Presentación de PowerPointhitosoncologicos.com/wp-content/uploads/2017/11/01_M2.Dr_.ManuelDomine.… · Del19 L858R Del19 and L858R Subgroups Combined OS analysis of LUX-lung 3 and

El tratamiento actual de primera línea en CPNCP. EGFR mutado: balance entre eficacia/perfil de tolerancia

Manuel Dómine

Servicio de Oncología Médica. Hospital Universitario Fundación Jiménez Díaz

Instituto de Investigación Sanitaria- Fundación Jiménez Díaz (IIS-FJD).

• 17,664 patients with

NSCLC

• A genetic alteration

was recorded in about

50% of the analyses

• Presence of a genetic

alteration compared

with absence of a

genetic alteration was

associated with

improved:

first-line progression-

free survival (10·0

months [95% CI 9·2-

10·7] vs 7·1 months

[6·1-7·9]; p<0·0001)

overall survival (16·5

months [15·0-18·3] vs

11·8 months [10·1-

13·5]; p<0·0001)

Estudios Randomizados TKIs Vs Quimioterapia en pacientes con

mutaciones EGFR (TKIs 1ª generación)

Gefitinib

Estudio/ Fase Ramas de tratamiento Nºpacientes

(región) RR ( (%)

p m SLP

(meses) HR p

Supervivencia

SM (meses)

HR p

IPASS 1 2/III Gefitinib vs Carbo-taxol 261 Asia

71.2 vs 47.3 p<0.001

9.5 vs 6.3 0.48

p<0.001

21.6 vs 21.9

1

p= 0.990

First-SIGNAL 3/III Gefitinib vs Cis-gem 96

Corea 84.6 vs 37.5

p= 0.002 8.5 vs 6.7

0.54 p= 0.086

27.2 vs 25.6

1.043

p=0.428

WJTOC 3405 4 5/III Gefitinib vs Cis-docetaxel

177 Japón

62.1 vs 32.2 p< 0.0001

9.2 vs 6.3 0.488

p< 0.0001

36 vs 39

1.19

p= 0.443

NEJ002 6 7 /III Gefitinib vs Carbo-taxol

230 Japón

73.7 vs 30.7 p<0.001

10.4 vs 5.4

0.30 p<0.001

27.7 vs 26.6

0.887 p=0.483

RR: tasa de respuestas, mSLP: mediana de Supervivencia libre de progresión, SM: Supervivencia Mediana NR: no reportado



Erlotinib

Estudio/ Fase Ramas de tratamiento Nºpacientes

(región) RR ( (%)

p m SLP

(meses) HR p

Supervivencia

SM (meses)

HR p

OPTIMAL 8 9/III Erlotinib vs carbo-gem 154

China

83 vs 36

p< 0.0001

13.1 vs 4.6

0.16 p< 0.0001

22.8 vs 27.2

1.19 p = 0.2663

EURTAC 10/III Erlotinib vs cis-docetaxel 174

Europa 58 vs 15

p< 0.0001 9.7 vs 5.2

0.37 p< 0.0001

19.3 vs 19.5

1.04 p=0.87

ENSURE 11/III Erlotinib vs cis-gem 148 Asia

62.7 vs 33.6 p< 0.0001

11 vs 5.25 0.34

p< 0.0001

26.3 vs 25.5

0.91

p=0.607




(Afatinib)

Estudio/ Fase

Ramas de tratamiento

Nºpacientes (región)

RR ( (%) p

m SLP (meses)

HR p

Supervivencia SM

(meses)

HR p

LUX-LUNG 3/III Afatinib vs Cis-pem 345

Global 345

Global 11.1 vs 6.9

0.58 p= 0.001

28.2 vs 28.2

0.88

p=0.39

LUX-LUNG 6 /III Afatinib vs Cis-gem

364 China

67 vs 23 p< 0.0001

11 vs 5.6

0.28 p< 0.001

23.1 vs 23.5

0.93

p=061


L858R Del19

Del19 and L858R Subgroups

Combined OS analysis of LUX-lung 3 and LUX- lung 6 *

0.2

0.4

0.6

0.8

1.0

Estim

ate

d O

S p

rob

ab

ility

0.0

0 6 9 12 15 18 21 24 27 3 30 33 36 39 42 45 48 51

Time of overall survival (months)

Afatinib Chemotherapy

Del19

Afatinib (n=236)

Chemo (n=119)

Median, months 31.7 20.7

HR (95% CI)

P value

0.59 (0.45-0.77)

P=0.0001

L858R

Afatinib (n=183)

Chemo (n=93)

Median, months 22.1 26.9

HR (95% CI)

P value

1.25 (0.92-1.71)

P=0.1600

0 6 9 12 15 18 21 24 27

Time of overall survival (months)

0.0

3 30 33 36 39 42 45 48 51

0.4

0.6

0.8

1.0

Estim

ate

d O

S p

rob

ab

ility

0.2

Afatinib Chemotherapy

No. of patients:

Afatinib 183 181 167 154 141 128 11 91 80 70 64 51 27 20 11 30 0 0

Chemotherapy 93 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0

No. of patients:

Afatinib 236 230 223 217 202 192 173 160 145 131 117 90 50 38 22 6 1 0

Chemotherapy 119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0

*Yang et al. Lancet Oncology 2015

LUX-LUNG 7 STUDY DESIGN

Co-primary endpoints:

• PFS (independent review)

• TTF • OS

Secondary endpoints:

• ORR • Time to response • Duration of response • Tumour shrinkage • HRQoL

1:1

Patients (N=319)

• Stage IIIB/IV adenocarcinoma of the lung

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

• No prior treatment for advanced/metastatic disease

• ECOG PS 0/1

Stratified by

• Mutation type (Del19/L858R)

•Brain metastases (present/absent)

Afatinib

40 mg QD†

Gefitinib

250 mg QD

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

Primary PFS analysis conducted after ~250 events; primary OS analysis conducted after ~213 events and ≥32-mo follow-up

All statistical testing at two-sided 5% alpha level with no adjustment for multiplicity

PFS by Independent Review

No. at risk:

Afatinib 160 142 112 94 67 47 34 27 21 13 6 3 1 0 0

Gefitinib 159 132 106 83 52 22 14 9 7 5 3 3 1 1 0

1.0

0.8

0.6

0.4

0.2

0

0

Time of progression free survival (months)

Esti

mat

ed P

FS p

rob

abili

ty

Afatinib Gefitinib

Median, mo 11.0 10.9

HR (95% CI) P-value

0.73 (0.57-0.95) 0.0165

27%*

18%†

15% 8%

3 6 9 12 15 18 21 24 27 30 33 36 39 42

Afatinib

Gefitinib

Park K et al. Lancet Oncol. 2016;17(5):577-89; * P=0.0176 †. P=0.0184

PFS by Mutation Type (Independent Review) Del19

No. at risk:

Afatinib 93 83 67 58 43 31 22 18 14 9 4 2 1 0 0

Gefitinib 93 76 64 53 32 17 11 7 6 4 3 3 1 1 0

Time of progression-free survival (months)

Esti

mat

ed P

FS p

rob

abili

ty

1.0

0.8

0.6

0.4

0.2

0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

L858R

No. at risk:

Afatinib 67 59 45 36 24 16 12 9 7 4 2 1 0 0 0

Gefitinib 66 56 42 30 20 5 3 2 1 1 0 0 0 0 0


Esti

mat

ed P

FS p

rob

abili

ty

1.0

0.8

0.6

0.4

0.2

0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Afatinib (n=67)

Gefitinib (n=66)


HR (95% CI), P-value

0.71 (0.47-1.06) 0.0856

Afatinib

Gefitinib

Afatinib

Gefitinib

Afatinib (n=93)

Gefitinib (n=93)


HR (95% CI), P-value

0.76 (0.55-1.06) 0.1071

Park K et al. Lancet Oncol. 2016;17(5):577-89

Overall Survival (71% Maturity; April 2016) Es

tim

ated

Ove

rall

Surv

ival

Pro

bab

ility

No. at risk:

Afatinib 160 156 153 148 139 125 111 104 94 81 74 61 50 36 30 12 2 0

Gefitinib 159 153 148 142 133 119 105 90 80 71 62 56 48 44 27 7 0 0

Time to Death (months)

0.8

1.0

0.6

0.4

0.2

0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Afatinib Gefitinib

Events 109 117


HR (95% CI) P-value

0.86 (0.66-1.12) 0.2580

Afatinib

Gefitinib

61%#

51%

48%$

40%

* #P=0.0756; $P=0.1321. Paz-Ares L et al. Ann Oncol, 2017 epub ahead of print

Os by EGFR mutation subtype. (Update Dec. 2016)

OS trends with afatinib were consistent across mutational (Del19, 30.7 months; L858R, 25.0 months) subgroups

Del19

L858R

Corral J et al., ELCC 2017; #93PD

Drug-Related AEs (≥20, updated)

Low rates of treatment discontinuation due to drug-related AEs were observed in each arm (6,3% each)

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

All Gr Grade ≥3* All Gr Grade ≥3*

Any AE, n (%) 156 (97.5) 50 (31.3) 153 (96.2) 31 (19.5)

Diarrhoea 144 (90.0) 21 (13.1)† 97 (61.0) 2 (1.3)

Rash/Acne‡ 142 (88.8) 15 (9.4) 129 (81.1) 5 (3.1)

Stomatitis‡ 103 (64.4) 7 (4.4) 38 (23.9) 0

Paronychia‡ 90 (56.3) 3 (1.9) 28 (17.6) 1 (0.6)

Dry skin 52 (32.5) 0 59 (37.1) 0

Pruritus 37 (23.1) 0 36 (22.6) 0

Fatigue‡ 33 (20.6) 9 (5.6) 23 (14.5) 0

ALT increased 15 (9.4) 0 38 (23.9) 13 (8.2)†

AST increased 10 (6.3) 0 33 (20.8) 4 (2.5)

Paz-Ares L et al Paz-Ares L et al. Ann Oncol, 2017

Median PFS was similar in patients who had dose reductions in the first 6 months and those who remained on afatinib 40 mg once daily

Yang J et al. J Clin Oncol 33, 2015 (suppl; abstr 8073); Schuler M et al., ELCC 2016, #138PD; Hirsh V JCO 34, 2016 (suppl; abstr 9046

<40 mg in first 6 months

≥40 mg in first 6 months

Time (months)

1.0

0.6

0.4

0.2

0

Estim

ate

d P

FS

pro

ba

bility

0 3 6 9 12 15 18 21 24 27

0.8

Estim

ate

d P

FS

Pro

ba

bility

Time (months)

1.0

0.6

0.4

0.2

0

0 3 6 9 12 15 18 21 24 27

0.8

Estim

ate

d P

FS

pro

ba

bility


1.0

0.8

0.6

0.4

0.2

0

0 3 6 9 12 15 18 21 24 27 30 33 36 39

LUX-Lung 3

LUX-Lung 6

LUX-Lung 7

Phase III trial ARCHER 1050

Dacomitinib vs Gefitinib for the First-Line Treatment of Advanced NSCLC

Mok T, et al. ASCO 2017. Abstract LBA9007.

AE Occurring in ≥ 15% in Either Arm, %

Dacomitinib (n = 227) Gefitinib (n = 224)

Any Gr 1 Gr 2 Gr 3 Any Gr 1 Gr 2 Gr 3

Diarrhea* 87.2 49.8 28.6 8.4 55.8 46.0 8.9 0.9

Paronychia 61.7 20.3 33.9 7.5 20.1 13.4 5.4 1.3

Dermatitis acneiform 48.9 16.3 18.9 13.7 28.6 19.2 9.4 0

Stomatitis 43.6 22.5 17.6 3.5 17.9 14.7 2.7 0.4

Decreased appetite 30.8 17.6 10.1 3.1 24.6 21.4 2.7 0.4

Dry skin 27.8 18.5 7.9 1.3 17.0 15.6 1.3 0

Weight decrease 25.6 13.7 9.7 2.2 16.5 9.8 6.3 0.4

Alopecia 23.3 18.1 4.8 0.4 12.5 11.6 0.9 0

Cough 21.1 17.2 4.0 0 18.8 16.1 2.2 0.4

Pruritis 19.8 11.9 7.5 0.4 13.8 10.7 1.8 1.3

ALT increase 19.4 16.3 2.2 0.9 39.3 20.1 10.7 8.5

Outcome Dacomitinib

(n = 227) Gefitinib (n = 224)

Serious AE, n (%) •Any •Treatment related

• Causing discontinuation • Causing death

62 (27.3) 21 (9.3) 22 (9.7) 2 (0.9)*

50 (22.3) 10 (4.5) 15 (6.7) 1 (0.4)†

Median time to dose reduction, mos (range) 2.8 (0.3-20.3) 3.3 (1.2-25.7)

Median duration of dose reduction, mos (range) 11.3 (0.1-33.6) 5.2 (0.3-17.8)

Reduced dose given, n (%) •30 mg/day •15 mg/day

87 (38.3) 63 (27.8)

NA

Pts requiring dose reduction, n (%) 150 (66.1) 18 (8.0)

ARCHER 1050: Serious AE and Dose Modification

*Gr 5 diarrhea, n = 1. Otherwise, no listed AE with severity above grade 3 in either arm.

JO25567: erlotinib vs erlotinib + bevacizumab PFS by independent review in all patients

(primary endpoint)

75 72 69 64 60 53 49 38 30 20 13 8 4 4 0

77 66 57 44 39 29 24 21 18 12 10 5 2 1 0 T

A+T

Number at risk

0 0

1.0

Time (months)

4 8 12 2 6 10 14 18 22 26 16 20 24 28

0.2

0.4

0.6

0.8

PF

S p

robabili

ty

9.7 16.0

HR=0.54 (0.36–0.79) Log-rank p<0.0015

Avastin + Tarceva

Tarceva

Seto, et al. Lancet Oncol, 2014

JO25567: PFS by EGFR mutation type

Seto, et al. Lancet Oncol, 2014

Seto, et al. Lancet Oncol 2014

JO25567: AEs in >20% of patients

First line EGFR m+ Erlotinib + BVZ BELIEF Phase II trial

• Ph II BELIEF (2015 ECC)

– 1st Line: erlotinib + BVZ

– n=109 EGFRm+ (Del 19, L858R)

– 37 pts T790m+ pretreatment

• SLP 1a: 72.4%

• SLPm 16m

• TRO: 70.3%

– 72 pts T790m- pretreatment

• SLP 1a: 49.4%

• SLPm: 10.5m

• TRO: 79.2%

Rosell R, et al. Lancet Respir Med. 2017;5:435-444

FLAURA: Phase III TRIAL Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm

advanced NSCLC

Soria et al. NEJM 2017; November 18, 2017DOI: 10.1056/NEJMoa1713137

FLAURA: Phase III TRIAL Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced

NSCLC



advanced NSCLC



advanced NSCLC


Median PFS, months (95% CI)

18.9 (15.2, 21.4)

10.2 (9.6, 11.1)

1.0

Pro

bab

ility

of

pro

gre

ssio

n-f

ree

surv

ival

0.2

0.4

0.6

0.8

0.0

0 3 6 9 12 15 18 21 24 27

Time from randomisation (months)

279

277

262

239

233

197

210

152

178

107

139

78

71

37

26

10

4

2

0

0

No. at risk

Osimertinib

SoC

Osimertinib

SoC

HR 0.46

(95% CI 0.37, 0.57)

p<0.0001

# Pre-existing T-790M IN

34-35% of patients.

Rosell Lancet Respiratory

2017, Rosell CCR11

Osimertinib in first line increase PFS because target clones with T790M from the beginning OR RELAPSE THE APARITION OF T790M AS THE FIRST

RESISTANCE MECHANISM ?

All causality AE in

≥15% of patients, %

Osimertinib (n=279) SoC (n=277)

Any grade Grade 3 Grade 4 Any grade Grade 3 Grade 4

Diarrhoea 161 (58) 6 (2) 0 159 (57) 6 (2) 0

Dry skin 88 (32) 1 (<1) 0 90 (32) 3 (1) 0

Paronychia 81 (29) 1 (<1) 0 80 (29) 2 (1) 0

Stomatitis 80 (29) 1 (<1) 1 (<1) 56 (20) 1 (<1) 0

Dermatitis acneiform 71 (25) 0 0 134 (48) 13 (5) 0

Decreased appetite 56 (20) 7 (3) 0 51 (18) 5 (2) 0

Pruritus 48 (17) 1 (<1) 0 43 (16) 0 0

Cough 46 (16) 0 0 42 (15) 1 (<1) 0

Constipation 42 (15) 0 0 35 (13) 0 0

AST increased 26 (9) 2 (1) 0 68 (25) 12 (4) 0

ALT increased 18 (6) 1 (<1) 0 75 (27) 21 (8) 4 (1)

FLAURA: Phase III TRIAL Adverse Events


AEs

Gefitinib

ARCHER

Erlotinib

JO25567

Afatinib

LL7

Dacomitinib

ARCHER

Osimertinib

FLAURA

Erlo + BVZ

JO25567

Any/Grade ≥ 3 Any/Grade ≥ 3 Any/Grade ≥ 3 Any/Grade ≥ 3 Any/Grade ≥ 3 Any/Grade ≥ 3

Diarrhoea 55.8/0.9 78/1 90/13.1 87.2/8.4 58/2 81/1

Dry skin 17/0 75/3 52/0 27.8/1.3 32/<1 76/3

Paronychia 20.1/1.3 65/4 56.3/13.1 61.7/7.5 29/<1 75/3

Stomatitis 17.9/0.4 60/3 64.4/4.4 43.6/3.5 29/<2 63/1

Dermatitis acneiform 28.6/0 99/19 88.8/9.4 48.9/13.7 25/0 99/25

Decreased appetite 24.6/0.4 32/1 17/0 30.8/3.1 20/3 35/1

Pruritus 13.8/1.3 42/0 23.1/0 19.8/0.4 17/<1 45/1

AST/ALT increased 39.3/8.5 51/18 16/0 19.4/0.9 18/1 44/8

Hypertension - 13/10 - - - 76/60

Haemorrhagic Event

- 29/0 - - - 72/3

Proteinuria - 4/0 - - - 52/8

AEs causing

discontinuation %

8

18

6.3

9.7

13

16

Randomized Trials EGFR TKIs Trials Adverse Events

First Line Trials with TKIs EGFR + Progression Free survival (months)

0

2

4

6

8

10

12

14

16

18

20

Gefitinib Erlotinib Afatinib Dacomitinib Erlo + Bvz Osimertinib

IPA

SS

Fir

st

Sig

nal

WJT

OG

NE

J002

OP

TIM

AL

EU

RT

AC

EN

SU

RE

LU

X -

LU

NG

3

LU

X -

LU

NG

6

LU

X -

LU

NG

7 AR

CH

ER

1050

J025567

BE

LIE

F

FL

AU

RA

PFS comparison second vs third gen TKIs

35.8%

LL7 ARCHER FLAURA

Efficacy of Afatinib in Uncommon mutations

Preliminary results: poziotinib induces partial response in 73% of patients with EGFR Exon 20 mutations

-11 EGFR exon 20 patients with baseline and follow

up scans at 2 m (longest on treatment=6 months).

-Activity: 8/11 PR observed; 2 patients have had

additional follow up scans confirming PR.

-duration of response not yet evaluable; only one

patient with PD thus far.

-Evidence of CNS activity in patient with CNS

metastasis and another with LMD

-additional patient treated on compassionate use IND

(CIND) also had PR

-Toxicities: significant EGFR-related toxicities

include rash, diarrhea, paronychia, mucositis

consistent with those previously described.

-55% underwent dose reduction to 12mg thus far

-6 0

-4 5

-3 0

-1 5

0

1 5

3 0

4 5

Ma

xim

um

Re

sp

on

se

fro

m

Ba

se

lin

e

V7

69

ins

GS

V

H7

73

ins

AH

H7

73

du

pP

R

N7

71

ins

HH

D7

70

ins

G

P7

72

ins

DN

P

A7

67

du

pA

SV

S7

68

I

S7

68

du

pS

VD

D7

70

de

l in

sG

Y

D7

70

ins

Y H

77

3Y

S E,AA,P

PoziotinibPrior Therapy:

P = AP32788

S= ASP 8273

E = Erlotiniib

A = Afatinib

Abstract ID 10369, Elamin et al. Elamin et al. IASLC 2017 Ab 10369

Poziotinib in exon 20 inertions EGFR Exon 20 insertions have a sterically hindered binding pocket

Robichaux et al WCLC 2016

EGFR D770insSVD EGFR T790M

PD: rebiopsy Initial biopsy PD: rebiopsy

Thress et al, NEJM 2015, Ortiz-Cuaran et al, CCR 2016,

Fassunke et al, in prep.

Erlotinib, Gefitinib,

Afatinib (10m) T790M Osimertinib (10m) EGFRde

l 19

L858R

also: liquid biopsy

Osimertinib (20m)

EGFR

C797S

EGFR

G724S

hl MET

amp.

HER2

amp.

KRAS

mut

clinical

trials

Chemotherapy

Targeted treatments are evaluated in resistance to 3rd gen inhibitor

also: liquid biopsy also: liquid biopsy

OS in patients treated with a subsequent 3rd-generation EGFR TKI

20% / 17% who discontinued afatinib / gefitinib received 3rd gen TKIs (osimertinib, olmutinib and rociletinib)

Corral J et al., ELCC 2017; #93PD

35

¿Cuál es la secuencia óptima para EGFR mutados?

1ª generación TKI

(10 meses)

Osimertinib en T790M

(10 meses) OS 27

meses

OS 22

meses

2ª generación TKI

(14-16 meses)


(10 meses)

QT

(5 meses)

Osimertinib

(19 meses)

OS ?

OS 27

meses

QT

(5 meses)

QT

(5 meses) OS ?

Erlotinib + BVZ

(16 meses)


(10 meses)

QT

(5 meses)

OS ?

OS ?

CONCLUSIONES

• Osimertinib es el fármaco más eficaz en términos de SLP

• Osimertinib es el que presenta mejor perfil de tolerancia

• ¿Debe ser nuestra primera opcíón de tratamiento en todos los pacientes?

• Si en pacientes con metastasis cerebrales

• Si en pacientes con mutaciones de T790M de novo

• En pacientes con mutaciones no comunes (18-21 (L861Q, G719S, G719A, G719C,

S768I, y otras), afatinib ha mostrado una eficacia alta y podría ser la primera opción.

• En el resto de pacientes los tratamientos secuenciales con TKIs de 1ª y 2ª generación

seguido de orsimetinib en T790M + pueden obtener SLP comparables a osimetinib en

1ª línea. Inserciones 20: Pociotinib

• La secuencia óptima todavia es incierta y todavía está pendiente de los resultados de

supervivencia de los estudios AURA y FLAURA

• Pendientes de resultados de estudios de combinaciones con antiangiogénicos e

inmmunoterapia

Documents

Presentación de PowerPointhitosoncologicos.com/wp-content/uploads/2017/11/01_M2.Dr_.ManuelDomine.… · Del19 L858R Del19 and L858R Subgroups Combined OS analysis of LUX-lung 3 and