Danilo Rocco
Pneumologia ad indirizzo Oncologico
La terapia del paziente EGFR
mutato
Percorso
facile………
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
GEFITINIBCb/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
GEFITINIBCb/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
GEFITINIBCis/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
ERLOTINIBCis/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
ERLOTINIBP/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
ERLOTINIBP/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
AFATINIBCis/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
AFATINIBCis/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
ingombrante
1,2Questo causa ingombro sterico, che riduce il legame degli EGFR-TKIs, erlotinib e gefitinib, a EGFR
1,21. 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
Fractional velocity*
-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
Fractional velocity*
-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
3 rd 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
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+
AURA
2Studio 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
AURA
3Disegno dello Studio
1AURA 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 sperimentatore
11. Mok T.S. et al, NEJM 2016
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 3
11. Mok T.S. et al, NEJM 2016
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 CITOLOGICOCASO CLINICO
ANALISI MOLECOLARE BASALECASO 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?
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………
Is there a difference in efficacy among TKIs?
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
Yu YL, Clin Lung Cancer 2018
Yu YL, Clin Lung Cancer 2018
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
Slide 4
Presented By Tony Mok at 2018 ASCO Annual Meeting
Slide 6
Presented By Tony Mok at 2018 ASCO Annual Meeting
Slide 8
Presented By Tony Mok at 2018 ASCO Annual Meeting
Slide 5
Presented By Tony Mok at 2018 ASCO Annual Meeting
Slide 9
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 <br />to erlotinib in patients with untreated NSCLC <br />harboring activating EGFR‐mutations:<br /> 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
Presented By Atsushi Nakamura at 2018 ASCO Annual Meeting
Progression-Free Survival 1<br /><br /><br /><br />
Presented By Atsushi Nakamura at 2018 ASCO Annual Meeting
Overall Survival
Presented By Atsushi Nakamura at 2018 ASCO Annual Meeting
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 Osimertinib 10.1 mesi tot. 21.1
Conti dell’Oste
Afatinib 11.1 mesi Osimertinib 10.1 mesi tot. 21.2
Dacomitinib 14.7 mesi
Osimertinib 10.1 mesi
tot. 24.8
Strategia terapeutica futura dei con EGFRmut+
Farmaco ultima generazione?
Terapia sequenziale farmaco A+B ?
Farmaco A Farmaco B
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?
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
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?
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
