Symposium «Evaluation of the Belgian Cancer Plan» Brussels, November 26th, 2012 Personalized oncology in Europe: only a dream if national health systems do not get involved in diagnostics and pivotal cancer clinical trials Martine J. Piccart-Gebhart, MD, PhD Jules Bordet Institute, Brussels, Belgium Université Libre de Bruxelles Breast International Group (BIG aisbl), Chair ESMO President
Empirical Oncology One size fits all What needs to be addressed for this transition to happen? Stratified Oncology Personalized Oncology 2 to 3 sizes fit all One customized shoe for each patient What has been accomplished No overtreatment, no undertreatment, and the right treatment for every patient
FOCUS ON EARLY BREAST CANCER SURGICAL THERAPY = locoregional therapy RADIOTHERAPY = locoregional therapy systemic therapies with anticancer drugs
Is the medical therapy for early BC «personalized» in Europe?
BREAST CANCER «Adjuvant» medical therapies Lung Liver Bone Chemotherapy Endocrine therapy Targeted therapies Localized disease Curable Generalized disease Very difficult to cure
Cure : 70 % With systemic therapy «cure» rate ±85 %...but 60 to 80 percent of women are exposed to chemo for this result, indicating significant overtreatment Node negative BC Relapse : 30 %
Barriers to the development of diagnostic tests in Europe PRECISE DIAGNOSIS PRECISION MEDICINE TODAY IN EUROPE Low willingness to pay for diagnostics in most European countries/lack of knowledge of the limitations of traditional diagnostic tests No clear path towards reimbursement of diagnostic tests (lack of central EU authority to clear validity / utility of tests) Very slow reimbursement very slow uptake contrary to the US! Heterogeneity of reimbursement among EU countries
Treatment decision making in oncology Who can be spared the treatment? Which treatment will work best? Prognostic tests needed Predictive tests needed
Microscope Gene expression signatures (microarray technology) Severe limitations of traditional diagnostics Hope for more robust or reproducible diagnostic methods VERY SLOW PROGRESS IN EVALUATING THE RISK OF RELAPSE!
IMPROVED RISK ASSESSMENT OF EARLY BREAST CANCER THROUGH GENE EXPRESSION PROFILING Microarray Gene-expression profile Good signature ~4% die of breast cancer ~96% survive breast cancer Poor signature ~50% die of breast cancer ~50% survive breast cancer Supported by the EU framework VI programme N Engl J Med, Vol 347 (25), Dec. 2002
Endorsement of innovative diagnostic tests in the EU: the example of Mammaprint TM 2002 2003 2008 2015 Signature published External validation of the signature Conduct of MINDACT MINDACT results Virtually no use in the clinics in Europe
EORTC-BIG Mindact Trial Design 6.000 node negative & 1-3 node positive women 70-gene signature (Mammaprint) risk AND Clinical-Pathological risk Both high risk Discordant cases Both low risk Chemotherapy Randomization No chemotherapy
TailorX Trial Design 9740 Node Negative and HR Positive Oncotype DX RS < 11 RS 11-25 RS > 25 Arm A Hormonal Therapy Randomly assigned Tumor size, menopausal status,planned CT and RT Arm D Hormonal Therapy + Chemotherapy 16% 17% Arm C Arm B Hormonal Therapy + Hormonal Therapy Chemotherapy 67% Courtesy of Dr. Ana M. G. Angulofrom MD Anderson Cancer Center, Houston, Texas
Endorsement of innovative diagnostic tests in the USA: the example of ONCOTYPE DX TailorX will deliver its results in 2015 Today in the US, 60% of patients eligible for the test do have the test ordered by their oncologist
Treatment decision making in oncology Who can be spared the treatment? Which treatment will work best? Prognostic tests needed Predictive tests needed
CHEMOTHERAPY MOLECULAR TARGETED THERAPIES No biomarker of «benefit» has been validated do far! Companion diagnostic tests measuring the «target»
Trastuzumab: a gigantic leap on the road towards personalized medicine for BC Normal HER2 gene in 80 percent of breast cancers Amplified HER2 gene in 20 percent of breast cancers As a result, these cancers express 2 million HER2 receptors on the cell surface, resulting in accelerated growth The anti-her2 monoclonal antibody, trastuzumab, reduces the risk of death of these women by one third
METHODS FOR TESTING HER-2 STATUS OVEREXPRESSION (Protein) AMPLIFICATION (DNA) IHC FISH Necessary and sufficient for access to trastuzumab in most EU countries Large clinical trials with central pathology review indicate a false + rate of 15%! Required in Belgium for access to trastuzumab Also subject to error testing
SUBOPTIMAL DIAGNOSTICS IN THE ERA OF MOLECULAR TARGETED THERAPIES False negative HER2 testing (5-10%) False positive HER2 testing ( 15%) Right HER2 testing but the tumor is resistant to trastuzumab Cost of 1 year of trastuzumab to prevent metastases: 34,000
The Context of Trastuzumab Resistance: Early Disease HERA Trial BIG 1-01 DFS (%) 100 RESISTANT 80 EFFECTIVE 60 40 3-year Events DFS HR 95% CI p value UNNECESSARY 20 218 316 80.6 74.0 0.63 0.53, 0.75 <0.0001 0 0 6 12 18 24 30 36 Months from randomisation No. 1703 1591 1434 1127 742 383 140 at risk 1698 1533 1301 930 606 322 114 -Smith IE, Lancet (2007)
HER2 positive Breast Cancer Moving from stratified to personalized therapy What we know today A relevant «target» has been found but 1) It is not measured well in 20% of breast tumours 2) It is ignored by half of HER2+ cancers What needs to be adressed Lack of support to pathologists Suboptimal accreditation mechanism for labs Suboptimal T.R. in practice changing trials with support mostly from PHARMA Minimal support for tumor banking in the context of prospective clinical trials
HER2 positive Breast Cancer Moving from stratified to personalized therapy What we know today What needs to be adressed Cancer cells rely on signalling networks Full genome sequencing offers a unique opportunity to dissect these networks Europe is neither equipped nor prepared to embark the high speed train of NGS for precision medicine
Directing personalized therapy on the basis of genetic tumor markers Drug selection List of actionable targets Marketing genetic tests Mutations Copy n changes Rearrangements NEXT GEN SEQUENCING
In the U.S., target gene sequencing is knocking at the door of oncologists
Concrete proposals for accelerating personalized cancer medicine in Europe EMPIRICAL ONCOLOGY STRATIFIED ONCOLOGY PERSONALIZED ONCOLOGY Molecular «Diagnostics» needs to be taken seriously «Phase III trials likely to change practice» need EU/government support
The optimal duration of expensive targeted drugs: the example of trastuzumab DFS (%) 100 80 60 RESISTANT EFFECTIVE 40 20 3-year Events DFS HR 95% CI p value 218 316 80.6 74.0 0.63 0.53, 0.75 <0.0001 UNNECESSARY 0 0 6 12 18 24 30 36 Months from randomisation No. 1703 1591 1434 1127 742 383 140 at risk 1698 1533 1301 930 606 322 114 Smith IE, Lancet (2007)
Simulation of costs related to adjuvant trastuzumab administration in the EU 50.000 women found to be HER2 positive HER2 positive pts receive one year of trastuzumab (1y), the duration arbitrarily chosen in almost all pivotal trials If governements outside Finland had also invested in a 3m trastuzumab arm... and if this arm had performed as well as the 1y arm... = 50.000 x 40.000 /pt = 2 billion /year = 50.000 x 10.000 /pt = 500 million /year
Shorter vs Longer Duration Trastuzumab Trials PHARE: French National Cancer Centre Persephone Trial: Cambridge Hellenic Oncology Research Group Finish Breast Cancer Group Universitaria di Modena 3380 patients 4000 patients 478 patients 3000 patients 2500 patients R R 12 months adjuvant Trastuzumab 6 months adjuvant Trastuzumab 12 months adjuvant Trastuzumab 9 weeks adjuvant Trastuzumab M E T A A N A L Y S I S
The ALTTO Trial HER2 positive early breast cancer CHEMOTHERAPY Trastuzumab x 1y Lapatinib x 1y Trastuzumab then lapatinib Trastuzumab combined with lapatinib 8000 women recruited by 939 Institutions in 44 countries
ALTTO in the EU 18 participating countries Only 3 accepted to support the cost of trastuzumab (which is standard of care!) Huge costs for Pharma dramatically reduce budget for T.R.
Proposal Health insurance to cover the costs of «standard therapy» in phase III clinical trials
Concrete proposals to National Cancer Plans for accelerating personalized cancer medicine in Europe Genome medicine: inventory and brainstorming Support to pathologists * Personalized medicine Reimbursement of standard therapy in pivotal trials Possible contribution to pivotal trials for «shorter» treatment arms that Pharma is unwilling to support * To become coordinators of a few top molecular diagnostics centers?
THANK YOU!!