MOLEKULÁRIS DIAGNOSZTIKA KLINIKAI FELHASZNÁLÁSA

Átírás

1 MOLEKULÁRIS DIAGNOSZTIKA KLINIKAI FELHASZNÁLÁSA Dr. PetákIstván Ph.D., Oncompass Medicine Zrt. University of Illinois at Chicago Istvan Petak, MD, PhD Semmelweis University, Department Of Pharmacology and Pharmacotherapy University of Illinois at Chicago, Department Of Biopharmaceutical Sciences Oncompass Medicine Inc.

2 May 15, 2017 FDA grants breakthrough therapy designation to entrectinib for NTRK fusion positive solid tumors (3%) Secretory Breast Cancer (8 years old girl) NTRK LOXO101 (J. Baselga ESMO 2017)

3 BCR/ABL EML4/ALK KIT M+ EGFR M+ BRAF M+ ROS1+ VEMURAFENIB DABRAFENIB/ TRAMETINIB CRIZOTINIB ENTRECTINIB LORLATINIB CRIZOTINIB CERITINIB GEFITINIB ERLOTINIB AFATINIB IMATINIB SUNITINIB DASATINIB IMATINIB NILOTINIB DASATINIB 2000 NTRK/X ENTRECTINIB LEROTRECTINIB HER2 M+ TRASTUZUMAB PERTUZUMAB LAPATINIB 2018 RET+ LOXO292 CML ALL GIST MELANOMA NSCLC OVÁRIUM GYOMOR NSCLC NEURO- BLASTOMA NSCLC CHOL.C. MELANOMA NSCLC PML VHOL.C TRAMETINIB LORLATINIB ROPOTRECTINIB TPX-0005 ALECTINIB BRIGANTINIB, ENSARTINIB LORLATINIB AFATINIB OSIMERTINIB DASATINIB DASATINIB BOSUTINIB SZOLID DAGANATOK EMLŐ NSCLC NYÁLMIRIGY LAPATINIB NERATINIB TDM1 PAJZSMIRIGY CC NSCLC SZOLID DAGANATOK

4 DRIVERS EGFR KRAS ALK ROS1 BRAF HER-2 C-MET Etc. CAUSE AND CONSEQUENCE CHEMOTHERAPY Proliferation Neo-Angiogenesis Immunotolerance (e.g.jak-pdl1) TARGETED THERAPIES Kinase inhibitors (e.g. afatinib, nintedanib) MABs (cetuximab, bevacizumab, anti-pd1/pdl1)

5 EVOLUTION OF TREATMENT STRATEGY OF CANCER HGP 2013 CGP CHEMOTHERAPY BASED ON RANDOMIZED STUDIES Microscopic symptom-based Tissue diagnostics Immunohistochemistry Biomarkers Companion diagnostics 2017 Biomarker research in (in 4 arms) phase III trials (e.g. KRAS, NRAS, cetuximab, panitumumab, EGFR, gefitinib, erlotinib, afatinib) On Target Single Arm Phase 0 (I/II) accelerated approval (e.g.alk/crizotinib, EGFR/Osimertinib) Molecular profile based tissue agnostic basket and umbrella and adaptive ( Bayesian ) trials (NCI-Match:TAJPUR) Molecular-mechanism based clinical practice and case studies (e.g ROS1/crizotinib, BRAF/dabrafenib-trametinib) Molecular-mechanism based registration of pembrolizumab PRECISION MEDICINE = TARGETING THE MOLCULAR CAUSE OF CANCER

6 HUNTING THE MOLECULAR CAUSE OF CANCER SCIENCE AWARD IMATINIB IN CML (BCR/ABL+ CANCERS) Dr. Brian Druker

7 CLINICAL DISCOVERY OF KIT-IMATINIB DRIVER-DRUG PAIR IN GIST REPORTED IN CASE REPORT AWARD 2014 From molecular biology to Lazarus effect JoensuuH et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N EnglJ Med Apr 5;344(14): Department of Oncology, Helsinki University Central Hospital, Finland.

8 AMPLIFICATION AND MUTATION OF THE EPIDERMAL GROWTH FACTOR RECEPTOR IN METASTATIC LUNG CANCER WITH REMISSION FROM GEFITINIB IN 2003 Schwab R, et al. Modern treatment of lung cancer: case 1. Amplification and mutation of the epidermal growth factor receptor in metastatic lung cancer with remission from gefitinib. J Clin Oncol. 2005

9 RESPONSE TO CRIZOTINIB, A DUAL MET/ALK INHIBITOR, IN A SQUAMOUS CELL LUNG (SCC) CARCINOMA PATIENT WITH C- MET AMPLIFICATION Schwab R, Petak I, et al.major partial response to crizotinib, a dual MET/ALK inhibitor, in a squamous cell lung (SCC) carcinoma patient with de novo c-met amplification in the absence of ALK rearrangement. Lung Cancer Jan;83(1):

10 DRAMATIC RESPONSE IN BRAF M+ CHOLANGIOCARCINOMA PATIENT TO DABRAFENIB+TRAMETINIB 59 yrs, female, chemotherapy-refracter, metastatic extrahepatic cholangiocarinoma (EHCCA), lungand CNS metastases failure of 1st line cisplatin + gemcitabine Tumor sequencing: BRAF- V600E,TP53-Q16fs*28, ATM-R337H, PIK3R1- M326I Kocsis J, et al. J Gastrointest Oncol Apr;8(2):E32-E38

11 NEW DRUGS BY = 47 drugs approved = 2000 in development s 1970s 1980s 1990s 2000s 2010s

12 META-ANALYSIS OF MATCHING VS NON-MATCHING PHASE II TRIALS OF TARGETED THERAPIES (570 STUDIES; 32,149 PATIENTS) Schwaederle M, et al. J Clin Oncol Aug 24.

13 META-ANALYSIS OF MATCHING VSNON-MATCHING PHASE I TRIALS OF TARGETED THERAPIES MATCHED NON-MATCHED Tsimberidou AM, et al. Clin Cancer Res Sep 15;20(18):

14 PRECISION ONCOLOGY

15 ESMO 2017 MESSAGES 1. Perform the multigenetest during 0-1 lines (29,2% chance versus 17,2% in 2+ line (MSKCC) and 7% last line (Goustave- Roussy) to change therapy) Test early and plan ahead. 2. We should treat newly diagnosed cancer with targeted therapy (CML experience) 3. We should consider personalized combination therapy (San Diego experience). (Raselle Kurzrock CureMatch)

16 MIRE VAN SZÜKSÉG A PRECÍZIÓS ONKOLÓGIA KLINIKAI ALKALMAZÁSÁHOZ? 1. MOLEKULÁRIS DIAGNOSZTIKA 2. ORVOSBIOLÓGIAI ÉS BIOINFORMATIKAI INTERPRETÁCIÓ 3. KLINIKAI INTERPRETÁCIÓ MOLEKULÁRIS ONKOTEAMEKBEN

17 MOLEKULÁRIS BIOLÓGIAI INTERPRETÁCIÓS TEAM FELADATAI 1. A molekuláris alterációk bioinformatikai kiszűrése minőségi és mennyiségi paraméterek alapján 2.A molekulárisalterációkfunkcionálisannotációja: kiválasztania szomatikus és herediter driver mutációkat a passenger mutációk, az SNP-k és a VUS-ok közül. A driver alterációk fontossági sorrendjének megállapítása. 3.A molekulárisalterációkfarmakodiagnosztikaiinterpretációja: Összegyűjteni azokat az evidenciákat amelyek az adott molekuláris alterációkat forgalomban lévő vagy klinikai vizsgálatokban lévő hatóanyagokkal pozitív vagy negatív kapcsolatba hozza

18 EVIDENCE-BASED MEDICINE A PRECÍZIÓS ONKOLÓGIÁBAN LEVELS A B C D E DRUGS Approved companion diagnostics Clinical evidence with this drug in this tumor type Clinical evidence with this drug in another tumor type Preclinical evidence with this drug Indirect computational evidence with this drug TRIALS Molecular inclusion criteria Clinical evidence with this compound or sameclass of compounds in this tumor type Clinical evidence with this compound or sameclass of compounds in another tumor type Preclinical evidence with this compound or sameclass of compounds Indirect computational evidence with this compound or same class of compounds Mandatory Complementer Adapted from Van Allen EM, et al. Nat Med Jun;20(6):682-8.

19 MOLEKULÁRIS ONCOTEAM FELADATAI A molekulárisinformációintegrálásaa klinikaiinformációkkal(stage, általános állapot, mellékhatás profil, co-morbiditás, beteg referenciák stb.) 1. Törzskönyvezett célzott kezelések közötti döntés kötelező vagy komplementer biomarkerek alapján) 2. Célzott kezelések, immunterápia és kemoterápiás(vagy más) kezelések közötti döntés(célzott terápia nem adása is molekuláris alapú döntés) 3. Beteg referálása(molecular matching) klinikai vizsgálatokba(vagy éppen ellenjavallata) a molekuláris 4. Célpont alapú célzott kezelések off-label indikációja(vagy kontraindikációja)

20 THE CHALLENGE ,5 million

21 RULE-ENGINES PRECISION ONCOLOGY TUMOR DRIVER GENE TARGET DRUG A A+B (A+B)+B B B B B B C C C

22 EVOLUTION OF PRECISION MEDICINE Single Gene Tests Multigene Tests Decision Support EGFR, HER-2, KRAS, EGFR, HER-2, KRAS, BRAF, PDL1...

23 TOOLS OF PRECISION ONCOLOGY MOLECULAR DIAGNOSTICS BIO- INFORMATICS BIOMEDICAL ANNOTATION AI/ML DECISION SUPPORT CLINICAL DECISION Analitically validated single gene tongs panels, FISH, IHC Quality filtering with validated softwares Curated databases to link alterations toguidelines, registration etc. Standardizedand reproducable ( deterministic ) method (algorithm) to rank therapies based on molecular evidence Decision based on the molecular evidenceand clinical factors (sideeffects, costs, patient preference etc.

24 DRIVER TARGETS IN NON-SMALL CELL LUNG CANCER

25 43 évesférfi, tüdőadenocarcinoma, multiplex nyirokcsomó és csontáttétek 50 génes NGS liquid biopszia EGFR-L747_T751delLREAT (a vizsgált DNS 1,5%-ában), EGFR-K754E (a vizsgált DNS 4,8%-ában), TP53-G154V(a vizsgált DNS 2,8%-ában). KRAS WT PDL1 70%+

26 DRIVER GENETIC ALTERATIONS IN EGFR 194 somaticmutations69% of mutations analyzed as impactful and 31% as functionally neutral. ~84% Del19 /L858R ~16% Uncommon mutations Exon 20 insertions (9%) Uncommon mutations with Del19 or L858R complex mutations (30%)Del19+ 18G721D; Del19+ 19L732P; Del19+ 20L792P; Del19+ 20S768I + 20V774M; Del19+ 21L858R + 21K860I; 21L858R + 18E709X; 21L858R + 20S768I; 21L858R + 20V786E; 21L858R + 20T790M; 21L858R + 20 insertion; 21L858R + 21L833Vl 21L858R + 21K860I; 21L858R + 18G719X +20 insertion Uncommon mutation alone or in combination with other uncommon mutations (61%)18I715V; 18K716E; 18V717G; 18G719X; 19L747P;19 insertion; 20A763_Y764 insfqea; 20S768I; 20G779F; 21L861Q; 18G719X+21L861Q; 18E709X + 18G719X; 18G719X +20S768I; 20T790 M+ 21L861Q; 21M825L +21R831C; 18V703L + 18L707W +18G719X; 18E709X + 18T710S + 18G719X; 19V742F + 19A743 V+ 20H773R Stewart et al. Transl Lung Cancer Res.2015;4:67; 2. Shen et al. Lung Cancer. 2017;110:56-62; Yang et al. J Clin Oncol. 2008;26:2745; 3. Wu et al. Clin Cancer Res. 2011;17:3812; 4 Berger AH, et al. High-throughput Phenotyping of Lung Cancer Somatic Mutations. Cancer Cell Aug 8;30(2):

27 ELSŐ, MÁSODIK ÉS HARMADIK GENERÁCIÓS EGFR TKI PREKLINIKAI AKTIVITÁSA VADTÍPUSÚ ÉS EXON 19, 21 MUTÁCIÓK ESETÉBEN Hirano T Oncotarget Oct 15 PubMed PMID:

28 SURVIVAL BENEFIT WITH AFATINIB IN DEL19 EGFR MUTANTS Yang JC et Lancet Oncol Feb;16(2):

29 "EGFR K754E PROMOTED TUMOR FORMATION IN VIVO. HOWEVER,, LESS SENSITIVE TO ERLOTINIB THAN WILD-TYPE EGFR Berger AH, et al. High-throughputPhenotypingof LungCancerSomaticMutations. CancerCell Aug8;30(2):

30 FIGHTING SECONDARY RESISTANCE

31 TARGETING THE DRIVER ALTERATIONS WITH THE BEST INHIBITORS IN CONTINOUS MEDICINE 1-2 G T790M (60%) 2G 1-2 G 3G 3G BRAF/c-MET/((HER-2)) /KRAS/ALK TKI/CHEMOTHERAPY T790M/C797S 3G + 1G/2G BRAF/c-MET/HER-2/ KRAS/ALK TKI/CHEMOTHERAPY 3G BRAF/c-MET/HER-2 /KRAS/ALK TKI/CHEMOTHERAPY?

32 43 éves férfi, tüdő adenocarcinoma, multiplex nyirokcsomó és csontáttétek Kezelési stratégia: Afatinib, osimertinib, gefitinib(vagy erlotinib?) Progresszió esetén ismételt molekuláris vizsgálat vagy liquid monitorozás T790M, MET, BRAF, KRAS T790M= osimertinib MET, BRAF= crizotinib, dabrafenib PDL1 (70%)= pembrozilumab? P53 kapcsolatos indirekt célpontok: CDK 1,2,9i, CHECKi, ATRi, WEEi, PLK1i = palbociclib, abemaciclib

33 3 ÉVES TÚLÉLÉS EGFR MUTÁNS METASZTATIKUS NEM-KISSEJTES TÜDŐRÁKBAN 1ST-LINE AFATINIB AND 2 ND -LINE OSIMERTINIB* KÖSZÖNÖM A MEGTISZTELŐ FIGYELMÜKET! * POOLED ANALYSIS FROM LUX-LUNG 3,-6 AND -7 SequistL et al., ESMO 2017 poster #1349