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

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

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

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cha

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(%

)

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

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Tosc

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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

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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

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ba

selin

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ta

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sio

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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


11 Exon 18 Exon 18 RP

15 Exon 19 Exon 19 + T790M PD


35 Exon 19 Exon 19 +T790M SD





50 Exon 19 EGFR Wild type PD



70 Exon 19 Exon 19+T790M PD





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

[email protected]@ao.pr.it

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

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