EGFR e meccanismi di resistenza agli inibitori

Presentazione sul tema: "EGFR e meccanismi di resistenza agli inibitori"— Transcript della presentazione:

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 2

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 3

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 4

5 Mutations in the EGFR gene
Unclear effect on sensitivity to EGFR TKIs Confer sensitivity/resistance to EGFR TKIs EGFR transcript 18 Extracellular domain P694X V700D E709X 18 Exons 1–16 G719A/S G735S V738F V742A T751I S752Y D761N EGFR Deletions 19 L730F P733L E746K Trans- membrane domain Exon 17 D761Y A763V N765A S768I T783A L792P L798F G810S Tyrosine- kinase domain D770_N771 insNPG 20 Exons 18–24 T790M L858R 21 N826S L838V T847I I853T A859T E866K L833V H835L H850N V851X G863DA864T Regulatory domain 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
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-line EGFR29* (central) LUX-Lung 6 N=364 Afatinib vs. Gemcitabine/ cisplatin *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
Del19 n=408 L858R n=330 Uncommon n=100 LUX-Lung 2 Phase II N=129 n=52 n=54 n=23 LUX-Lung 3 Phase III N=345 n=170 n=138 n=37 LUX-Lung 6 N=364 n=186 n=40 Patients with uncommon mutations treated with afatinib Uncommon n=75 n=23 n=26 n=26

9 Subgroups of patients with uncommon mutations
Categories De novo T790M Exon 20 insertions Other (exon 18, 19, 20, 21) n= 75 14 23 38 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 analyzed T790M+ Exon 20 insertion Other 838 1.6% 2.7% 4.5%

10 Outcome in patients with uncommon mutations
De novo T790M (n=14): T790M alone, T790M+Del19, T790M+L858R, T790M+G719X, T790M+L858R+G719X Exon 20 insertions (n=20) Other (n=33): L861Q, G719X, G719X+S768I, G719X+L861Q, E709G or V+L858R, S768I+L858R, S768I, L861P, R776H+L858R, L861Q+Del19, K739_1744dup6 T790M Exon 20 ins Other Response rate (%) 14.3 8.7 71.1 DCR (%) 64.2 65.2 84.2 PFS (months) 2.9 2.7 10.7 OS (months) 14.9 9.4 18.6

11 How afatinib compares to reversible EGFR-TKIs
in presence of uncommon EGFR mutations? Reversible EGFR-TKIs1 Afatinib 2,3,4 EGFR N RR (%) PFS (months) OS (months) Exon 19-21 278 74.1 8.5 19.6 3084 60.8 13.6 - Wild-type 272 16.5 2.0 10.4 423 1.0 7.2 Exon 20 insertion 11 1.4 4.8 202 8.7 2.7 9.4 G719 15 53.3 8.1 16.4 182 78.0 13.8 26.9 L861 60.0 6.0 15.2 162 56.0 8.2 16.9 Other 20.0 1.6 11.1 1 100 Istituto Toscano Tumori-Livorno-Italy Il gruppo dei cosiddetti other dello studio di afatinib include un solo paziente con mutazione non comune in quanto gli altri 7 pazienti hanno anche la mutazione G719 (5 casi) o la mutazione 21 (2 casi). Pertanto non si può affermare, su un solo caso, se afatinib funziona o meno nel gruppo definito “other” 1Wu J et al. Clin Cancer Res 2011; 2Yang Y et al. WCLC 2013; 3 Ahn et al, ESMO 2012; 4Sequist et al JCO 2013

12 Mutazioni Uncommon Yang 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 12

13 Mutazioni Uncommon Yang 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

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 in vitro sensitivity to EGFR TKIs (erlotinib or gefitinib)
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 exon 19 insertions exon 20 A763_Y764 insFQEA exon 20 insertions (others) resistant T790M exon 21 L858R L861Q

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) 5·1 9·7 15·8 6·0 Patients at risk G2 G4 G3 G1 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 LNA-PCR/Sanger sequencing
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= 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%) 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? 24

25 Meccanismi di resistenza a EGFR-TKIs

26 Clinical EGFR Inhibitors
Drug Stage Covalent Overcome T790M Structure Gefitinib Approved No Quinazoline Erlotinib Dacomitinib Phase III Yes Afatinib AP26113 Phase I/II ? Pyrimidine CO-1686 Phase I AZD9291 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 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 27

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 Number of Previous EGFR TKI lines
67% RECIST response rate in evaluable T790M+ patients treated at 900mg BID 8 of 9 patients progressed on TKI immediately prior to CO-1686 Number of Previous EGFR TKI lines 1 2 4 * * * * * 6 * * * * 22 15 24 18 11 8 21 30 Weeks on treatment * 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 Model Wild-type LoVo cells EGFR+ PC9 cells EGFR+/ T790M H1975 cells AZD9291 phospho-EGFR IC50 nM 480 17 15 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
40 20 10 –10 –20 –30 –40 –50 –60 –70 –80 –90 –100 30 D 40 D D D 40 20* 40* D 20 40 20 80 20 20 20 20 D# 40 20 80 80 40 20 D# 40 20 80 20 20 20 40 40 80 20 80 20 40 20 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) 20 Best overall response‡ 40 15/35 patients evaluated had a partial response (confirmed + unconfirmed) 9/18 patients with T790M+ tumours achieved a partial response (confirmed + unconfirmed) ‡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 Number of patients without event Number of patients with event Grade 1 Grade 2 Grade 3 Total Rash 73 15 1 16 Diarrhoea 74 13 Preliminary data, cut-off 27 September 2013

34 Target therapies in EGFR resistant
Treatment RR (%) PFS/TTP (mos) Reference Everolimus + gefitinib or erlotinib 3 Riely CCR ‘07 Vorinostat + erlotinib NR Regaurt PASCO ‘09 Cetuximab + erlotinib Janjigian CCR ‘11 Dasatinib + erlotinib vs Dasatinib 0.9 0.5 Johnson JTO ‘11 HCQ vs HCQ + erlotinib 5 1.8 2 Goldberg JTO ‘12 XL647 3.5 Pietanza JTO ‘12 Neratinib 3.6 Sequist JCO ‘10 IPI-504 4 2.8 Afatinib vs Placebo (LUX-1) 7 <1 3.3 1.1 Miller Lancet Oncol ‘12 Afatinib (LUX-4) 8 4.4 Katakami JCO ‘13 AUY922 + erlotinib 16 Johnson PASCO ‘13 AUY922 20 Garon PASCO ‘12 Afatinib + cetuximab 32 4.7 Janjigian ESMO ‘12 CO-1686 67 Soria WCLC ‘13 AZD9291 46 Ranson WCLC ‘13 Target therapies in EGFR resistant

35 Response in Pts Receiving Re-Biopsy *
Pt ID EGFR Status baseline Before afatinib Best response to afatinib 2 Exon 19 Exon 18 PD 3 Exon 19+ T790M 4 Exon 19 + T790M SD 5 Exon 21 EGFR Wild type 9 10 11 RP 15 31 35 Exon 19 +T790M 42 43 45 47 50 55 67 Exon 21 + T790M 70 Exon 19+T790M 73 79 80 83 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 % AZD % 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) 36

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 Multiple genetic events contributing
PATIENT BIOPSY EGFR T790M GENES HARBORING SOMATIC MUTATIONS FUSION GENES COPY NUNUMBER ALTERED GENES AMPLIFICATION DELETION 1 Pre-treatment Post-resistance Present KIT, KRAS, PDGFRA, PIK3CA, SMO EGFR BRCA2, FLT3, GAS6 2 MET KRAS 3 MYH11, RXRA 4 EGFR, SMO, MET 5 BRCA2, FLT3, FGFR1 6 TP53, BRCA2, GAS6, RXRA, FLT3, SMO, MET TP53 7 MLL 8 EML4-ALK 9 10 FLT3, RXRA 11 MYH11 TPM3-ROS1 12 13 CTNNA2 14 15 16 SMAD4 Multiple genetic events contributing 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