Molecular portraits/landscape of lung cancer in France Jean-Charles SORIA Frédérique NOWAK Fabien CALVO U981
2 Disclosure Slide Member of the SAB of the french NCI (INCA). Appointed by the Ministry of Health in 2010 Consultancy fees from Abbott, Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, EOS, GSK, Lilly, Merck-Serono, MSD, Pfizer, Roche-Genentech, Servier, Sanofi.
What is lung cancer? The old perception
Current definition of cancer Significantly mutated pathways in adenocarcinoma of the lung a tumor an organ a pathological sample = A definition from the XIXth century Ding et al. Nature 455, 1069, 2008
NCSLC 80% no clear driver or oncogenic event 20% NSCLC Oncogene Addicted LARGE CELL cisplatin + pemetrexed ADENOCARCINOMAS doublet + bevacizumab SQUAMOUS platinum doublet ALK translocated crizotinib EGFR mutated gefitinib, erlotinib 2 nd generation panher
Selecting the right therapy Cancer Patient Tumor type Therapy Oncologist Select therapy based on experience or tumor site Modified from D Weaver, On-Q-ity Wrong match The right drug for the tumor type Wrong match
The DNA Sequencing Revolution
3 Added value of antineoplastic drugs in metastatic lung cancer 80 70 60 50 40 30 20 10 0 Median overall survival (months) 77 One-year survival rate (%) 56,5 50 43,5 40 35 25 15 10 6 7,5 9 10 12 14 10 2-4 1970 1980 1980 1990 1990 2000 2000 2005 2005 2007 2007 2008 2008 2010 2011 Chemotherapy > BSC Pemetrexed 2nd line Bevacizumab + CT 1st line ECOG subgroup analysis ADK Docetaxel 2nd line Erlotinib 2nd/3rd line Alimta 1st line Crizotinib
Institut national du cancer (INCa) The French National Cancer Institute is a health and science agency dedicated to oncology. INCa was created in 2004 INCa is involved in all aspects of the fight: Public health : Observation Prevention - Screening Care: Improve the quality of care for all cancer patients Research: Orient the national cancer policy towards international competition Information: Give every individual the means to help fight cancer 9
The cancer plan 2009-2013 The Cancer Plan 2009-2013: follows on from the Cancer Plan 2003-2007 5 areas : Research Observation Prevention-screening Patient care Life during and after cancer 30 measures/ 118 actions 10
Predictive tests for targeted therapies prescription BCR-ABL translocation: 1- BCR-ABL detection 2- BCR-ABL quantification 3- ABL mutation KIT and PDGFRA mutations HER2 amplification KRAS mutations Chronic Myeloïd Leukemia/ Acute Lymphoblastic Leukemia GIST Breast and gastric cancers Colorectal cancer Imatinib prescription 1- Imatinib prescription 2- Monitoring of minimal residual disease 3- Resistance to Imatinib Imatinib prescription Trastuzumab prescription Panitumumab and cetuximab prescription EGFR mutations Lung cancer Gefitinib and erlotinib prescription ALK translocations Lung cancer Crizotinib prescription BRAFV600 mutation Melanoma Vemurafenib prescription 11
Ensuring equity of access to innovation: France organisation of molecular centres for personalized medicine Provides nationwide molecular diagnostic tests The programme is operated by the INCa/Ministry of Health since 2006 St Cloud/ Paris (2) : AP-HP, Curie Versailles Villejuif Objectives 28 regional centres Lille Perform molecular testing for all patients; Whatever the healthcare institution status (public hospitals, private hospitals ); Partnerships between several laboratories located in University hospitals and cancer centres Regional organization Brest Rouen Caen Rennes Angers Tours Nantes Poitiers Bordeaux Limoges Reims Nancy Strasbourg Mulhouse/ Colmar Dijon Besançon Clermont Lyon Ferrand St Etienne Grenoble Perform high quality tests; leukemia, solid tumours Cooperation between pathologists and biologists Toulouse Montpellier/ Nîmes Nice Marseille 12
Benefit for all patients Molecular tests are performed : For all patients free of charge for patients & hospitals With compensation of local pathologists for sample shipments Ensure that all patients effectively benefit from molecular testing 13
Non contributive results (%) Nombre de patients Rapid access to innovation: EGFR testing in lung cancer June 2009 : gefitinib approval by EMA for patients with activating mutations of EGFR in their tumours Mutations : 9,6% 60 % of external prescriptions 20000 16834 20761 Median time for results : 7 days Non contributive results : 10000 5,2% 1269 2667 5,0 3,7% 0 2008 2009 2010 2011 1,5% 0,0 non amplifiable DNA depleted sample Rate of tumor cells below detection thresold
2011: a new approach for rapid access to targeted therapies Biomarkers for targeted therapies currently evaluated in clinical trials (Phases I to III) tested within INCA platforms Cancer Lung Colon - rectum Breast Melanoma Molecular target EGFR mutations KRAS mutations HER2 exon 20 mutations BRAF mutation PI3KCA mutations EML4-ALK translocation KRAS mutations BRAF mutation microsatellite instability if < 60 years HER2 amplification BRCA1/2 germinal mutations PI3KCA mutations BRAF mutation ckit mutation Source: Inca (Institut national du cancer)
nb of patients 25000 20000 Lung cancer patients screened for a molecular alteration in 2011 9,6 % 25,4 % 15000 1,8 % 10000 5000 0,9 % 2,1 % 4,6 % 0 EGFR mutations KRAS mutations BRAF mutations HER2 mutations PI3KCA mutations ALK translocations No mutation Non contributive results Mutation
Nb of patients Patients screened for a molecular alteration in 2011 25000 20000 15000 10000 5000 0
Nb of patients Nb of patients 25000 Lung cancer patients screened for a molecular alteration in 2011 5000 Lung cancer patients with a molecular alteration in 2011 20000 20761 17153 4500 4000 4358 15000 3500 3000 10000 10017 7731 2500 2000 2009 5000 5329 4543 1500 1000 0 500 0 184 69 111 200
EGFR Mutation screening activity
Funding mechanisms Offer the best treatment to patients considering the cost effectiveness ratio Seed fundings from INCa for the test set-up Performance and cost evaluation Recurrent annual fundings from the French Ministry of Health insurance This programme benefits also from INCa/private partnerships 20
Example of gefitinib treatment : 69M spared cost for the health insurance EGFR testing for lung cancer patients 1.7M (gefinitib treatment: 8 weeks DFS; Mok 2009) 15 000 patients - 1 724 patients + (gefinitib treatment: 38 weeks DFS; Mok 2009) 69M 35M Spared cost of gefitinib treatment Cost of gefitinib treatment 21
Anticipate the launch of new molecules The INCa allocated 3.5M in 2010 and 2.8M in 2011 for the prospective detection of emerging biomarkers For the 20,000 patients with lung adenocarcinoma, additional analysis of : - EGFR mutations conferring resistance to TKI-EGFR; - KRAS, HER2, PI3KCA and BRAF mutations; - ALK translocation. For the 17,000 patients with colorectal cancer, additional analysis of : - BRAF mutation; - MSI test. BRAF and ckit mutations for patients with melanoma Be ready to perform the test as soon as the therapy is available
French-NCI labeled phase I units
Improve interface with research Make the most of the generated data=> implementation of a lung cancer database : funded by INCa, coordinated by IFCT (Intergroupe Français de Cancérologie Thoracique) and molecular genetics centres representatives evaluate the correlation between molecular alteration identification and targeted therapy prescription collect both clinical data, molecular data and clinical follow up of patients Improve interfaces with clinical research Potential evolution of their mission : molecular genetics centres could become testing laboratories for clinical trials Improve interfaces with translational research Upgrade some of the regional platforms to NGS capacities 24
The path of survival of NSCLC patient Specific mutation/amplification MOLECULAR PORTRAIT - Sequencing - CGH, FISH EGFR ALK K-RAS FGFR1 Gefitinib/Erlotinib/PanHER Crizotinib MEKi, sorafenib, HSP90? BJG398, AZD4547, TKI258? Lung Cancer patient No mutation No portrait Histology-driven Tx Standard therapy
Incidence of single driver mutations in adenocarcinoma at IGR: the MSN study Mutation found in 67% STK11 EGFR MET TOP1 ALK (ampl) BRAF HER2 NRAS PDK1 KDR PI3K FGFR4 ALK No mutation KRAS No mutation detected 33% KRAS (28%) EGFR (13%) STK11( 10%) ALK -EML4 (2%) NRAS (2%) BRAF (2%) PDK1 (2%) HER2 (1%) KDR (1%) MET (1%) PI3K (1%) TOP1 (1%) FGFR4 (1%) ALK amplification (2%)
ORAL PRESENTATION FRIDAY APRIL 20 Hall C @ 3:45 PM Upfront genomic testing for patients with non-small cell lung cancer (NSCLC) receiving first-line platinum-based regimen: preliminary result of the MSN study Title of Module/Lecture D. Planchard 1, A. Rahal 1, L. Lacroix 1, M. Ngocamus 1, N.Auger 1, P. Saulnier 1, P. Dorfmuller 2, T. Le chevalier 1, J-C. Soria 1, B. Besse 1 1- Institut-Gustave-Roussy, Villejuif, France. 2- Marie Lannelongue Surgical Center, Plessis Robinson, France.