA’s conditionnal approval
Feb 04:
June 04:
Sept 06:
May 07:
Dec 07:
FDA approved
Erbitux
EMEA approved
Erbitux
FDA approved
Vectibix
EMEA rejected
Vectibix
EMEA approved
Vectibix for
mCRC WT KRAS
EMEA’s Scientific Advisory Group on Oncology found
the findings « interesting » but only « exploratory »…
Nevertheless, EMEA granted approval for KRAS WT
patients in tandem with a test
Conditional approval:
Availability of a test
Prospective data from 2 large Phase 3 trials
Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008
Biocentury, Proof is in the pudding, march 31, 2008
Ongoing studies
AMGEN’s PRIME trial
 Results expected late 2009
AMGEN’s 181 trial
 Working along with DxS
Why is the FDA reluctant?
Feb 04:
June 04:
Sept 06:
May 07:
Dec 07:
FDA approved
Erbitux
EMEA approved
Erbitux
FDA approved
Vectibix
EMEA rejected
Vectibix
EMEA approved
Vectibix for
mCRC WT KRAS
Retrospective data = hypothesis generating
Sampling bias
Selective data dredging
Would create a « free-for-all »
 Need for well-designed prospective trials
Unlike EMEA, FDA regulates diagnostics
 Many commercial/homebrew tests
Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008
Biocentury, Proof is in the pudding, march 31, 2008
AMGEN’s counterarguments
Sample size similar to the original trial (427 vs
463 patients)
Original pre-specified endpoints
Vectibix already on US market, KRAS marker has a
high clinical significance
Strong biological rationale
Saves the expenses and side-effects of futile
therapy
Idea of KRAS mutation emerged late after trials
was started (2006)
Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008
Place for an alternative?
Create an alternative regulatory pathway
Little safety risk attached to the diagnostic
Provisional approval based on retrospective
data might be granted if:
Endpoints pre-specified
Sampling non-biased
Provide prospective data later
“In cases like this, in which the test merely
excludes nonresponding patients, is the extra
level of regulation really necessary?”
Nature Biotechnology
Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008
June 2008
Feb 04:
FDA approved
Erbitux
June 04:
EMEA approved
Erbitux
Sept 06:
FDA approved
Vectibix
May 07:
EMEA rejected
Vectibix
Dec 07:
EMEA approved
Vectibix for
mCRC WT KRAS
June 08:
EMEA approved
Erbitux for
mCRC WT KRAS
ASCO Annual Meeting
Results of Erbitux retrospective analysis
EMEA granted Erbitux approval in WT KRAS patients
Key Opinion Leaders encourages KRAS testing
HMO (US) beginning to implement routine and to
establish reimbursement guidelines
Still not approved by the FDA for WT KRAS patients
ASCO: American Society for Clinical Oncology
HMO: Health Management Organisation
December 2008
Feb 04:
FDA approved
Erbitux
June 04:
EMEA approved
Erbitux
Sept 06:
FDA approved
Vectibix
May 07:
EMEA rejected
Vectibix
Dec 07:
EMEA approved
Vectibix for
mCRC WT KRAS
June 08:
EMEA approved
Erbitux for
mCRC WT KRAS
Dec 08:
FDA accept
retrospective
analysis
FDA convened a panel meeting
6 trials: retrospective analysis
Accepted retrospective biomarker analysis
Set guidelines for forthcoming personalized
drugs approval
Benefit segmentation of market
Is it better to have the market of
second line entirely or a part of the
market of first line?
Benefit segmentation of market
55 000 to 83 000 patients so an
increase of 51 % of patients
Treatment duration is longer
32 weeks vs 20 weeks
Patients stratification’s effect on sales
« the pond is smaller but deeper » says
Phyllis Carter, Merck spokeswoman
• Patients living longer
• Use in 1st line
•Deeper market
Predictible
sales increase
• Narrowed market
• Sales decline in 2nd
and 3rd line
A Market in expansion
Sales of Erbitux
Sales in europe
Q3 2007 118 m€
Q3 2008 134 m€
Growth up of 13 %
Erbitux sustained double digit growth due to :
Increasing market penetration in established
2nd/3rd line head & neck cancer indication
Translation/line extension to 1st line in metastatic
colorectal (mCRC)
Merck kgaa
Sales of Erbitux
160
Erbitux sales in europe
140
120
100
80
60
40
20
0
Q1
Q2
Q3
2004
Q4
Q1
Q2
Q3
2005
Q4
Q1
Q2
Q3
2006
Indication EMEA
Head and neck
cancer
Q4
Q1
Q2
Q3
Q4
Q1
2007
Janvier 2007
publication étude
Crystal with Kras
Continuous growth during four years
Q2
Q3
Q4
2008
Mai 2008
First line
with Kras
Sales of Erbitux
Erbitux sales in europe
150.0
145.0
140.0
135.0
130.0
125.0
120.0
115.0
110.0
105.0
100.0
Q1
Q2
Q3
2007
Q4
Q1
Q2
Q3
2008
Mai 2008
1 ère ligne
après Kras
Sales decrease since last quarter
Q4
Are KRAS test really performed ?
Number of KRAS test declarated
In France :
2007: 1 100 test KRAS have been
performed
2008 : January August 4 000 tests have
been performed
2008 : September December 5 700 tests
(estimation)
10000
+1000 %
8000
6000
4000
At medium term 20 000 tests by year
are planned
2000
0
2007
2008
KRAS test are performed in France that means that
in France EMEA recommendation are followed
Réunion des biologistes de France Inca compte rendu de réunion
Sales of Vectibix 2008
Vectibix can’t explain the
sales stagnation
US Erbitux CA repartition without KRAS
test allowed by FDA
CRC represents 50% of sales of Erbitux
The first line represent 35 % of the sale
without MA and growth by 30 % since 3Q07
First line + ASCO
ASCO 2005 : presentation phase II
international study
2nd Q05 : positive data
1st Q06 : large phase III
2nd Q06 WCGIC: 2 positive phase II
3rd Q06 : Crystal Phase III 1241 patients
ASCO 2007 and WCGIC : presentation of
Crystal
Q4 07 : retrospective data analysis show
benefit for wt-KRAS
ASCO 2008 : presentation of
restrospective data analysis of Crystal
Conclusion
Theranostic : a step forward in health care
“tailoring the right drugs, to the
right patients, at the right time”
Patient stratification (
market )
Regulatory update (FDA + EMEA)
KRAS and now… BRAF
BRAF is part of the same enzymatic cascade
(MAPK)
BRAF mutation may explain another 12%
resistance
Adding Sorafenib (BRAF inhibitor) restores the
sensitivity to Cetuximab
Even considering BRAF and KRAS, still 52% of
non-responsive patients…
Is there another mutation involved?
J Clin Oncol. 2008 Dec 10, 26, 5668-70
Symposium on Molecular Targets and Cancer Therapeutics in Geneva on Thursday, October 23 2008
To be continued . . .
Thank you for your attention