La presentazione è in caricamento. Aspetta per favore

La presentazione è in caricamento. Aspetta per favore

Marcello Tiseo U.O. Oncologia Medica Azienda Ospedaliero-Universitaria di Parma EGFR e meccanismi di resistenza agli inibitori.

Presentazioni simili


Presentazione sul tema: "Marcello Tiseo U.O. Oncologia Medica Azienda Ospedaliero-Universitaria di Parma EGFR e meccanismi di resistenza agli inibitori."— Transcript della presentazione:

1 Marcello Tiseo U.O. Oncologia Medica Azienda Ospedaliero-Universitaria di Parma EGFR e meccanismi di resistenza agli inibitori

2 Mutazioni di EGFR e TKIs: punti fermi Netto impatto dei trattamenti in OS: 2-3 anni Netto impatto dei trattamenti in OS: 2-3 anni 8 studi random di I linea vs CT 8 studi random di I linea vs CT - TKI > CT in RR (60-70%), PFS (9-13 mesi), tossicità 3 TKIs in I linea (2 rev e 1 irr) 3 TKIs in I linea (2 rev e 1 irr) - non disponibili confronti diretti di fase III Efficacia in qualunque linea di terapia Efficacia in qualunque linea di terapia Tossicità peculiari Tossicità peculiari Instaurarsi di resistenza: Instaurarsi di resistenza: - differenti meccanismi e diverse potenziali strategie

3 Mutazioni di EGFR e TKIs: quesiti aperti Quale il migliore TKI in I linea Quale il migliore TKI in I linea Circa 30% dei pazienti mutati non risponde a TKI Circa 30% dei pazienti mutati non risponde a TKI Scarsa conoscenza in caso di mutazioniuncommon e in caso di combinazione di diverse mutazioni Scarsa conoscenza in caso di mutazioniuncommon e in caso di combinazione di diverse mutazioni Non chiara efficacia in caso di T790M de novo Non chiara efficacia in caso di T790M de novo Non chiara definizione della terapia alla progressione a TKI Non chiara definizione della terapia alla progressione a TKI

4 Mutazioni di EGFR e TKIs: quesiti aperti Quale il migliore TKI in I linea Quale il migliore TKI in I linea Circa 30% dei pazienti mutati non risponde a TKI Circa 30% dei pazienti mutati non risponde a TKI Scarsa conoscenza in caso di mutazioniuncommon e in caso di combinazione di diverse mutazioni Scarsa conoscenza in caso di mutazioniuncommon e in caso di combinazione di diverse mutazioni Non chiara efficacia in caso di T790M de novo Non chiara efficacia in caso di T790M de novo Non chiara definizione della terapia alla progressione a TKI Non chiara definizione della terapia alla progressione a TKI

5 Mutations in the EGFR gene Riely, et al. Clin Cancer Res 2006 Exons 1–16 Exons 18–24 Exons 25–28 EGFR transcript Exon 17 Extracellular domain Trans- membrane domain Tyrosine- kinase domain Regulatory domain Confer sensitivity/resistance to EGFR TKIs Unclear effect on sensitivity to EGFR TKIs Deletions L858R G719A/S L861X P694X V700D E709X G735S V738F V742A T751I S752Y D761N A763V N765A S768I T783A L792P L798F G810S N826S L838V T847I I853T A859T E866K L833V H835L H850N V851X G863DA864T L730F P733L E746K D761Y D770_N771 insNPG T790M EGFR TKI = tyrosine-kinase inhibitor

6 Activity of afatinib in uncommon epidermal growth factor receptor (EGFR) mutations: Findings from three prospective trials of afatinib in EGFR mutation- positive lung cancer J. C.-H. Yang 1, L.V. Sequist 2, S. L. Geater 3, C.-M. Tsai 4, T. Mok 5, M. H. Schuler 6, N. Yamamoto 7, D. Massey 8, V. Zazulina 8, Yi-Long Wu 9 1 National Taiwan University Hospital, Taipei, Taiwan; 2 Massachusetts General Hospital, Boston, MA, USA; 3 Division of Respiratory and Respiratory Critical Care Medicine, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand; 4 Taipei Veterans General Hospital, Taipei, Taiwan; 5 The Chinese University of Hong Kong, Hong Kong; 6 West German Cancer Center, University Duisburg-Essen, Essen, Germany; 7 Shizuoka Cancer Center, Shizuoka, Japan; 8 Boehringer Ingelheim Limited, Bracknell, UK; 9 Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China

7 LUX-Lung clinical trials and eligibility *EGFR mutations detected by TheraScreen EGFR29 test: – Common: 19 deletions in exon 19 and L858R in exon 21 – Uncommon: 3 insertions in exon 20, L861Q, T790M, G719S, G719A and G719C, S768I Treatment Line of treatment Mutation test LUX-Lung 2 Phase II N=129 Afatinib First- and second- line (after chemo) Direct sequencing (central) LUX-Lung 3 Phase III N=345 Afatinib vs. Pemetrexed/ cisplatin First-lineEGFR29* (central) LUX-Lung 6 Phase III N=364 Afatinib vs. Gemcitabine/ cisplatin First-lineEGFR29* (central)

8 EGFR mutation-positive patients in LUX-Lung trials Patients with uncommon mutations treated with afatinib n=23 n=26 Del19 n=408 L858R n=330 Uncommon n=100 LUX-Lung 2 Phase II N=129 n=52n=54n=23 LUX-Lung 3 Phase III N=345 n=170n=138n=37 LUX-Lung 6 Phase III N=364 n=186n=138n=40 Uncommon n=75

9 Subgroups of patients with uncommon mutations Categories De novo T790M Exon 20 insertions Other (exon 18, 19, 20, 21) n= Mutations (n) T790M alone (3) T790M+Del19 (3) T790M+L858R (6) T790M+G719X (1) T790M+L858R+G719X (1) n/a L861Q alone (12) G719X alone (8) G719X+S768I (5) G719X+L861Q (3) E709G or V+L858R (2) S768I+L858R (2) S768I alone (1) L861P alone (1) P848L alone (1) R776H+L858R (1) L861Q+Del19 (1) K739_1744dup6 (1) Total analyzedT790M+Exon 20 insertionOther %2.7%4.5%

10 Outcome in patients with uncommon mutations Exon 20 insertions (n=20) De novo T790M (n=14): T790M alone, T790M+Del19, T790M+L858R, T790M+G719X, T790M+L858R+G719X Other (n=33): L861Q, G719X, G719X+S768I, G719X+L861Q, E709G or V+L858R, S768I+L858R, S768I, L861P, R776H+L858R, L861Q+Del19, K739_1744dup6 T790MExon 20 insOther Response rate (%) DCR (%) PFS (months) OS (months)

11 Reversible EGFR-TKIs 1 Afatinib 2,3,4 EGFRN RR (%) PFS (months) OS (months) N RR (%) PFS (months) OS (months) Exon Wild-type Exon 20 insertion G L Other Wu J et al. Clin Cancer Res 2011; 2 Yang Y et al. WCLC 2013; 3 Ahn et al, ESMO 2012; 4 Sequist et al JCO 2013 How afatinib compares to reversible EGFR-TKIs in presence of uncommon EGFR mutations? Istituto Toscano Tumori-Livorno-Italy

12 Mutazioni Uncommon Yang et al: considerazioni Il più grande data set prospettico sulle mutazioni uncommon, trattate in modo omogeneo Il più grande data set prospettico sulle mutazioni uncommon, trattate in modo omogeneo Conferma che costituiscono circa 10% delle mutazioni di EGFR Conferma che costituiscono circa 10% delle mutazioni di EGFR Gruppo eterogeneo Gruppo eterogeneo Efficacia modesta in caso di inserzione del 20 e T790M de novo degli attuali EGFR TKIs Efficacia modesta in caso di inserzione del 20 e T790M de novo degli attuali EGFR TKIs Efficacia contro altre mutazioni uncommon (G719, L861) simile alle comuni e simile fra TKIs Efficacia contro altre mutazioni uncommon (G719, L861) simile alle comuni e simile fra TKIs

13 Mutazioni Uncommon Yang et al: considerazioni Il più grande data set prospettico sulle mutazioni uncommon, trattate in modo omogeneo Il più grande data set prospettico sulle mutazioni uncommon, trattate in modo omogeneo Conferma che costituiscono circa 10% delle mutazioni di EGFR Conferma che costituiscono circa 10% delle mutazioni di EGFR Gruppo eterogeneo Gruppo eterogeneo Efficacia modesta in caso di inserzione del 20 e T790M de novo degli attuali EGFR TKIs Efficacia modesta in caso di inserzione del 20 e T790M de novo degli attuali EGFR TKIs Efficacia contro altre mutazioni uncommon (G719, L861) simile alle comuni e simile fra TKIs Efficacia contro altre mutazioni uncommon (G719, L861) simile alle comuni e simile fra TKIs

14 Clinical, structural and biochemical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer Hiroyuki Yasuda, MD 1* ; Eunyoung Park, PhD 2* ; Cai-Hong Yun, PhD 6* ; Natasha J. Sng, MS 1 ; Wee-Lee Yeo, MD 1 ; Antonio R. Lucena-Araujo, PhD 1 ; Sohei Nakayama, MD 1 ; Kota Ishioka, MD 1 ; Mark S. Huberman, MD 1 ; David W. Cohen, MD 1 ; Norihiro Yamaguchi, MD, MPH 1 ; Megan Hanna, PhD 2 ; Geoffrey R. Oxnard, MD 2 ; Christopher S. Lathan, MD, MPH 2 ; Teresa Moran, MD 3 ; Lecia V. Sequist, MD, MPH 3 ; Jamie E. Chaft, MD 4 ; Gregory J. Riely, MD, PhD 4 ; Maria E. Arcila, MD 4 ; Ross A. Soo, MBBS 5 ; Matthew Meyerson, MD, PhD 2 ; Michael J. Eck, MD, PhD 2# ; Susumu S. Kobayashi, MD, PhD 1# ; Daniel B. Costa, MD, PhD 1# 1 Beth Israel Deaconess Medical Center, 2 Dana-Farber Cancer Institute, 3 Massachusetts General Hospital, all at Harvard Medical School, Boston, MA, USA; 4 Memorial Sloan Kettering Cancer Center, New York, NY, USA; 5 National University Cancer Institute, National University of Singapore, Singapore; and 6 Peking University Health Science Center, Beijing, China Daniel B. Costa, MD, PhD, MMSc Division of Hematology/Oncology BIDMC WCLC 2013 (October 29 th 2013) ABSTRACT # 747 MO16 - Prognostic and Predictive Biomarkers IV Funding source:

15 EGFR exon 20 insertion mutations: cluster within or following the regulatory C-helix of EGFR and most, outside A763_Y764insFQEA, are insensitive to reversible EGFR TKIs EGFR mutation type in vitro sensitivity to EGFR TKIs (erlotinib or gefitinib) exon 18 G719X sensitive exon 19 deletions sensitive exon 19 insertions sensitive exon 20 A763_Y764 insFQEA sensitive exon 20 insertions (others) resistant exon 20 T790M resistant exon 21 L858R sensitive exon 21 L861Q sensitive

16 EGFR exon 20 insertion mutated non-small-cell lung cancers (NSCLC): All tumors, outside EGFR-A763_Y764insFQEA-bearing ones, displayed lack of objective radiographic or clinical responses to reversible EGFR TKIs (gefitinib and erlotinib) in a retrospective review of five academic medical centers in the United States and Singapore *

17 Implications of the crystal structure of typical EGFR exon 20 insertion: Crystal structure of D770_N771insNPG (insNPG). The inserted residues form a wedge at the end of the C-helix that may effectively lock the helix in its inward, active position. Structure and enzyme kinetic studies, shows that this insertion mutant binds EGFR TKIs with a binding mode and apparent affinity similar to that of wild-type (WT) EGFR

18 Progression-free survival according to treatment group and T790M mutation status G3: Chemotherapy and T790M present (n=28) G1: Erlotinib and T790M present (n=34) G4:Chemotherapy and T790M absent (n=17) G2: Erlotinib and T790M absent (n=16) 5·19·715·86·0 Patients at risk G2 G4 G3 G1 Rosell et al, Poster WCLC 2013

19 Pretreatment evaluation of T790M mutation and its correlation with response to tyrosine kinase inhibitors (TKIs) or chemotherapy in advanced non- small cell lung cancer (NSCLC) patients with activated EGFR mutations Francesco Grossi, Maria Giovanna Dal Bello, Erika Rijavec, Claudio Sini, Carlo Genova, Giulia Barletta, Carlotta Defferrari, Simona Coco, Anna Truini, Angela Alama, Simona Zupo, Mariella Dono Lung Cancer Unit National Institute for Cancer Research Genova, Italy 15 th World Conference on Lung Cancer Prognostic and Predictive Biomarkers V Sydney, 30 October 2013

20 363 Tested for EGFR mut 58 (16 %) EGFR MUT RT-PCR Sanger sequencing 305 (84 %) EGFR WT 4 * (6.9 %) T790M + 17 (40.5%) T790M + 25 § (59.5 %) T790M - 54 (93.1 %) T790M - 42 (77.7 %) LNA-PCR/Sanger sequencing 12 (22.2 %) Insufficient tissue Selection of patients and samples 19 T790M+ * 2 pts ineligible: 1 second primary tumor, 1 treatment data not available (second opinion) 23 T790M- §2 pts ineligible: early stages

21 PFS* & OS according to the EGFR T790M status …. T790M mutated Median PFS= 8.55 months __ T790M wild-type Median PFS= 7.99 months *First-line PFS …. T790M mutated Median OS= months __ T790M wild-type Median OS= months

22 RR and PFS to first-line treatment with EGFR TKIs or CT

23 RR and PFS to first treatment with afatinib or erlotinib/gefitinib

24 EGFR T790M de novo: considerazioni Con metodiche più sensibili percentuale più elevata (da circa 4-5% a 40%) Con metodiche più sensibili percentuale più elevata (da circa 4-5% a 40%) Arterfatto in paraffina, non in frozen? High T790M detection rate in TKI-naïve, Truth or Artifact ? Ye et al, JTO 2013 Arterfatto in paraffina, non in frozen? High T790M detection rate in TKI-naïve, Truth or Artifact ? Ye et al, JTO 2013 Probabilità di risposta a TKI inferiore Probabilità di risposta a TKI inferiore Pazienti con buona prognosi Pazienti con buona prognosi Quale la migliore strategia? TKI o CT come prima linea? Quale TKI? Quale la migliore strategia? TKI o CT come prima linea? Quale TKI?

25 Meccanismi di resistenza a EGFR-TKIs

26 Clinical EGFR Inhibitors DrugStageCovalentOvercome T790MStructure GefitinibApprovedNo Quinazoline ErlotinibApprovedNo Quinazoline DacomitinibPhase IIIYesNoQuinazoline AfatinibApprovedYesNoQuinazoline AP26113Phase I/IINo?Pyrimidine CO-1686Phase IYes Pyrimidine AZD9291Phase IYes Pyrimidine Janne, Mini Symposium MS27, WCLC 2013 Third generation compounds selectively target EGFR T790M They are 30- to 100-fold more potent against EGFR T790M and up to 100-fold less potent against WT EGFR than quinazoline-inhibitors

27 Nuovi farmaci alla resistenza: CO-1686 e AZD9291 First-In-Human Evaluation of CO-1686, an Irreversible, Highly Selective Tyrosine Kinase Inhibitor of Mutations of EGFR (Activating and T790M) Soria et al AZD9291: an irreversible, potent and selective tyrosine kinase inhibitor (TKI) of activating (EGFR+) and resistance (T790M) mutations in advanced NSCLC. The AURA study Ranson et al

28 CO-1686: BaselineCO-1686: 3W Afatinib: BaselineAfatinib : 3W Afatinib dosed at MTD - potency limited by WT EGFR inhibition CO-1686 generates complete responses in L858R/T790M transgenic model

29 * 67% RECIST response rate in evaluable T790M+ patients treated at 900mg BID EGFRi immediately before CO-1686 * Weeks on treatment ** * * * * * Number of Previous EGFR TKI lines of 9 patients progressed on TKI immediately prior to CO-1686 *

30 Classical AEs observed with WT-EGFR inhibition uncommon with CO-1686 % patients with event Comparator data from US prescribing information

31 In vitro and In vivo activity of AZD9291 AZD9291 is a potent oral, irreversible inhibitor of EGFR that contains EGFR- TKI-sensitising (EGFR+) and resistance mutations (T790M) Good potency and high selectivity demonstrated in enzymatic and cellular in vitro assays 1 Updated long-term dosing of H1975 (L858R/T790M) xenograft with indicated doses of AZD9291 Profound regression in EGFR-mutant tumour models, showing sustainable complete macroscopic tumour response out to at least 200 days ModelWild-type LoVo cells EGFR+ PC9 cells EGFR+/ T790M H1975 cells AZD9291 phospho-EGFR IC 50 nM Cross et al. Abstract A109, AACR-EORTC-NCI conference, Boston, 2013

32 Best % change from baseline in target lesions, n=34 % change from baseline in target lesion –10 –20 –30 –40 –50 –60 –70 –80 –90 – * * D D DD D D#D# D#D# 80 T790M status Negative Positive Unknown D Discontinued treatment * Imputed # Progressive disease due to new lesion Dose (mg/day) received noted on bar Population: patients with observed or imputed target lesion data (n=34) Best overall response 15/35 patients evaluated had a partial response (confirmed + unconfirmed) 9/18 patients with T790M+ tumours achieved a partial response (confirmed + unconfirmed) Preliminary data, cut-off 27 September 2013 Response Evaluation Criteria in Solid Tumors v1.1, programmatically calculated from investigator-recorded tumour measurements T790M result from local testing except for some expansion patients where local testing result unknown (central test result used)

33 Summary of adverse events 89 patients have received at least one dose of AZD9291 (data cut-off 27 September) No DLTs seen at dose levels of 20–160 mg/day There have been no dose reductions to date Rash and diarrhoea were mostly mild Preliminary data, cut-off 27 September 2013 Number of patients without event Number of patients with event Grade 1Grade 2Grade 3Total Rash Diarrhoea

34 TreatmentRR (%) PFS/TTP (mos) Reference Everolimus + gefitinib or erlotinib 03Riely CCR 07 Vorinostat + erlotinib0NRRegaurt PASCO 09 Cetuximab + erlotinib03Janjigian CCR 11 Dasatinib + erlotinib vs Dasatinib Johnson JTO 11 HCQ vs HCQ + erlotinib Goldberg JTO 12 XL Pietanza JTO 12 Neratinib33.6Sequist JCO 10 IPI Sequist JCO 10 Afatinib vs Placebo (LUX-1) 7 < Miller Lancet Oncol 12 Afatinib (LUX-4)84.4Katakami JCO 13 AUY922 + erlotinib16NRJohnson PASCO 13 AUY92220NRGaron PASCO 12 Afatinib + cetuximab324.7Janjigian ESMO 12 CO NRSoria WCLC 13 AZD929146NRRanson WCLC 13 Target therapies in EGFR resistant

35 Pt IDEGFR Status baseline EGFR Status Before afatinib Best response to afatinib 2Exon 19Exon 18PD 3Exon 19Exon 19+ T790MPD 4Exon 19Exon 19 + T790MSD 5Exon 21EGFR Wild typeSD 9Exon 19 SD 10Exon 19 PD 11Exon 18 RP 15Exon 19Exon 19 + T790MPD 31Exon 21Exon 19PD 35Exon 19Exon 19 +T790MSD 42Exon 19 SD 43Exon 19 PD 45Exon 19 PD 47Exon 19Exon 19 + T790MSD 50Exon 19EGFR Wild typePD 55Exon 19Exon 19 + T790MSD 67Exon 21Exon 21 + T790MSD 70Exon 19Exon 19+T790MPD 73Exon 19Exon 18SD 79Exon 19Exon 18PD 80Exon 19 PD 83Exon 19Exon 18SD Response in Pts Receiving Re-Biopsy * *22/24 evaluable pts 97 pts EGFR mutati Afatinib in linea avanzata RR 10.4% PFS 3.9 mesi OS 7.3 mesi Cappuzzo, Tiseo, Chiari et al, Poster WCLC 2013

36 Nuovi farmaci alla resistenza: considerazioni Nuovi irreversibili potenti e molto selettivi Nuovi irreversibili potenti e molto selettivi Dati di risposta in caso di T790M molto promettenti Dati di risposta in caso di T790M molto promettenti - CO % - AZD % Ridotta tossicità Ridotta tossicità A fter too many trials showing too little efficacy or too much toxicity for acquired resistance, this is a drug that has the potential to make a major impact on this diseaseA fter too many trials showing too little efficacy or too much toxicity for acquired resistance, this is a drug that has the potential to make a major impact on this disease (Oxnard, Discussant AZD9291)

37 MO21.05: Integrated genomic analysis by whole exome and transcriptome sequencing of tumor samples from EGFR-mutant non-small-cell lung cancer (NSCLC) patients with acquired resistance to erlotinib Presenting Author: Petros Giannikopoulos, M.D. Cancer Therapeutics Innovation Group Co-Authors: Trever Bivona, Carlota Costa, Niki Karachaliou, John St. John, Joel Parker, Aleah F. Cauhlin, Oscar Westesson, Nick Hahner, Urvish Parikh, Maria D. Lozano, Santiago Viteri, Jose L. Perez-Gracia, Alessandra Curioni, Eloisa Jantus-Lewintre, Carlos Camps, Alain Vergnenegre, Radj Gervais, Anne Wellde, Jonathan Barry, George W. Wellde Jr., Andres F. Cardona, Rolf Stahel, William R. Polkinghorn, Rafael Rosell, Jonathan Weissman

38 PATIENTBIOPSYEGFR T790M GENES HARBORING SOMATIC MUTATIONS FUSION GENES COPY NUNUMBER ALTERED GENES AMPLIFICATIONDELETION 1 Pre-treatment Post-resistancePresent KIT, KRAS, PDGFRA, PIK3CA, SMO EGFR BRCA2, FLT3, GAS6 2 Pre-treatment MET KRAS Post-resistancePresent MET 3 Pre-treatment Post-resistancePresent MYH11, RXRA 4 Pre-treatment Post-resistancePresent EGFR, SMO, MET 5 Pre-treatment EGFR BRCA2, FLT3, FGFR1 Post-resistancePresent 6 Pre-treatment TP53, BRCA2, GAS6, RXRA, FLT3, Post-resistancePresent SMO, MET TP53 7 Pre-treatment Post-resistance MLL 8 Pre-treatment EML4-ALK Post-resistance EML4-ALK 9 Pre-treatment Post-resistance KRAS 10 Pre-treatment Post-resistance FLT3, RXRA 11 Pre-treatment MYH11 Post-resistance TPM3-ROS1 12 Pre-treatment Post-resistance 13 Pre-treatment Post-resistance CTNNA2 14 Pre-treatment Post-resistance 15 Pre-treatment EGFR Post-resistance EGFR 16 Pre-treatment Post-resistance SMAD4 MO21.05: Integrated genomic analysis by whole exome and transcriptome sequencing of tumor samples from EGFR-mutant non-small-cell lung cancer (NSCLC) patients with acquired resistance to erlotinib Petros Giannikopoulos, M.D.

39 Conclusioni u Nessuna novità che impatti sulla pratica clinica u Miglioramento delle conoscenze sulle mutazioni EGFR uncommon u Ancora poco chiara la migliore strategia in caso di T790M de novo u Risultati molto promettenti con inibitori di EGFR irreversibili di terza generazione u Potenziali nuovi drivers in caso di resistenza

40 Grazie per lattenzione


Scaricare ppt "Marcello Tiseo U.O. Oncologia Medica Azienda Ospedaliero-Universitaria di Parma EGFR e meccanismi di resistenza agli inibitori."

Presentazioni simili


Annunci Google