marcello tiseo u.o. oncologia medica azienda ospedaliero-universitaria di parma
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EGFR e meccanismi di resistenza agli inibitori. Marcello Tiseo U.O. Oncologia Medica Azienda Ospedaliero-Universitaria di Parma. Mutazioni di EGFR e TKIs: punti fermi. Netto impatto dei trattamenti in OS: 2-3 anni 8 studi random di I linea vs CT - PowerPoint PPT PresentationTRANSCRIPT
Marcello TiseoMarcello TiseoU.O. Oncologia MedicaU.O. Oncologia Medica
Azienda Ospedaliero-Universitaria di ParmaAzienda Ospedaliero-Universitaria di Parma
EGFR e meccanismi di EGFR e meccanismi di resistenza agli inibitoriresistenza agli inibitori
Mutazioni di EGFR e TKIs: Mutazioni di EGFR e TKIs: punti fermipunti fermi Netto impatto dei trattamenti in OS: 2-3 anniNetto impatto dei trattamenti in OS: 2-3 anni 8 studi random di I linea vs CT8 studi random di I linea vs CT
- TKI > CT in RR (60-70%), PFS (9-13 mesi), - TKI > CT in RR (60-70%), PFS (9-13 mesi),
tossicitàtossicità 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- non disponibili confronti diretti di fase III Efficacia in qualunque linea di terapiaEfficacia in qualunque linea di terapia Tossicità peculiariTossicità peculiari Instaurarsi di resistenza:Instaurarsi di resistenza:
- differenti meccanismi e diverse potenziali strategie- differenti meccanismi e diverse potenziali strategie
Mutazioni di EGFR e TKIs: Mutazioni di EGFR e TKIs: quesiti apertiquesiti aperti
Quale il “migliore” TKI in I lineaQuale il “migliore” TKI in I linea Circa 30% dei pazienti mutati non risponde a TKICirca 30% dei pazienti mutati non risponde a TKI Scarsa conoscenza in caso di mutazioni Scarsa conoscenza in caso di mutazioni
“uncommon” e in caso di combinazione di diverse “uncommon” e in caso di combinazione di diverse mutazionimutazioni
Non chiara efficacia in caso di T790M de novoNon chiara efficacia in caso di T790M de novo Non chiara definizione della terapia alla Non chiara definizione della terapia alla
progressione a TKIprogressione a TKI
Mutazioni di EGFR e TKIs: Mutazioni di EGFR e TKIs: quesiti apertiquesiti aperti
Quale il “migliore” TKI in I lineaQuale il “migliore” TKI in I linea Circa 30% dei pazienti mutati non risponde a TKICirca 30% dei pazienti mutati non risponde a TKI Scarsa conoscenza in caso di mutazioni Scarsa conoscenza in caso di mutazioni
“uncommon” e in caso di combinazione di diverse “uncommon” e in caso di combinazione di diverse mutazionimutazioni
Non chiara efficacia in caso di T790M de novoNon chiara efficacia in caso di T790M de novo Non chiara definizione della terapia alla Non chiara definizione della terapia alla
progressione a TKIprogressione a TKI
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
Extracellulardomain
Trans-membrane
domain
Tyrosine-kinase domain
Regulatory domain
Confer sensitivity/resistance to EGFR TKIs
Unclear effect on sensitivity to EGFR TKIs
18
18
19
20
21
Deletions
L858R
G719A/S
L861X
P694X
V700D
E709X
G735SV738F V742AT751IS752YD761N
A763VN765AS768IT783AL792PL798FG810S
N826S
L838VT847I
I853TA859T
E866K
L833VH835L
H850NV851X
G863DA864T
L730F P733L
E746K
D761Y
D770_N771 insNPG
T790M
EGFR
TKI = tyrosine-kinase inhibitor
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
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
EGFR mutation-positive patients in LUX-Lung trials
Patients with uncommon mutations treated with afatinib
Uncommonn=75
Subgroups of patients with uncommon mutations
CategoriesDe 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%
Outcome in patients with uncommon mutations
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
Ma
xim
um
cha
nge
fr
om
ba
se
line
(%
)
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
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
Reversible EGFR-TKIs1 Afatinib 2,3,4
EGFR N RR (%)
PFS (months)
OS (months) 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 0 1.0 7.2
Exon 20 insertion 11 0 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 15 60.0 6.0 15.2 162 56.0 8.2 16.9
Other 15 20.0 1.6 11.1 1 100 - -
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
How afatinib compares to reversible EGFR-TKIs in presence of uncommon EGFR mutations?
Istit
uto
Tosc
ano
Tum
ori-L
ivor
no-It
aly
Mutazioni UncommonMutazioni UncommonYang et al: considerazioniYang et al: considerazioni
Il più grande data set prospettico sulle mutazioni Il più grande data set prospettico sulle mutazioni uncommon, trattate in modo omogeneouncommon, trattate in modo omogeneo
Conferma che costituiscono circa 10% delle Conferma che costituiscono circa 10% delle mutazioni di EGFRmutazioni di EGFR
Gruppo eterogeneoGruppo eterogeneo Efficacia modesta in caso di inserzione del 20 e Efficacia modesta in caso di inserzione del 20 e
T790M de novo degli attuali EGFR TKIsT790M de novo degli attuali EGFR TKIs Efficacia contro altre mutazioni uncommon Efficacia contro altre mutazioni uncommon
(G719, L861) simile alle comuni e simile fra TKIs(G719, L861) simile alle comuni e simile fra TKIs
Mutazioni UncommonMutazioni UncommonYang et al: considerazioniYang et al: considerazioni
Il più grande data set prospettico sulle mutazioni Il più grande data set prospettico sulle mutazioni uncommon, trattate in modo omogeneouncommon, trattate in modo omogeneo
Conferma che costituiscono circa 10% delle Conferma che costituiscono circa 10% delle mutazioni di EGFRmutazioni di EGFR
Gruppo eterogeneoGruppo eterogeneo Efficacia modesta in caso di Efficacia modesta in caso di inserzione del 20 inserzione del 20 e e
T790M de novo T790M de novo degli attuali EGFR TKIsdegli attuali EGFR TKIs Efficacia contro altre mutazioni uncommon Efficacia contro altre mutazioni uncommon
(G719, L861) simile alle comuni e simile fra TKIs(G719, L861) simile alle comuni e simile fra TKIs
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, MMScDivision of Hematology/OncologyBIDMC WCLC 2013 (October 29th 2013)ABSTRACT # 747MO16 - Prognostic and Predictive Biomarkers IV
Funding source:
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
G719Xsensitive
exon 19 deletions
sensitive
exon 19 insertions
sensitive
exon 20
A763_Y764
insFQEA
sensitive
exon 20 insertions
(others)resistant
exon 20
T790Mresistant
exon 21
L858Rsensitive
exon 21
L861Qsensitive
762 763 764 765 766 767 768 769 770 771 772 773 774762 763 764 765 766 767 768 769 770 771 772 773 774
A7
63_Y
76
4in
sF
QE
A
Y7
64_V
76
5in
sH
H
M7
66
_A
76
7in
sA
I
A7
67_V
76
9du
pA
SV
D7
70
_N
77
1in
sN
PG
H7
73
_V
77
4in
sH
C-helix
loop following C-helix
D7
70
_N
77
1in
sS
VD
exon 19 deletions
exon 21L858RL861Q
exon 18G719S
exon 20 insertions
N-lobe
C-lobe
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
Best response to reversible EGFR TKI
EGFR mutation drug PR SD PD RR [%]
A763_Y764insFQEA erlotinib 2 1 - 66.6%
Y764_V765insHH gefitinib - 1 - 0%
M766_A767insASV erlotinib - - 1 0%
A767_V769dupASV gefitinib - - 1 0%
V769_D770insASV erlotinib - - 1 0%
D770_N771insGL erlotinib - - 2 0%
D770_N771insGT erlotinib - - 1 0%
D770_N771insSVD erlotinib - 1 1 0%
delD770insGY erlotinib - - 2 0%
P772_H773insYNP gefitinib - - 1 0%
P772_V774insPHV erlotinib - - 1 0%
H773_V774insHgefitinib/erlotinib
- - 2 0%
H773_V774insNPH erlotinib - - 1 0%
Best response to reversible EGFR TKI
EGFR mutation drug PR SD PD RR [%]
A763_Y764insFQEA erlotinib 2 1 - 66.6%
Y764_V765insHH gefitinib - 1 - 0%
M766_A767insASV erlotinib - - 1 0%
A767_V769dupASV gefitinib - - 1 0%
V769_D770insASV erlotinib - - 1 0%
D770_N771insGL erlotinib - - 2 0%
D770_N771insGT erlotinib - - 1 0%
D770_N771insSVD erlotinib - 1 1 0%
delD770insGY erlotinib - - 2 0%
P772_H773insYNP gefitinib - - 1 0%
P772_V774insPHV erlotinib - - 1 0%
H773_V774insHgefitinib/erlotinib
- - 2 0%
H773_V774insNPH erlotinib - - 1 0%
*
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
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 15·86·0
Patients at risk
G2
G4
G3G1
Rosell et al, Poster WCLC 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 UnitLung Cancer Unit
National Institute for Cancer Research National Institute for Cancer Research Genova, ItalyGenova, Italy
15th World Conference on Lung CancerPrognostic and Predictive Biomarkers V
Sydney, 30 October 2013Sydney, 30 October 2013
363Tested for EGFR mut
58 (16 %)EGFR MUT
RT-PCRSanger 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 sequencing12 (22.2 %)
Insufficient tissue
Selection of patients and samplesSelection of patients and samples
19T790M+*2 pts ineligible: 1 second primary tumor,
1 treatment data not available (second opinion)
23T790M- §2 pts ineligible: early stages
PFS* & OS according to PFS* & OS according to the EGFR T790M statusthe 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
RR and PFS to first-line treatment RR and PFS to first-line treatment with EGFR TKIs or CTwith EGFR TKIs or CT
RR and PFS to first treatment with RR and PFS to first treatment with afatinib or erlotinib/gefitinibafatinib or erlotinib/gefitinib
EGFR T790M de novo: EGFR T790M de novo: considerazioniconsiderazioni
Con metodiche più sensibili percentuale più Con metodiche più sensibili percentuale più elevata (da circa 4-5% a 40%)elevata (da circa 4-5% a 40%)
Arterfatto in paraffina, non in frozen? Arterfatto in paraffina, non in frozen? High High T790M detection rate in TKI-naïve, Truth or T790M detection rate in TKI-naïve, Truth or Artifact ? Ye et al, JTO 2013Artifact ? Ye et al, JTO 2013
Probabilità di risposta a TKI inferioreProbabilità di risposta a TKI inferiore Pazienti con buona prognosiPazienti con buona prognosi Quale la migliore strategia? TKI o CT come Quale la migliore strategia? TKI o CT come
prima linea? Quale TKI? prima linea? Quale TKI?
Meccanismi di resistenza Meccanismi di resistenza a EGFR-TKIsa EGFR-TKIs
Clinical EGFR InhibitorsDrug Stage Covalen
tOvercome T790M Structure
Gefitinib Approved No No Quinazoline
Erlotinib Approved No No Quinazoline
Dacomitinib Phase III Yes No Quinazoline
Afatinib Approved Yes No Quinazoline
AP26113 Phase I/II No ? Pyrimidine
CO-1686 Phase I Yes Yes Pyrimidine
AZD9291 Phase I Yes Yes Pyrimidine
Janne, Mini Symposium MS27, WCLC 2013
Third generation compounds selectively target EGFR T790MThey are 30- to 100-fold more potent against EGFR T790M and up to 100-fold less potent against WT EGFR than quinazoline-inhibitors
Nuovi farmaci alla resistenza: Nuovi farmaci alla resistenza: CO-1686 e AZD9291CO-1686 e AZD9291
First-In-Human Evaluation of First-In-Human Evaluation of CO-1686CO-1686, an Irreversible, , an Irreversible, Highly Selective Tyrosine Kinase Inhibitor of Mutations of Highly Selective Tyrosine Kinase Inhibitor of Mutations of EGFR (Activating and T790M) EGFR (Activating and T790M) Soria et alSoria et al
AZD9291AZD9291: an irreversible, potent and selective tyrosine : an irreversible, potent and selective tyrosine kinase inhibitor (TKI) of activating (kinase inhibitor (TKI) of activating (EGFREGFR+) and resistance +) and resistance (T790M) mutations in advanced NSCLC. The AURA study(T790M) mutations in advanced NSCLC. The AURA studyRanson et al Ranson et al
-100
-80
-60
-40
-20
0
20
40
60
80
100200400600
Cha
nge
from
Bas
elin
e (%
)
PD
SD
PR
CR
Afatinib20mg/kg
CO-168650mg/kg BID
L858R/T790MTransgenic Model
CO-1686: Baseline CO-1686: 3W
Afatinib: Baseline Afatinib : 3W
Afatinib dosed at MTD - potency limited by WT EGFR inhibition
CO-1686 generates complete responses in L858R/T790M transgenic model
*
67% RECIST response rate in evaluable T790M+ patients treated at 900mg BID
EGFRi immediately before CO-1686 *
1 2 2 2 4 2 2 1 1
Weeks on treatment
******
*
Number of Previous EGFR TKI lines
6
22 15 1824 11 8 21 30
8 of 9 patients progressed on TKI immediately prior to CO-1686
*
Classical AEs observed with WT-EGFR inhibition uncommon with CO-1686
% patients with eventComparator data from US prescribing information
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 assays1
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
Model Wild-typeLoVo cells
EGFR+
PC9 cells
EGFR+/T790M H1975 cells
AZD9291 phospho-EGFRIC50 nM
480 17 15
1. Cross et al. Abstract A109, AACR-EORTC-NCI conference, Boston, 2013
Best % change from baseline in target lesions, n=34
% c
ha
ng
e f
rom
ba
selin
e in
ta
rge
t le
sio
n
40
20
10
0
–10
–20
–30
–40
–50
–60
–70
–80
–90
–100
30 4040 40*
40
4040
40
40 40
40
40
20
20
2020
20202020
2020
2020
202020
20
20*
DD D D
D
D#
D#
80
80 80
80
80 80
T790M status
Negative
Positive
Unknown
D Discontinued treatment* Imputed# Progressive disease due to new lesionDose (mg/day) received noted on barPopulation: 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 measurementsT790M result from local testing except for some expansion patients where local testing result unknown (central test result used)
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 1 Grade 2 Grade 3 Total
Rash 73 15 1 0 16
Diarrhoea 74 13 1 1 15
Treatment RR (%)
PFS/TTP (mos)
Reference
Everolimus + gefitinib or erlotinib
0 3 Riely CCR ‘07
Vorinostat + erlotinib 0 NR Regaurt PASCO ‘09
Cetuximab + erlotinib 0 3 Janjigian CCR ‘11
Dasatinib + erlotinib vs Dasatinib
00
0.90.5
Johnson JTO ‘11
HCQ vsHCQ + erlotinib
05
1.82
Goldberg JTO ‘12
XL647 3 3.5 Pietanza JTO ‘12
Neratinib 3 3.6 Sequist JCO ‘10
IPI-504 4 2.8 Sequist JCO ‘10
Afatinib vsPlacebo (LUX-1)
7<1
3.31.1
Miller Lancet Oncol ‘12
Afatinib (LUX-4) 8 4.4 Katakami JCO ‘13
AUY922 + erlotinib 16 NR Johnson PASCO ‘13
AUY922 20 NR Garon PASCO ‘12
Afatinib + cetuximab 32 4.7 Janjigian ESMO ‘12
CO-1686 67 NR Soria WCLC ‘13
AZD9291 46 NR Ranson WCLC ‘13
Target Target therapies therapies in EGFR in EGFR resistantresistant
Pt ID EGFR Statusbaseline
EGFR Status Before afatinib
Best response to afatinib
2 Exon 19 Exon 18 PD
3 Exon 19 Exon 19+ T790M PD
4 Exon 19 Exon 19 + T790M SD
5 Exon 21 EGFR Wild type SD
9 Exon 19 Exon 19 SD
10 Exon 19 Exon 19 PD
11 Exon 18 Exon 18 RP
15 Exon 19 Exon 19 + T790M PD
31 Exon 21 Exon 19 PD
35 Exon 19 Exon 19 +T790M SD
42 Exon 19 Exon 19 SD
43 Exon 19 Exon 19 PD
45 Exon 19 Exon 19 PD
47 Exon 19 Exon 19 + T790M SD
50 Exon 19 EGFR Wild type PD
55 Exon 19 Exon 19 + T790M SD
67 Exon 21 Exon 21 + T790M SD
70 Exon 19 Exon 19+T790M PD
73 Exon 19 Exon 18 SD
79 Exon 19 Exon 18 PD
80 Exon 19 Exon 19 PD
83 Exon 19 Exon 18 SD
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
Nuovi farmaci alla resistenza: Nuovi farmaci alla resistenza: considerazioniconsiderazioni Nuovi irreversibili potenti e molto selettiviNuovi irreversibili potenti e molto selettivi Dati di risposta in caso di T790M molto promettentiDati di risposta in caso di T790M molto promettenti
- CO-1686 67%CO-1686 67%- AZD9291 50%AZD9291 50%
Ridotta tossicitàRidotta tossicità
““AAfter too many trials showing too little efficacy or too much fter too many trials showing too little efficacy or too much toxicity for acquired resistance, this is a drug that has the toxicity for acquired resistance, this is a drug that has the
potential to make a major impact on this disease” potential to make a major impact on this disease” (Oxnard, Discussant AZD9291)(Oxnard, Discussant AZD9291)
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
PATIENT BIOPSY EGFR T790MGENES HARBORING SOMATIC
MUTATIONSFUSION GENES
COPY NUNUMBER ALTERED GENES
AMPLIFICATION DELETION
1Pre-treatment
Post-resistance Present KIT, KRAS, PDGFRA, PIK3CA, SMO EGFR BRCA2, FLT3, GAS6
2Pre-treatment MET KRAS
Post-resistance Present MET
3Pre-treatment
Post-resistance Present MYH11, RXRA
4Pre-treatment
Post-resistance Present EGFR, SMO, MET
5Pre-treatment EGFR BRCA2, FLT3, FGFR1
Post-resistance Present
6Pre-treatment TP53, BRCA2, GAS6, RXRA, FLT3,
Post-resistance Present SMO, MET TP53
7Pre-treatment
Post-resistance MLL
8Pre-treatment EML4-ALK
Post-resistance EML4-ALK
9Pre-treatment
Post-resistance KRAS
10Pre-treatment
Post-resistance FLT3, RXRA
11Pre-treatment MYH11
Post-resistance TPM3-ROS1
12Pre-treatment
Post-resistance
13Pre-treatment
Post-resistance CTNNA2
14Pre-treatment
Post-resistance
15Pre-treatment EGFR
Post-resistance EGFR
16Pre-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.
ConclusioniConclusioni
Nessuna novità che impatti sulla pratica clinicaNessuna novità che impatti sulla pratica clinica Miglioramento delle conoscenze sulle mutazioni Miglioramento delle conoscenze sulle mutazioni
EGFR uncommonEGFR uncommon Ancora poco chiara la migliore strategia in caso Ancora poco chiara la migliore strategia in caso
di T790M de novodi T790M de novo Risultati molto promettenti con inibitori di Risultati molto promettenti con inibitori di
EGFR irreversibili di terza generazioneEGFR irreversibili di terza generazione Potenziali nuovi drivers in caso di resistenzaPotenziali nuovi drivers in caso di resistenza
Grazie per l’attenzioneGrazie per l’attenzione
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