EGFR gene mutations Ex 19 Ex 21 Paez et al, Science 2004

(1)

Evolution of knowledge in NSCLC

(2)

Fattori da considerare nella

scelta terapeutica del NSCLC nel 2012

Stadio di malattia

PS

Età

Comorbidità

Compliance

Compliance e desiderio del paziente

e desiderio del paziente

Istologia (squamoso vs non

Istologia (squamoso vs non--squamoso)

g ( q

squamoso)

q

)

Mutazioni di EGFR

Riarrangiamento

Riarrangiamento di ALK (EML

di ALK (EML 4ALK)

4ALK)

(3)

EGFR gene mutations

Ex 19

Paez et al, Science 2004

(4)

EGFR gene mutations

Activating mutations with Activating mutations with ligandligand independent receptor independent receptor

activity activity activity activity

90% in 90% in exonsexons 19 (deletion) and 21 (LB58R)19 (deletion) and 21 (LB58R)

Global incidence: 10%Global incidence: 10% caucasianscaucasians; 30; 30--40% Asiatic pts40% Asiatic pts

Global incidence: 10% Global incidence: 10% caucasianscaucasians; 30; 30--40% Asiatic pts40% Asiatic pts

++ never++ never--smoker or lightsmoker or light--smokersmoker

More frequent in female sexMore frequent in female sex

++ ++ adenocarcinomaadenocarcinoma (in particular BAC non (in particular BAC non mucinousmucinous))

Predictive factor of EGFRPredictive factor of EGFR--TKIs, TKIs, gefitinibgefitinib and and

,, gg

erlotinib

erlotinib (in retrospective and prospective studies)(in retrospective and prospective studies)

(5)

IPASS: Study design

Endpoints Gefitinib (250 mg / day) Patients •Chemonaïve •Age ≥18 years Primary •Progression-free survival (non-inferiority) Endpoints (250 mg / day) 1:1 randomisation •Adenocarcinoma histology

•Never or light

ex-smokers*

Secondary

•Objective response rate

•Overall survival •Quality of life Carboplatin (AUC 5 or 6) / paclitaxel •Life expectancy ≥12 weeks •PS 0-2 y •Disease-related symptoms

•Safety and tolerability

E l t

(200 mg / m2₎ 3 weekly#

•Measurable stage IIIB /

IV disease

Exploratory

•Biomarkers

•EGFR mutation

•EGFR-gene-copy number

•EGFR protein expressionp p

•

(6)

Progression

Progression--free survival

free survival in

in

EGFR

mutation positive and negative patients

EGFR mutation positive EGFR mutation negative

HR (95% CI) = 0.48 (0.36, 0.64) p<0 0001 Gefitinib (n=132) Carboplatin / paclitaxel (n=129) HR (95% CI) = 2.85 (2.05, 3.98) p<0 0001 0.8 1.0 e surv iv al 0.8 1.0 e surv iv al Gefitinib (n=91) Carboplatin / paclitaxel (n=85) p<0.0001

No. events gefitinib, 97 (73.5%) No. events C / P, 111 (86.0%)

p<0.0001

No. events gefitinib , 88 (96.7%) No. events C / P, 70 (82.4%) 0.4 0.6 progression-fre e 0.4 0.6 progression-fre e 0 4 8 12 16 20 24 0.0 0.2 P robability of 0 4 8 12 16 20 24 0.0 0.2 P robability of 132 71 31 11 3 0 129 108103 37 7 2 1 0 0 4 8 12 16 20 24 Gefitinib C / P At risk : 91 4 2 1 0 0 85 2158 14 1 0 0 0 0 4 8 12 16 20 24 Months Months

Treatment by subgroup interaction test, p<0.0001

(7)

IPASS: Response Rates and

Quality of life

Mutation Positive M+ HR: 2 75;P=0 0001 Carboplatin/paclitaxel 60 70 80 _71.2% Gefitinib M+ HR: 2.75; P=0.0001 M– HR: 0.04; P=0.0013 30 40 50 ORR 60 47.3% 23 5% N=91 1.1% 0 10 20 N=132 N=129 N=85 23.5% Mutation Negative Mutation Positive

Mok et al, NEJM 2009

Thongprasert et al, JTO 2011

(8)

Randomized studies of

EGFR TKI

CT i fi t

EGFR TKI

CT i fi t li

li

th

EGFR TKIs vs CT in first

EGFR TKIs vs CT in first--line therapy

line therapy

Author

Author StudyStudy N N

(EGFR +) (EGFR +) RR, % RR, % (TKI vs CT) (TKI vs CT) PFS, months PFS, months (HR, 95%CI) (HR, 95%CI) OS, months OS, months Mok et al, 2009 IPASS CT vs GefitinibGefitinib 261 71.2 vs 47.3 9.5 vs 6.4 0.48 0.48(0.36-0.64) 21.6 vs 21.9 Lee et al First-SIGNAL 42 84 6 vs 37 5 8 4 vs 6 7 30 6 vs 26 5 Lee et al, 2009 First-SIGNAL PG vs GefitinibGefitinib 42 84.6 vs 37.5 8.4 vs 6.7 0.61 0.61(0.31-1.22) 30.6 vs 26.5 Mitsudomi et al, 2009 WJTOG 3405 PD vsGefitinibGefitinib 172 62.1 vs 32.2 9.2 vs 6.3 0 49 0 49(0 34-0 71) 36 vs 39 (ASCO 12) PD vs GefitinibGefitinib 0.490.49(0.34 0.71) (ASCO 12) Maemondo et al, 2010 NEJGSG002 CT vs GefitinibGefitinib 230 74.5 vs 29 10.8 vs 5.4 0.32 0.32 (0.24-0.44) 27.7 vs 26.6 Zhou et al, 2011 OPTIMAL CG vs ErlotinibErlotinib 154 83 vs 36 13.7 vs 4.6 0.16 0.16 (0.10-0.26) 22.7 vs 28.6 (ASCO 12) Rosell et al, EURTAC 174 58.1 vs 14.9 9.7 vs 5.2 19.3 vs 19.5 2012 P-bas vs ErlotinibErlotinib 0.370.37(0.25-0.44)

Yang et al, ASCO 2012 LUX-LUNG 8 PA vs AfatinibAfatinib 345 56.1 vs 22.6 11.1 vs 6.9 0.58 0.58(0.43-0.78) NR vs NR

(9)

Meccanismi di resistenza

a EGFR

a EGFR TKIs

TKIs

a EGFR

a EGFR--TKIs

TKIs

(10)

FISH Assay for

ALK

Rearrangement

t(2;5) ALK gene b k i t i 2p23 region Telomere Centromere ALK 29.3 p23.2 p22.3 p24.1 p24.3 p25.2 p23.2 p22.3 p24.1 p24.3 p25.2 ~250 kb ~300 kb breakpoint region 3’ 5’ EML4 42.3 p12 p13.2 p14 p16.1 p16.3 p22.1 p12 p13.2 p14 p16.1 p16.3 p22.1 250 kb 300 kb

Break-apart FISH assay for ALK-fusion genes1

23 2 q22.2 q22.1 q21.2 q14.3 q14.1 q12.3 q12.1 q23 2 q22.2 q22.1 q21.2 q14.3 q14.1 q12.3 q12.1 q32.1 q32.3 q33.2 q31.3 q24.3 q24.1 q23.2 q q32.1 q32.3 q33.2 q31.3 q24.3 q24.1 q23.2 N lit i l

ALK break-apart FISH assay q36.1 q36.3 q37.2 q34 q33.2 q36.1 q36.3 q37.2 q34 q Split signal Non-split signal b ea apa t S assay

[Courtesy John Iafrate, Massachusetts General Hospital]

Shaw AT et al. J Clin Oncol 2009 Shaw AT et al. J Clin Oncol 2009

Assay is positive if rearrangements can be detected in ≥15% of cells FISH = fluorescence in situ hybridization

(11)

ALK rearrangements:

clinico

clinico pathologic characteristics

pathologic characteristics

clinico

clinico--pathologic characteristics

pathologic characteristics

Global incidence: ~ 5%; + EML4-ALK translocation Determination with FISH; ongoing studies with IHC ++ never-smoker or light-smoker; ++ young pts

Similar incidence in Caucasians and Asiatic pts

++ adenocarcinoma with acinar o solid patterns (in

ti l i t i t ll ) particular signet ring-type cells)

In general mutually exclusive with EGFR and K-ras

mutations mutations

Factor of EGFR-TKI resistance; preliminary data of

higher response to pemetrexedg p p

(12)

Tumor Responses to Crizotinib for

Patients with

ALK

--positive NSCLC

positive NSCLC

60 Progressive disease Stable disease

p

40 20 Stable disease

Confirmed partial response Confirmed complete response

r size (%) 0 –20 g e in tumo r –30% –40 –60 m um chan g No. prior regimens* ORR % (n/N) –80 –100 Maxi m regimens % (n/N) 0 80 (4/5) 1 52 (14/27)

2 67 (10/15) Objective response rate (ORR):

*Partial response patients with 100% change have non-target disease present

*

2 67 (10/15)

≥3 56 (19/34)

j p ( )

57% (95% CI: 46, 68%)

(13)

Responses to

Responses to Crizotinib

Crizotinib:

:

update PROFILE trial 1001 (149

update PROFILE trial 1001 (149 pts

p

(

pts))

p

p ))

133 pts with measurable disease 39 pts treated beyond PD

RR: 60.8%

DCR: 82.5% at week 88

70.6% at week 16

RR: similar regardless age, sex, PS, line

PFS: 9.7 months (7.7-12.8 months) I line 18.3 months

Camidge et al, Lancet Oncol 2012

II line or later 9.2 months

(14)

Crizotinib

Crizotinib PROFILE Program

PROFILE Program

PROFILE 1007 (N=318)

R A

N Crizotinib 250 mg b.i.d. (n=159)[continuous]

PROFILE 1007 (N=318)

ALK‐positive by central laboratory

1 prior chemotherapy (platinum‐based) N D O M I S E [continuous] Pemetrexed 500 mg/m2_or docetaxel 75 mg/m2_(n₌₁₅₉₎

infused on day 1 of a 21‐day cycle

PROFILE 1005 (N=400)

ALK‐positive by central laboratory

≥1 prior chemotherapy and not eligible for

E infused on day 1 of a 21 day cycle

Crossover on PD Crizotinib 250 mg b.i.d. (N=400) [continuous] p py g 1007 PROFILE 1014 (N=334) R A N Crizotinib 250 mg b.i.d. (n=167) [continuous] PROFILE 1014 (N 334)

ALK‐positive locally advanced / metastatic non‐

squamous NSCLC

No prior treatment for advanced disease

N D O M I S E Crossover on PD [ ] Pemetrexed/cisplatin or pemetrexed/carboplatin (n=167) i f d d 1 f 21 d l

E infused on day 1 of a 21‐day cycle

(15)

PROFILE 1007: PFS by independent

radiological review (ITT)

(16)

PROFILE 1007: ORR by independent

radiological review (ITT)

(17)

Resistenza a Crizotinib

(18)

EGFR e ALK e relativi

inibitori a confronto

Variable EGFR and TKI ALK and TKI notes

Pts characteristics ADK, NS o Light-S ADK, NS o Light-S Ex 20 vs 35%, S 5%

Prognostic factor Yes (good) Y/N

RR and PFS 70% and 9-12 months 60% and 7-9 months Regardless line

Resp and mutation type > Del 19 than L858R < atypical mut

Probably diff according to variants

Toxicity and outcome Skin (60%), early outcome correlation

Visual (60%), early (14 days) ?

Flare at stop (%) Yes (23%) Yes (?)

Res mechanisms 1st_{T790M and others} ₁st_{C1156Y, L1196M and others} _{T790M intratorax PD}

Brain PD in Crizo

Overcome Res Many strategies Many strategies Hsp90, Beyond PD and local therapy

Resp to CT > than EGFR wt Resp to PEM > than ALK neg

EGFR gene mutations Ex 19 Ex 21 Paez et al, Science 2004

Evolution of knowledge in NSCLC

Stadio di malattia

EGFR gene mutations

Paez et al, Science 2004

EGFR gene mutations

activity activity activity activity

erlotinib

IPASS: Study design

ex-smokers*

Progression

EGFR mutation positive EGFR mutation negative

IPASS: Response Rates and

Mok et al, NEJM 2009

Randomized studies of

Author

Meccanismi di resistenza

t(2;5) ALK gene b k i t i 2p23 region Telomere Centromere ALK 29.3 p23.2 p22.3 p24.1 p24.3 p25.2 p23.2 p22.3 p24.1 p24.3 p25.2 ~250 kb ~300 kb breakpoint region 3’ 5’ EML4 42.3 p12 p13.2 p14 p16.1 p16.3 p22.1 p12 p13.2 p14 p16.1 p16.3 p22.1 250 kb 300 kb

ALK rearrangements:

ti l i t i t ll ) particular signet ring-type cells)

Tumor Responses to Crizotinib for

60 Progressive disease Stable disease

Responses to

133 pts with measurable disease 39 pts treated beyond PD

Crizotinib

N Crizotinib 250 mg b.i.d. (n=159)[continuous]

PROFILE 1007 (N=318)

infused on day 1 of a 21‐day cycle

PROFILE 1005 (N=400)

E infused on day 1 of a 21 day cycle

PROFILE 1007: PFS by independent

inibitori a confronto

Variable EGFR and TKI ALK and TKI notes

From target to therapy approved