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Marcello Tiseo U.O. Oncologia Medica Azienda Ospedaliero-Universitaria di Parma

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

  2. Mutazioni di EGFR e TKIs: punti fermi • Netto impatto dei trattamenti in OS: 2-3 anni • 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) • - non disponibili confronti diretti di fase III • Efficacia in qualunque linea di terapia • Tossicità peculiari • Instaurarsi di resistenza: • - differenti meccanismi e diverse potenziali strategie

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

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

  5. Trans- membrane domain Regulatory domain Tyrosine- kinase domain Extracellulardomain 18 Mutations in the EGFR gene Unclear effect on sensitivity to EGFR TKIs Confer sensitivity/resistance to EGFR TKIs EGFR transcript P694X V700D E709X 18 Exons1–16 G719A/S G735S V738F V742A T751IS752Y D761N EGFR Deletions 19 L730F P733L E746K Exon 17 D761Y A763V N765A S768I T783A L792P L798F G810S 20 D770_N771 insNPG T790M Exons 18–24 N826S L838VT847I I853TA859T E866K L833VH835L H850NV851X G863DA864T L858R 21 L861X Exons 25–28 TKI = tyrosine-kinase inhibitor Riely, et al. Clin Cancer Res 2006

  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. Yang1, L.V. Sequist2, S. L. Geater3, C.-M. Tsai4, T. Mok5, M. H. Schuler6,N. Yamamoto7, D. Massey8, V. Zazulina8, Yi-Long Wu9 1National Taiwan University Hospital, Taipei, Taiwan; 2Massachusetts General Hospital, Boston, MA, USA; 3Division of Respiratory and Respiratory Critical Care Medicine, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand; 4Taipei Veterans General Hospital, Taipei, Taiwan; 5The Chinese University of Hong Kong, Hong Kong; 6West German Cancer Center, University Duisburg-Essen, Essen, Germany; 7Shizuoka Cancer Center, Shizuoka, Japan; 8Boehringer Ingelheim Limited, Bracknell, UK; 9Guangdong 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

  8. EGFR mutation-positive patients in LUX-Lung trials Uncommonn=75 n=26 n=26 n=23 Patients with uncommon mutations treated with afatinib

  9. Subgroups of patients with uncommon mutations

  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

  11. How afatinib compares to reversible EGFR-TKIs in presence of uncommon EGFR mutations? Istituto Toscano Tumori-Livorno-Italy 1Wu J et al. Clin Cancer Res 2011; 2Yang Y et al. WCLC 2013; 3Ahn et al, ESMO 2012; 4Sequist et al JCO 2013

  12. Mutazioni UncommonYang et al: considerazioni • Il più grande data set prospettico sulle mutazioni uncommon, trattate in modo omogeneo • Conferma che costituiscono circa 10% delle mutazioni di EGFR • Gruppo eterogeneo • 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

  13. Mutazioni UncommonYang et al: considerazioni • Il più grande data set prospettico sulle mutazioni uncommon, trattate in modo omogeneo • Conferma che costituiscono circa 10% delle mutazioni di EGFR • Gruppo eterogeneo • 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

  14. Clinical, structural and biochemical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer Hiroyuki Yasuda, MD1*; Eunyoung Park, PhD2*; Cai-Hong Yun, PhD6*; Natasha J. Sng, MS1; Wee-Lee Yeo, MD1;Antonio R. Lucena-Araujo, PhD1; Sohei Nakayama, MD1; Kota Ishioka, MD1; Mark S. Huberman, MD1; David W. Cohen, MD1; Norihiro Yamaguchi, MD, MPH1; Megan Hanna, PhD2; Geoffrey R. Oxnard, MD2; Christopher S. Lathan, MD, MPH2; Teresa Moran, MD3; Lecia V. Sequist, MD, MPH3; Jamie E. Chaft, MD4; Gregory J. Riely, MD, PhD4; Maria E. Arcila, MD4; Ross A. Soo, MBBS5; Matthew Meyerson, MD, PhD2; Michael J. Eck, MD, PhD2#; Susumu S. Kobayashi, MD, PhD1#; Daniel B. Costa, MD, PhD1# 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 29th 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

  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 G1: Erlotinib and T790M present (n=34) G2: Erlotinib and T790M absent (n=16) G3: Chemotherapy and T790M present (n=28) G4:Chemotherapy and T790M absent (n=17) G2 G4 G1 5·1 6·0 9·7 15·8 G3 Patients at risk Rosell et al, Poster WCLC 2013

  19. 15th World Conference on Lung Cancer Prognostic and Predictive Biomarkers V Sydney, 30 October 2013 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

  20. Selection of patients and samples 363 Tested for EGFR mut 305 (84 %) EGFR WT 58 (16 %) EGFR MUT RT-PCR Sanger sequencing 4* (6.9 %) T790M + 54 (93.1 %) T790M - 42 (77.7 %) LNA-PCR/Sanger sequencing 12 (22.2 %) Insufficient tissue 17(40.5%) T790M + 25§(59.5 %) T790M - 19 T790M+ 23 T790M- *2 pts ineligible: 1 second primary tumor, 1 treatment data not available (second opinion) §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= 32.23 months __ T790M wild-type Median OS= 22.99 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%) • 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 • Pazienti con buona prognosi • Quale la migliore strategia? TKI o CT come prima linea? Quale TKI?

  25. Meccanismi di resistenza a EGFR-TKIs

  26. Clinical EGFR Inhibitors Third generation compoundsselectively target EGFR T790M They are 30- to 100-fold more potentagainst EGFR T790M and up to 100-fold lesspotentagainst WT EGFR thanquinazoline-inhibitors Janne, Mini Symposium MS27, WCLC 2013

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

  29. 67% RECIST response rate in evaluable T790M+ patients treated at 900mg BID 8 of 9 patients progressed on TKI immediately prior to CO-1686 * * * * * * * * * 6 22 15 Weeks on treatment 11 8 21 24 18 30 * EGFRi immediately before 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 Updated long-term dosing of H1975 (L858R/T790M) xenograft with indicated doses 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 assays1 • Profound regression in EGFR-mutant tumour models, showing sustainable complete macroscopic tumour response out to at least 200 days 1. Cross et al. Abstract A109, AACR-EORTC-NCI conference, Boston, 2013

  32. Best % change from baseline in target lesions, n=34 D D 40 D D 40 20* 40* D 20 40 40 30 20 80 20 20 20 20 20 D# 40 20 10 80 80 40 20 D# 40 0 20 20 80 20 20 40 40 –10 80 20 80 20 –20 40 –30 20 % change from baseline in target lesion –40 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) T790M status –50 Negative Positive Unknown 20 –60 Best overall response‡ –70 40 –80 –90 • 15/35 patients evaluated had a partial response (confirmed + unconfirmed) • 9/18 patients with T790M+ tumours achieved a partial response (confirmed + unconfirmed) –100 ‡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) Preliminary data, cut-off 27 September 2013

  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

  34. Target therapies in EGFR resistant

  35. Response in Pts Receiving Re-Biopsy * • 97 pts EGFR mutati • Afatinib in linea avanzata • RR 10.4% • PFS 3.9 mesi • OS 7.3 mesi *22/24 evaluable pts Cappuzzo, Tiseo, Chiari et al, Poster WCLC 2013

  36. Nuovi farmaci alla resistenza: considerazioni • Nuovi irreversibili potenti e molto selettivi • Dati di risposta in caso di T790M molto promettenti • CO-1686 67% • AZD9291 50% • Ridotta tossicità • “After 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. 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 • Nessuna novità che impatti sulla pratica clinica • Miglioramento delle conoscenze sulle mutazioni EGFR uncommon • Ancora poco chiara la migliore strategia in caso di T790M de novo • Risultati molto promettenti con inibitori di EGFR irreversibili di terza generazione • Potenziali nuovi drivers in caso di resistenza

  40. Grazie per l’attenzione mtiseo@ao.pr.it