La terapia del paziente EGFR mutato - AIOM · 3rd generation EGFR-TKIs targeting T790M Drug Company...

Danilo Rocco

Pneumologia ad indirizzo Oncologico

La terapia del paziente EGFR

mutato

Percorso facile……………

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885

EGFR mut+ patients

L858R exon 21 Del exon 19 uncommon

Afatinib Erlotinib Gefitinib

exon 20 Exon 18

clinically relevant endpoints:

tolerability

quality of life

comorbidities

drug interaction

life expectancy

Consider TKI

CTx

Algorithm in A-NSCLC EGFR +

patients

Study TKI CTx N # PFS mos HR 95% CI OS mos OS HR 95%

CI

IPASS GEFITINIB Cb/Pac 261 9.5 vs. 6.3 0.48 0.36 - 0.64

21.6 vs. 21.9 1.00 0.76 – 1.33

NEJ002 GEFITINIB Cb/Pac 194 10.8 vs. 5.4 0.32 0.22 – 0.41

27.7 vs. 26.6 0.89 0.63 – 1.24

WJTOG 3405 GEFITINIB Cis/Doc 172 8.4 vs. 5.3 0.33 0.21 – 0.54

36.0 vs 39.0 1.19 0.73 – 1.83

OPTIMAL ERLOTINIB Cis/Gem 164 13.1 vs.4.6 0.16 0.10 – 0.26

22.7 vs. 28.9 1.04 0.69 – 1.58

EURTAC ERLOTINIB P/Doc or

Gem 174 10.4 vs 5.4 0.47

0.28 – 0.78 19.3 vs. 19.5 1.04

0.65 – 1.68

ENSURE ERLOTINIB P/Gem 217 11.0 vs 5.6 0.34 0.22- 0.51

26.3 vs. 25.5 0.91 0.62 – 1.31

LUX-LUNG 3 AFATINIB Cis/Pem 308 11.1 vs.6.9 0.49 0.37 – 0.65

31.6 vs 28.3 0.78 0.58 – 1.06

LUX-LUNG 6 AFATINIB Cis/Gem 364 11.0 vs. 5.6 0.28 0.20 – 0.39

23.6 vs. 23.5 0.83 0.62 – 1.09

ARCHER 1050 DACOMITINIB Gef 452 14.7 vs 9.2 0.59

0.47-0.74 - -

Mechanisms of therapeutic

resistance to kinase

Target modification

Patient-specific factors

Tumor-intrinsic factors

Other mechanisms

Histologic transformation

Bypass signaling

Target gene amplification

Plasma drug levels

Coexistent genetic

alterations in the drug target

Increased growth factor production

Epithelial-to-mesenchymal

transition

Activation of ‘compensatory

loops’ to circumvent the

inhibited target

‘Second site’ mutation within the target gene

Drug–drug interactions Coexistent

mutations in other signaling

genes

Phenotypic change from

NSCLC to SCLC

Inactivation of proapoptotic

pathways

Alternative splicing of the

target gene

Examples of strategies to overcome acquired resistance

Alternative dose or schedule

Next-generation inhibitors

Drug combinations

Dual-target blockade

Therapeutic resistance

Primary resistance

Acquired resistance

Lovly and Shaw. Clin Cancer Res 2014; Ohashi et al. J Clin Oncol 2013

Acquired resistance to EGFR

inhibition

± Pharmacokinet

ic failure

± Exogenous factors eg, HGF, IL-

6

~30–40%

Activation of other receptor tyrosine kinases? (eg, ERBB2 amplification) FAS / NFχB activation?

~60% second-site EGFR mutations (mostly T790M)

~1% BRAF mutations

~5% small-cell cancer

transformation ~5% PIK3CA

mutations 5–10% MET

amplification

Epithelial-mesenchymal transition? (AXL, Slug activation?) Loss or spliced variant of BIM? Other? (eg, CRKL or ERK amplification)

Potenziale meccanismo attraverso il quale la mutazione T790M provoca

resistenza ad EGFR-TKIs

Ipotesi 1: Prevenzione del legame di EGFR-TKIs La mutazione T790M EGFR-TKI resistente, derivante dalla sostituzione di treonina con metionina nell’amminoacido “gatekeeper” 790, determina una catena laterale più ingombrante1,2

Questo causa ingombro sterico, che riduce il legame degli EGFR-TKIs, erlotinib e gefitinib, a EGFR1,2

1. Kobayashi S, et al. N Engl J Med 2005;352:786–792; 2. Cross DA, et al. Cancer Discov 2014;4:1046–1061

Il legame di erlotinib a EGFR-WT determinato mediante cristallografia (Fig. A) è impedito dall’ingombro sterico, dovuto alla presenza della catena laterale della metionina nella mutazione T790M (Fig. B mostrata in arancione) nella tasca di legame dell’ATP.

• La Fig. C mostra l’ingombro sterico del complesso di gefitinib

e EGFR con la mutazione T790M.

• La Fig. D mostra il legame di un altro inibitore EGFR non

correlato (CL-387,785) a EGFR con la mutazione T790M (il

cambiamento strutturale introdotto dalla mutazione T790M è

mostrato in arancione).

A B

C D

Potenziale meccanismo attraverso il quale la mutazione T790M provoca

resistenza ad EGFR-TKIs

T790M aumenta l’affinità di legame di EGFR per l’ATP

Poichè gefitinib e erlotinib sono ligandi reversibili che competono con l’ATP al sito di legame

chinasico di EGFR, una maggiore affinità per l’ATP significa una riduzione nella potenza di questi

EGFR-TKIs

Ipotesi 2: Aumetata affinità di legame per l’ATP

Modificate da: Yun C-H, et al. Proc Natl Acad Sci U S A 2008;105:2070–2075. Copyright (2008) National Academy of Sciences, U.S.A.

1.0

1.1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

-0.1

Fra

ctio

na

l ve

locity*

-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

EGFR-sensitising mutation L858R:

Even at cellular ATP concentrations (~1 mM), EGFR remains sensitive to EGFR-TKI

binding

L858R plus T790M mutation:

At cellular concentrations of ATP

(~1 mM), EGFR-TKI binding is reduced

L858R

0.01 mM ATP

1.00 mM ATP

[Gefitinib] µM

1.0

1.1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

-0.1

Fra

ctio

na

l ve

locity*

-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

L858R/T790M

0.01 mM ATP

1.00 mM ATP

[Gefitinib] µM

3rd generation EGFR-TKIs targeting T790M

Drug Company Clinical Stage ORR DCR PFS

(month)

AZD9291 Astra

Zeneca

Phase III

(Approved) 61% 95% 9.6

CO-1686 Clovis Phase II/III

(stopped) 59% 93% 13.1

HM61713 Hanmi/BI Phase II/III

(stopped) 43% 86% －

ASP8273 Astellas Phase II 30% － 6.8

EGF816 Novartis Phase I 47% 87% 9.7

AC0010 Acea Bio Phase I 39% 78% －

PF-

06747775 Pfizer Phase I/II NR NR NR

Chee-Seng Tan et al. Lung Cancer 2016;

Pasi Janne et al. NEJM 2015; Sequist LV. NEJM 2015;

Zhang Li et al. ESMO 2016; Daniel Shao-Weng Tan. ASCO 2016 Abs 9044. #6009: Novel Tyrosine Kinase Inhibitors in Lung Cancer –Caicun Zhou

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I tre studi del Programma AURA

Gli Studi AURA

Programma di studi clinici per valutare sicurezza e attività di osimertinib, un EGFR-TKI

orale, potente, irreversibile, selettivo per mutazioni sensibilizzanti e di resistenza T790M

in pazienti con NSCLC avanzato EGFRm+ in progressione dopo terapia con un farmaco

EGFR-TKI.

1. Janne PA, et al. NEJM 2015; 2. Mitsudomi T, et al. Lancet Oncol 2016; 3. Mok T.S. et al, NEJM 2016.

Aumento della dose ed espansione (fase I) ed estensione (fase II)

Studio di fase I/II, open-label,

multicentrico per valutare

sicurezza, tollerabilità,

farmacocinetica ed attività

antitumorale di dosi crescenti

di osimertinib in pazienti con

NSCLC avanzato in

progressione dopo una

precedente terapia con un

farmaco EGFR-TKI

AURA

Studio di fase II

Studio di fase II, open-label,

con braccio singolo per

valutare sicurezza ed

efficacia di osimertinib in

pazienti con NSCLC

localmente avanzato o

metastatico in progressione

dopo una precedente terapia

con un farmaco EGFR-TKI e i

cui tumori sono EGFRm+ e

T790M+

AURA2

Studio confirmatorio di fase III

Studio di fase III, open-label,

randomizzato per valutare

sicurezza ed efficacia di

osimertinib vs doppietta

chemioterapica a base di

platino in pazienti con

NSCLC localmente avanzato

o metastatico,

EGFRm+/T790M+ in

progressione dopo una

precedente terapia con un

farmaco EGFR-TKI

AURA3

Disegno dello Studio1

AURA 3

1. Mok T.S. et al, NEJM 2016

T790M+

(n=610)

T790M-

Platinum-based doublet chemotherapyb

every 3 weeks (n=203)

osimertinib

(80 mg orally once daily; n=407)

Central testinga

of biopsy sample

Not eligible for enrollment

acobas® EGFR Mutation Test (Roche Molecular Systems).

Tissue and plasma samples will be collected so as to understand: a) the utility of multiple sample types for the identification of T790M+ tumors; b) the molecular evolution of the disease. b Pemetrexed 500 mg/m2 + carboplatin AUC5 or pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 – to be confirmed from feasibility.

AUC5 = area under the plasma concentration-time curve 5 mg/mL-1 per minute.

Randomization 2:1

Studio di fase III, open-label, randomizzato per valutare sicurezza ed efficacia di osimertinib vs doppietta chemioterapica a base di platino in 2a linea, in pazienti con NSCLC localmente avanzato/metastatico, EGFRm+/T790M+ in progressione dopo una precedente terapia con un farmaco EGFR-TKI.

AURA 3

PFS secondo valutazione dello sperimentatore1


Median

No. of Progression-free

Patients Survival

mo (95% CI)

Osimertinib 279 10.1 (8.3-12.3)

Platinum-pemetrexed 140 4.4 (4.2-5.6)

Hazard ratio for disease progression

or death, 0.30 (95% CI, 0.2 3-0.41)

P<0.001

No. at Risk

Osimertinib 279 240 162 88 50 13 0

Platinum- 140 93 44 17 7 1 0

pemetrexed

Beneficio di osimertinib osservato in pazienti con e senza metastasi cerebrali al

basale

Attività di osimertinib nelle metastasi cerebrali

Dati clinici dallo studio AURA 31


Pazienti con metastasi cerebrali

Median

No. of Progression-free

Patients Survival

mo (95% CI)

Osimertinib 93 8.5 (6.8-12.3)

Platinum-pemetrexed 51 4.2 (4.1-5.4)

Hazard ratio for disease progression

or death, 0.32 (95% CI, 0.2 1-0.49)

No. at Risk

Osimertinib 93 80 46 27 14 4 0

Platinum- 51 32 9 4 2 0 0

pemetrexed

Acquired resistance to 3rd-generation inhibitors

EGFR dependent -C797S (in trans: could be sensitive to combined therapy with first and third

generation TKI, cis:resistant), C797G, L798I, E790K, L692V, L781Q

-T790M reduction, disappearance or loss

-EGFR amplification

EGFR independent -HER2 amplification, MET amplification, PIK3CA mutations, PTEN loss, RAS-

MAPK pathway activation (KRAS mut, BRAF mut, MAPK1/AKT3), FGF2-

FGFR1 autocrine loop, EMT, NRAS mut/CNG, IGF1R activation, SCLC)

Thress KS et al. Nat Med 2015; 21(6): 560–2; Piotrowska Z et al. Cancer Discov 2015; 5(7): 713–22

T790-WT SCLC

T790-WT NSCLC

T790-positive NSCLC (EGFR-

amplified) (3

T790-positive NSCLC

Approaches for managing patients with resistant tumors

Osimertinib in combination with…

Ramucirumab (NCT02789345), bevacizumab

(NCT02803203)

Necitumumab (NCT02496663, NCT02789345)

Savolitinib (NCT02143466)

Durvalumab (NCT02454933, NCT027119671,

NCT02143466, NCT02664935)

INCB039110 (JAK inhibitor) (NCT02917993)

Selumetinib (NCT02143466, NCT02664935)

INK128 (TORC1 / 2) (NCT02503722)

Navitoclax (Bcl2) (NCT02520778)

AZD6094 (MET) (NCT02143466)

EGF816 + INC280 (MET), EGF816 + nivolumab

Agents targeting C797S

Targeting T790M-negative…

MET inhibition

MEK inhibitor combinations

EMT:AXL inhibition

SMO gene amplification (Hh receptor)

with MET activation

FGFR 1, 2, 3 activation

ErBB2 activation mutations

IGF1R activation

BRAF (Val600Glu, Gly469Ala) mutation

PIK3CA mutation

CASO CLINICO anamnesi

Giunge alla nostra osservazione nel novembre 2015:

• Antonio 15/01/1949, maschio, PS 0

• Non fumatore

• Pensionato, ex impiegato

• Nessuna comorbilità di rilievo

CASO CLINICO iter diagnostico-terapeutico

Storia clinica • Nel Dicembre 2013 diagnosi di adenocarcinoma polmonare IV stadio,

per lesioni epatiche, delezione dell’esone 19 del gene EGFR

• Intraprese subito trattamento con Gefitinib 250 mg/die

CASO CLINICO REFERTO CITOLOGICO

CASO CLINICO ANALISI MOLECOLARE BASALE

CASO CLINICO PD durante Gefitinib

• Per PD toracica ed epatica nell’ agosto 2015 intraprende 4 cicli di

CBDCA-PACLITAXEL, per ulteriore PD giunge alla nostra UOC nel

novembre dello stesso anno

•Si richiede BL per determinazione T790M

CASO CLINICO BL T790M+

CASO CLINICO trattamento dopo risultato BL

•Alla luce del dato molecolare il paziente viene inserito nello studio

ASTRIS ed inizia OSIMERTINIB 80 mg/die

CASO CLINICO SD DURANTE OSIMERTINIB REFERTO

CASO CLINICO SD DURANTE OSIMERTINIB IMMAGINE

CASO CLINICO PD DURANTE OSIMERTINIB REFERTO

CASO CLINICO PD DURANTE OSIMERTINIB IMMAGINE

CASO CLINICO BL IN PD DURANTE OSIMERTINIB

Open questions

Is there a difference in efficacy among TKIs?

Is there a role of TKI in uncommon EGFR mutations?

Is there a difference in safety among TKIs?

Percorso tortuoso……………

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Direct comparisons….

STUDY Comparison

CTONG 0901 Erlotinib vs Gefitinib

LUX-LUNG 7 Afatinib vs Gefitinib

ARCHER 1050 Dacomitinib vs Gefitinib

Erlotinib versus Gefitinib:

CTONG0901

Jin-Ji Yang, Denver 2015

Erlotinib was not superior to

Gefitinib in PFS and OS

Afatinib vs Gefitinib:

Lux-Lung-7

Treatment beyond progression allowed if deemed beneficial by investigator

RECIST assessment performed at Weeks 4, 8 and every 8 weeks thereafter until Week 64, and every 12 weeks thereafter

Afatinib 40 mg once daily†

Gefitinib 250 mg once daily

Primary endpoints:

• PFS (independent) • TTF • OS Secondary endpoints:

• ORR • Time to response • Duration of response • Duration of disease control • Tumor shrinkage • HRQoL • Safety

1:1

• Stage IIIB/IV adenocarcinoma of the lung

• EGFR mutation (Del19 and/or L858R) in the tumor tissue*

• No prior treatment for advanced/ metastatic disease

• ECOG PS 0/1

Stratified by • Mutation type (Del19/L858R) • Brain metastases (present/absent)

11 vs 10.9 mesi

27%

15%

18%

8%

Park K, Lancet Oncol 2016

Lux-Lung-7:

TTF e OS

Park K, Lancet Oncol 2016; Paz-Ares L, Ann Oncol 2017

27.9 versus 24.5 months

Yu YL, Clin Lung Cancer 2018

FLAURA

ASCO 2018: EGFR+

Dacomitinib: ARCHER 1050

Erlotinib + Bevacizumab: JO25567

Erlotinib + Bevacizumab: NEJ026

Gefitinib + Chemioterapia: NEJ009

Afatinib in real world

EGFR

Presented By Tony Mok at 2018 ASCO Annual Meeting

Erlotinib + bevacizumab: JO25567

Final Overall survival

Presented By Noboru Yamamoto at 2018 ASCO Annual Meeting

JO25567

Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR‐mutations: NEJ 026

Presented By Naoki Furuya at 2018 ASCO Annual Meeting

Primary endpoint ： PFS by independent review

Presented By Naoki Furuya at 2018 ASCO Annual Meeting

Phase III Study Comparing Gefitinib Monotherapy to Combination Therapy with Gefitinib, Carboplatin, and Pemetrexed for Untreated Patients with Advanced Non-Small Cell Lung Cancer with EGFR Mutations

(NEJ009)

Presented By Atsushi Nakamura at 2018 ASCO Annual Meeting

Study Design of NEJ009


Progression-Free Survival 1

Overall Survival


This non-interventional, observational, multi-country/site study used medical records

of TKI-naïve pts with EGFRm+ (Del19/L858R) NSCLC treated with first-line afatinib

Primary outcomes were % pts with adverse drug reactions (ADRs) by severity, time

on treatment, and time to progression

Halmos B, ASCO 2018

228 pts from 13 countries were included (Europe, Asia, North America)

Dose modifications were more frequent in females, older pts, Eastern Asian pts, and

lower body weight pts

67% of ≥40 mg starters underwent dose reductions, with 86% of those occurring in

the first 6 mos

There were no new safety signals, and fewer ≥G3 ADRs and SAEs than in LL3 (25%

vs 49% and 5% vs 14%)

Median time on treatment and TTP was 18.7 mos and 20.8 mos respectively and was

not impacted by reduced starting dose or dose modification

Halmos B, ASCO 2018

Post-ASCO18 Options for First-Line Treatment of EGFR mutation-positive NSCLC:

Presented By Lecia Sequist at 2018 ASCO Annual Meeting

Osimertinib is best first line treatment

Presented By Helena Yu at 2018 ASCO Annual Meeting

Gefitinib 10.8 mesi

Osimertinib 10.1 mesi

tot. 20.9

Erlotinib 11.0 mesi


tot. 21.1

Conti dell’Oste

Afatinib 11.1 mesi


tot. 21.2

Dacomitinib 14.7 mesi


tot. 24.8

Strategia terapeutica futura dei con

EGFRmut+

Farmaco ultima generazione?

Terapia sequenziale farmaco A+B ?

Farmaco A Farmaco B

Open questions




TKI in uncommon EGFR mutations

• Uncommon mutations:

Group 1: point mutations or duplications in exons 18–21

Group 2: de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations

Group 3: exon 20 insertions

Open questions




Costanzo R.. and Morabito A, Expert Rev Anticancer Ther 2013

Toxicity in randomized trials

Yang, IASLC 2015

CTONG 0901: toxicity Table 2.Treatment-Emergent AEs≥10% of Patients in Either Treatment Arm

AE

Gefitinib (n = 128) No. (%)

Erlotinib (n = 128) No. (%)

All grades Grade≥3 All grades Grade≥3

Rash 80 (62.5) 0 (0.0) 89 (69.5) 3 (2.3)

Cough 38 (29.7) 0 (0.0) 30 (23.4) 0 (0.0)

Diarrhea 24 (18.8) 0 (0.0) 22 (17.2) 0 (0.0)

Hand and foot syndrome

16 (12.5) 0 (0.0) 8 (6.3) 0 (0.0)

Nail changes 16 (12.5) 0 (0.0) 24 (18.8) 0 (0.0)

Anorexia 15 (11.7) 0 (0.0) 7 (5.4) 0 (0.0)

ALT increase 13 (10.2) 0 (0.0) 6 (4.7) 0 (0.0)

Bilirubin increase 13 (10.2) 0 (0.0) 7 (5.4) 3 (2.3)

Dry skin 11 (8.6) 0 (0.0) 13 (10.2) 0 (0.0)

Abbreviation: AE, adverse event. ALT, alanine aminotransferase.

LUX-LUNG-7: toxicity

†Plus 1 case of grade 4 diarrhea ; ‡Plus 1 case of grade 4 increased ALT ALT, alanine aminotransferase; AST, aspartate aminotransferase

AE category, %

Afatinib (n=160) Gefitinib (n=159)

All Grade 3 All Grade 3

Diarrhea 90.0 11.9† 61.0 1.3

Rash/acne* 88.8 9.4 81.1 3.1

Stomatitis* 64.4 4.4 23.9 -

Paronychia* 55.6 1.9 17.0 0.6

Dry skin 32.5 - 37.1 -

Pruritus 23.1 - 22.6 -

Fatigue* 20.6 5.6 14.5 -

Decreased appetite 16.3 0.6 11.9 -

Nausea 16.3 1.3 13.8 -

Alopecia 10.6 - 15.1 -

Vomiting 10.6 - 3.8 0.6

ALT increased 9.4 - 23.9 7.5‡

AST increased 6.3 - 20.8 2.5

LUX-LUNG-7:

toxicity in elderly

Yu YL, Clin Lung Cancer 2018

Grazie

La terapia del paziente EGFR mutato - AIOM · 3rd generation EGFR-TKIs targeting T790M Drug Company...

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