cáncer colorrectal · os con inhibidores de egfr en ccrm braf mt egfr inhibitors are authorised...

Cáncer Colorrectal P. García Alfonso

Jefe de Sección de Oncología Médica HGU Gregorio Marañón de Madrid

Metastatic Colorectal Cancer

« A continuum of care »

• Treatment is a continuum of care, as many patients progress through multiple lines of therapy

Van Cutsem E . ESMO consensus guidelines for management of patients

with mCRC. Annals of oncology 0:1-37, 2016.

30 months overall survival

10 months 6 months 3 months few months PFS

5FU, cape, TAS 102, oxaliplatino, irinotecan

Bevacizumab Panitumumab, cetu aflibercept , ramucirumab regorafenib

Significant improvement in

Trial Fluoropyrimidine Irinotecan or

oxaliplatin EGFR

inhibitor RR PFS OS

CRYSTAL Inf + bolus 5-FU Irinotecan Cetuximab + + +

COIN Inf + bolus 5-FU Oxaliplatin Cetuximab + + –

Capecitabine Oxaliplatin Cetuximab – – –

NORDIC Bolus 5-FU Oxaliplatin Cetuximab – – –

PRIME Inf + bolus 5-FU Oxaliplatin Panitumumab + + +

Resultados de los ensayos fase III con inhibidores de EGFR

Grothey & Lenz. J Clin Oncol 2012

Resultados de los ensayos fase III con Bevacizumab en

primera línea de CCRm

1. Hurwitz, et al. NEJM 2004; 2. Saltz, et al. JCO 2008; 3. Tebbutt, et al. JCO 2010 4. Cunningham, et al. ASCO GI 2013; Falcone NE Med 2014

Regimen

Tx

line N Post-study therapy

ORR

(%)

Median

PFS

(months)

Median

OS

(months)

Dobletes

IFL

IFL + bevacizumab1 1L 813 2L: ~50%

2L: ~50%

35

45*

6.2

10.6*

15.6

20.3*

XELOX/FOLFOX

XELOX/FOLFOX + bevacizumab2 1L 1,401 2L: 53%

2L: 46%

38

38

8.0

9.4*

19.9

21.3

Monoterapia

Capecitabine

Capecitabine + bevacizumab3 1L 313 68%

62%

30

38

5.7

8.5*

18.9

18.9

Capecitabine

Capecitabine + bevacizumab4 1L 280 37%

37%

10

19*

5.1

9.1*

16.8

20.7

*Statistically significant difference vs the control arm

NR = not reported

Selección de Tratamiento

Marcadores Clínicos

Marcadores Moleculares

Factores socioeconómicos y preferencias del

paciente

Caracteristicas del paciente Edad PS Comorbilidades QT adyuvante Características Tumorales Volumen tumoral - Posible cirugía

rescate - Síntomas y

agresividad - Localización

Biomarcadores Grado histológico CEA MSI KRAS NRAS BRAF

Calidad de vida Perfil de toxicidad

Selección de Tratamiento

Marcadores Clínicos

Marcadores Moleculares

Factores socioeconómicos y preferencias del

paciente

Edad PS Comorbilidades Volumen tumoral - Posible cirugía

rescate - Síntomas y

agresividad

Grado histológico CEA MSI KRAS NRAS BRAF Localización

tumoral

Marcadores moleculares

Mutaciones RAS

RAS wild-type

KRAS codon 12 mutant

KRAS codon 13 mutant

KRAS Exon 3 mutant

KRAS Exon 4 mutant

NRAS Exon 2 mutant

NRAS Exon 3 mutant

NRAS Exon 4 mutant

KRAS Exon 2

KRAS wild-type

KRAS codon 12 mutant

KRAS codon 13 mutant

Extended RAS wild-type

(2014) KRAS exon 2 wild-type

(2008)

CRYSTAL study: OS O

S es

tim

ate

Months

54 42 48

23.5

20.0

0.0

0.2

0.4

0.6

0.8

1.0

18 0 6 12 24 30 36

FOLFIRI (n=350)

HR 0.79 p=0.0093

Cetuximab + FOLFIRI (n=316)

KRAS exon 2 wt population1

54 42 48 18 0 6 12 24 30 36

28.4

20.2

0.0

0.2

0.4

0.6

0.8

1.0

Cetuximab + FOLFIRI (n=178)

FOLFIRI (n=189)

HR 0.69 p=0.0024

RAS wt population2

Adapted from 1. Van Cutsem E, et al. J Clin Oncol 2011;29:2011–2019 and 2.Ciardiello F, et al. ASCO 2014 (Abstract No. 3506)

Months

1. Douillard JY, et al. J Clin Oncol 2010;28:4697-705;

2. Douillard JY, et al. N Engl J Med 2013; 369:1023-34.

WT RAS, WT KRAS & NRAS exons 2/3/4

(includes 7 patients harbouring KRAS/NRAS codon 59 mutations)

WT KRAS exon 21

0

20

40

60

80

100

90

70

50

30

10

0 36 4 8 12 16 28 32 20 24

Events n (%)

Median (95% CI) months

Panitumumab + FOLFOX4 (n = 325)

165 (51) 23.9 (20.3–28.3)

FOLFOX4 (n = 331) 190 (57) 19.7 (17.6–22.6)

HR = 0.83 (95% CI, 0.67–1.02)

P = 0.072

Events n (%)

Median (95% CI) months

Panitumumab + FOLFOX4 (n = 259)

128 (49) 26.0 (21.7–30.4)

FOLFOX4 (n = 253) 148 (58) 20.2 (17.7–23.1)

Pro

po

rtio

n a

live

(%

)

Months

0 36 4 8 12 16 20

0

20

40

60

80

100

90

70

50

30

10

24 28 32

HR = 0.78 (95% CI, 0.62–0.99)

P = 0.043

Pro

po

rtio

n a

live

(%

)

Months

WT RAS2

PRIME study: OS

BRAF Mutations in CRC

• BRAF es el primer efector de las señales de KRAS

• Mutaciones BRAF :

– Ocurre con más frecuencia en exon 15 (V600E)

– Aparece en 4%-14% de los pacientes con CCRm

– Mutuamente exclusiva con la mutación RAS

– Pronóstico negativo con mediana OS de 10 meses

Raf

MEK

Erk

P

P P

P

Tumor cell proliferation and survival

EGF

Tumor Cell

Ras

Yarden. Nat Rev Mol Cell Biol. 2001;2:127; Di Nicolantonio. J Clin Oncol. 2008;26:5705; Artale. J Clin Oncol. 2008;26:4217.

OS con inhibidores de EGFR en CCRm BRAF MT

EGFR inhibitors are authorised only for RAS WT mCRC Pietrantonio, et al. Eur J Cancer 2015

Meta-analysis of randomised clinical trials of cetuximab or panitumumab

Bokemeyer 2012

Douillard 2013

Karapetis 2013

Seymour 2013

Peeters 2014

Stintzing 2014

Total (95% CI)

–0.478

–0.105

–0.174

0.61

–0.446

–0.139

Log (hazard ratio) Study

0.275

0.342

0.736

0.263

0.354

0.314

0.62 (0.36–1.06)

0.90 (0.46–1.76)

0.84 (0.20–3.56)

1.84 (1.10–3.08)

0.64 (0.32–1.28)

0.87 (0.47–1.61)

0.91 (0.62–1.34)

Hazard ratio (95% CI) SE

0.2 1 5

Favours control

Favours EGFR inhibitors

20.7

17.0

6.0

21.5

16.4

18.5

100.0

Weight (%)

Heterogeneity: Tau2=0.11; Chi2=10.09 df=5 (p=0.07); I2=50% Test for overall effect: Z=0.48 (p=0.63)

2 0.5

• Primary endpoint was met with 8/23 objective responses (as per protocol, 6/27 needed to declare the study positive)

• Disease control rate (DCR): 78%

1. Sartore-Bianchi A et al. Lancet Oncol 2016. Siena, et al. ASCO 2015 2. Raghav KPS et al. ASCO 2016< 34> 3517

Response n (%)

ORR 8 (34.7)

CR 1 (4.3)

PR 7 (30.4)

SD ≥4 months 7 (30.4)

SD <4 months 3 (13.0)

PD 5 (21.7)

Response rate

TTP

Surv

ival

pro

bab

ility

Time (months)

1.0

0.6

0.4

0.2

0

0 3

HER2 3+ (95% CI: 1.8–NR)

HER2 2+ (95% CI: 1.9–NR)

0.8

15

p=ns

6 9 12

4.2 7.3

HERACLES A Un 5% de pacientes KRAS WT son HER/2 N: 54 previamente tratados HER2 +

Posible factor predictivo negativo a respuesta a anti/EGFR (2)

• Predictor de respuesta la inmunoterapia

(Categoría IIB)

• Pronóstico desfavorable

• Orienta en el Consejo Genético

– Determinación: Puede determinarse por dos métodos en tumor:

– Pérdida de expresión por IHQ de alguna de las proteínas

reparadoras de DNA, hMLH1, hMSH2, hMSH6 y hPMS2.

– Existencia de Inestabilidad de microsatélites por PCR.

MSI

*NCCN guidelines validate testing for MSI-H 1. Sargent DJ et al. J Clin Oncol. 2010; 28(20):3219-3226. 2. NCCN Guidelines V.1.2017. 3. Venderbosch S et al. Clin Cancer Res. 2014; 20(20):5322-5330. 4.Richman S. Int J Oncol. 2015; 47(4):1189-1202 9. 5. Van Cutsem E et al. Ann Oncol. 2016; 27(8):1386–1422.

Genotipado del Colon Cancer:

Molecular

BRAF WT vs MUT

MSI vs MSS

RAS WT vs MUT

Ensayos de Inmunoterapia

• Características de los pacientes

Tratamiento de pacientes no subsidiarios de QT intensiva

Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016

Pembrolizumab: 10m g/k cada 2 semanas iv

Le DT et al. NEJM 2015

Anti-PD1 pembrolizumab in mCRC:

PFS and OS

N3 (n=70) N3 + I1 (n=30)

OS rate, % (95% CI) 6 mo 9 mo 12 mo

75.0 (58.5, 85.7) 65.6 (48.0, 78.6) 65.6 (48.0, 78.6)

85.1 (65.0, 94.2) 85.1 (65.0, 94.2)

NE

mOS, mo (95% CI) 17.1 (8.6, NE) NR (NE, NE)

N3 (n=70) N3 + I1 (n=30)

PFS rate, % (95% CI) 6 mo 9 mo 12 mo

45.9 (29.8, 60.7) 45.9 (29.8, 60.7) 45.9 (29.8, 60.7)

66.6 (45.5, 81.1)

NE NE

mPFS, mo (95% CI) 5.3 (1.5, NE) NE (3.4, NE)

Check Mate-142: Nivolumab / Ipilimumab in Patients With MSI-H mCRC

21

PFS

Nivo 70 19 13 9 5 0

Nivo + ipi 30 21 7 0 0 0

No. at Risk

0

13 1

0

0 3 6 9 12 15 21 Months

0

10

20

30

40

50

60

70

80

90

100

Pro

gre

ssio

n-F

ree

Su

rviv

al

(%

of

Pat

ien

ts)

18

OS

Nivo 70 34 24 20 12 0

Nivo + ipi 30 26 21 4 0 0

No. at Risk

0

21 5

0

0 3 6 9 12 15 21 Months

0 10

20

30

40

50

60

70

80

90

100

Ove

rall

Surv

ival

(

% o

f P

atie

nts

)

18

Nivo 3 mg/kg + ipi 1 mg/kg

Nivo 3 mg/kg

Nivo 3 mg/kg + ipi 1 mg/kg

Nivo 3 mg/kg

I1, 1 mg/kg ipilimumab; ipi, ipilimumab; mCRC, metastatic colorectal cancer; mOS, median overall survival; mPFS, median progression-free survival; MSI-H, microsatellite instability-high; N3, 3 mg/kg nivolumab; NE, not evaluable; nivo, nivolumab; OS, overall survival; PFS, progression-free survival.

Overman M et al. Poster presentation at ESMO 2016. 479P.

21

Guías ESMO 2016

Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016

Kopetz, S. et al. J Clin Oncol 2009; 27:3677-3683

Papel de la resección… La curación

Pacientes SIN

Resección Hepática

Pacientes CON

Resección Hepática

mOS 65.3 mo

mOS 26.7 mo

HR 0.35

Time (months)

0

12 24 36 48 60 72

20

40

60

80

100

OS

(%

)

La

nd

ma

rk

0

19.5%

55%

OS 5 años 55% vs 19.5%

Anti-EGFR en Metástasis Hepáticas de CCR

CELIM Folfox/Folfiri+ Cetuximab

PLANET

Abad et al. Presented at the 2014 European Society of Medical Oncology Meeting, September 26-30, 2014, Madrid, Spain; Abstract # 7823

Resection and response rates

% (95% CI)

Bev + FOLFOXIRI (n=41)

Bev + mFOLFOX6 (n=39)

Difference

p-value

Resection rate

R0/R1/R2a 61.0 (44.5–75.8) 48.7 (32.4–65.2) 12.3 (–11.0–35.5) 0.271

R0/R1 51.2 (35.1–67.1) 33.3 (19.1–50.2) 17.9 (–5.0–40.7) 0.106

R0 48.8 (32.9–64.9) 23.1 (11.1–39.3) 25.7 (3.9–47.5) 0.017

Overall response rate 80.5 (65.1–91.2) 61.5 (44.6–76.6) 18.9 (–2.1–40.0) 0.061

Intent to treat population. aOnly two-stage hepatectomy

Bridgewater, et al. ECC 2013. Abstract 2159

PEAK: PFS & OS WT KRASKRAS WT RAS

Schwartzberg LS. J Clin Oncol. 2014 Jul 20;32(21):2240-7

RAS WT

FIRE-3: PFS and OS

Heinemann V et al. Lancet 2014

OR: 62% FOLFIRI+ Cetu vs 58% FOLFIRI+Beva ; p=0.18

CALGB/SWOG 80405: Eficacia en RAS WT

OR: 69 vs 54% p< 0.01

Clinical Colorectal Cancer 2015

FIRE-3: Does depth of Response (DpR) correlates with OS?

Consistent efficacy and DpR in 4 1st line studies

0

10

20

30

40

50

60

70

80

PEAK1

46%

65% Dep

th o

f re

spo

nse

(D

pR

, %)

Beva+mFOLFOX6

Pmab+mFOLFOX6

P=0.0018

PRIME2

46%

54%

FOLFOX4

Pmab+FOLFOX4

p=0.0149

PLANET3

64%

71%

Pmab+FOLFIRI

Pmab+FOLFOX6

p= NR

3144

36%

59%

Pmab+FOLFIRI (RAS-MT)

Pmab+FOLFIRI (RAS-WT)

p= 0.018

1. Rivera F et al. ECC 2015. Abstract 2014 and poster. 2. Douillard JY et al. Eur J Cancer Oxf Engl 1990. 2015 Jul;51(10):1231–42. 3. Abad A et al. ECC 2015. Abstract 2128 and poster. 4. Karthaus M et al. ECC 2015, Abstract 2130 and poster.

Bev: Bevacizumab, DpR: Depth of response, LLD: Liver-limited disease, NR: not reported, Pmab: Panitumumab

(LLD)

1st Line

Note: Data shown are not from comparative studies and must be interpreted with caution.

Guías ESMO 2016

II-A

Guías ESMO 2016

Guías ESMO 2016

TUMOR LOCATION Dcho vs izdo

66 studies – 1.437.846 pts

Independent of the stage, race, adjuvant CT, year of study, number of participants and quality

of included studies

CALGB 80405: OS in all RAS WT patients

by tumor location

Lenz et al. ESMO 2016.

Right or left metastatic colon cancer:

will the side change your treatment?

12 24 36 48 60 72 84

13.6 29.2

0 12 24 36 48 60 72 84 96

32.6 39.3

1.0

0.8

0.6

0.4

0.2

0

OS

esti

mat

e

108

Time (months) Time (months)

Left-sided tumors Right-sided tumors 1.0

0.8

0.6

0.4

0.2

0

OS

esti

mat

e

0

BEV: 32.6 months (n=152) Cetuximab: 39.3 months (n=173)

BEV: 29.2 months (n=78) Cetuximab: 13.6 months (n=71)

HR=1.36 (95% CI: 0.93–1.99) Adjusted p=0.10

HR=0.77 (95% CI: 0.59–0.99) Adjusted p=0.04

N=325 N=149

∆5.7 mos ∆15.6 mos

Holch et al. Eur J Cancer 2017; 70: 87-98

• RAS WT/BRAF MUTADO

0 20 40 600

25

50

75

100

Months

Pe

rce

nt s

urv

iva

l

N

FOLFIRI + bev

Arm A

Median OS

FOLFOXIRI + bev

Arm B

Median OS

HR [95% CI]

ITT population 508 25.8 31.0 0.79 [0.63-1.00]

R&B evaluable 375 25.8 31.0 0.86 [0.65-1.12]

RAS mutated 218 23.1 30.8 0.86 [0.60-1.22]

BRAF mutated 28 10.8 19.1 0.55 [0.24-1.23]

All wt patients 129 34.4 41.7 0.85 [0.52-1.39]

RAS mutated – FOLFOXIRI plus bev

RAS mutated – FOLFIRI plus bev

BRAF mutated – FOLFOXIRI plus bev

BRAF mutated – FOLFIRI plus bev

All wt – FOLFOXIRI plus bev

All wt – FOLFIRI plus bev

Guías ESMO 2016

Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016

VISNÚ PROGRAM CTC Screening (n= 750 pts)

47%

≥3 CTC

(n=350)

VISNÚ 1 (TTD-12-01)

FOLFOX

+

Avastin

(n = 193)

R

FOLFOXIRI

+

Bevacizumab

(n = 175)

FOLFOX

+

Bevacizumab

(n = 175)

Design Randomized Phase III

Primary endpoint: PFS (superiority 8 m vs 11,2 m, HR: 0.71)

Secondary endpoint: RR, OS. R0 surgery, toxicity, CTC level

basal, KRAS, BRAF, PI3K, Pten

VISNÚ 2 (TTD-12-02)

KRAS

mut

(n=191)

53%

FOLFIRI

+

Cetuximab

N=97

< 3 CTC

(n=400)

BRAF WT, PI3K WT

(n=194)

R

FOLFIRI

+

Bevacizumab

N=97

KRAS WT N = 240

60%

BRAF MUT o PI3K MUT

(n=46)

Design: Randomized Phase II

Primary endpoint:

-Group without mutation: minimum value 8.5 months optimum value 13 months

and 1 year PFS rate IC less than (+/-10%)

- Group with mutation: minimum value 2,5 months optimum value 6 months

Secondary endpoint: TR, OS, R0 surgery, toxicity, CTC level basal, Pten

FOLFIRI

+

Cetuximab

N=23

R

FOLFIRI

+

Bevacizumab

N=23

VISNÚ

Comparison of RR and PFS for BRAFmut CRC

Doublet with EGFR

Vem + Panit 13% 3.2 months Yeager et al CCR ’14

Vem + Cetux 20% 3.2 months Tabernero et al ASCO ‘14

Encoraf + Cetux 23% 4.0 months Tabernero et al ESMO ‘14

Dabr + Panit 10% 3.4 months Atreya, ASCO ‘15

Triplet with EGFR

Vem + Cetux + Irinotecan 35% 7.7 months Hong, Monday 1:15p, Abs 3511

Dabr + Tramet + Panit 26% 4.1 months Atreya, ASCO ‘15

Encoraf + Cetux + Alpelisib 32% 4.4 months Tabernero et al ESMO ’14

Regimen Response rate PFS Citation

Single/Doublet BRAF/MEK

Vemurafenib 5% 2.1 months Kopetz, ASCO ’10

Dabrafenib 11% NR Falchook, Lancet ‘08

Encorafenib 16% NR Gomez-Roca, ESMO ‘14

Dabr +Tramet 12% 3.5 months Corcoran, ASCO ‘14

Phase III Registration Trial of Encorafenib in BRAF V600E mutated CRC

Safety Lead-in

Phase 3

• Binimetinib (45 mg BID) +

• Encorafenib (300 mg QD) +

• Cetuximab (400/250 mg/m2 Wkly)

N=20

Arm A • Binimetinib + Encorafenib

+ Cetuximab

Arm B • Encorafenib (300 mg QD) + • Cetuximab (400/250

mg/m2 Wkly)

R

a

n

d

o

m

i

z

e

Arm C • Irinotecan 180 mg/m2 q 2 wks + Cetuximab (400/250 mg/m2

Wkly)

Continue Arm A or B N=173

Interim analysis N=60

N=60

N=60 N=173 Total N=233

Final analysis

• 1° objective: confirm Phase 3 dose

• 1° objective: Overall Survival • Key 2°objective: ORR • Other 2°objectives: PFS, DOR, TTR

*

*Stratification factors: ECOG (0 vs. 1), prior irinotecan (yes vs. no), region (North America vs. rest of world)

Meta-analisis Beva maintenance

Clin Colorectal Cancer 2015

PFS

OS

2ª line

ESMO Guidelines 2014

Annals of Oncology 25 (Supplement 3): iii1–iii9, 2014

doi:10.1093/annonc/mdu260 Published online 4 September 2014

Anti-angiogenic treatment in mCCR

Antiangiogénicos en 2º línea

asociados a FOLFIRI

2º line: Anti-EGFR combination

¿Anti-VEGF vs Anti-EGFR ?

Hecht JR, et al. Clinical Colorectal Cancer 2015

Panitumumab + FOLFIRI (n=91)

Bevacizumab + FOLFIRI (n=91)

HR=1.01 (95%CI: 0.68–1.50)

Pro

po

rtio

n E

ve

nt-

Fre

e (

%)

100

60

80

40

20

0

50

70

30

10

90

PFS

Months

0 4 8 12 16 20 24 44 48 52 56 40 28 32 36

Months

Surv

ival P

robabili

ty (

%)

100

60

80

40

20

0

50

70

30

10

90

0 4 8 12 16 20 24 44 48 52 56

OS

40 28 32 36

HR=1.06 (95%CI: 0.75–1.49)

Panitumumab + FOLFIRI (n=91)

Bevacizumab + FOLFIRI (n=91)

• New RCT have to stratify by location

• If all the sequence matters we need prospective RCT based on molecular characteristics, in a dynamic scenario

• Primary endpoint: 2nd progression/exitus free rate. (PFS1+PFS2): 30 vs 20 months. Total of 332 patients

CR-SEQUENCE: Planned study design

PD, progressive disease.

Unresectable

left-side

mCRC

WT RAS/

WT BRAF

R

FOLFOX +

bevacizumab

FOLFOX + panitumumab

N cycles until PD, toxicity or conversion surgery

FOLFIRI + panitumumab

N cycles until PD or toxicity

FOLFIRI + bevacizumab

SEQUENCE 29/03/2017

Pro

gressio

n

Pro

gressio

n

Seq 1

Seq 2

Investigator choice: 1st line

reintroduction Or

Regorafenib Or

Other

3ª and 4ª line

ESMO 2016

RAS WT RAS MUT

Annals of Oncology 0: 1–37, 2016 doi:10.1093/annonc/mdw235

≥ 3rd line - anti-EGFR therapy

Price T. Lancet Oncol 2014; 15: 569–79.

ASPECCT trial: Panitumumab non inferior to

Cetuximab

Tumor Cell Endothelial Cell

Pericyte

RAS

RAF BRAF

MEK

ERK

Pl3K

AKT

mTOR

ONCOGÉNESIS

(KIT, RET, BRAF , RAF-1,PDGFR

) ANGIOGÉNESIS

(VEGFR1-3, TIE2)

TUMOR MICROENVIRONMENT (PDGFR-b, FGFR)

Regorafenib

FGFR

PDGFR-β

VEGFR1

VEGFR3 VEGFR2

EGFR KIT TIE-2 PDGFR-β

1. Grothey A, et al. Lancet. 2013; 381(9.863):303-12; 2. Wilhelm SM, et al. Int J Cancer 2011; 129:245-55.

MECANISMO DE ACCIÓN DE REGORAFENIB

Estudios con regorafenib

CORRECT CONCUR

SLP

SG

SLP

SG

Regorafenib 1.9 m

Placebo 1.7 m

Regorafenib 6.4 m

Placebo 5.0 m

Regorafenib 8.8 m

Placebo 6.3 m

Regorafenib 3.2 m

Placebo 1.7 m

Drug-related, treatment-emergent adverse events occurring in ≥10% of patients at any grade

Adverse event, % Regorafenib

N=500

Placebo N=253

All grades

G-3 G-4 All grades

Grade 3 Grade 4

Hand–foot skin reaction 46.6 16.6 0 7.5 0.4 0

Fatigue 47.4 9.2 0.4 28.1 4.7 0.4

Hypertension 27.8 7.2 0 5.9 0.8 0

Diarrhea 33.8 7.0 0.2 8.3 0.8 0

Rash/desquamation 26.0 5.8 0 4.0 0 0

Anorexia 30.4 3.2 0 15.4 2.8 0

Mucositis, oral 27.2 3.0 0 3.6 0 0

Thrombocytopenia 12.6 2.6 0.2 2.0 0.4 0

Fever 10.4 0.8 0 2.8 0 0

Nausea 14.4 0.4 0 11.1 0 0

Bleeding 11.4 0.4 0 2.8 0 0

Voice changes 29.4 0.2 0 5.5 0 0

Weight loss 13.8 0 0 2.4 0 0

Trifluridina/tipiracilo (TAS-102) es un novedoso nucleósido antitumoral por vía oral

NH

H N O

O

N

Cl

HCl.HN

HN

N

O

O

CF3

O HO

OH

+

2’-desoxi-5-(trifluorometilo)uridina

(trifluridina, FTD) [1]

monohidrocloruro de 5-cloro-6-

[(2-iminopirrolidin-1-il)metil]pirimidina-2,

4(1H,3H)-diona

(hidrocloruro de tipiracilo, TPI) [0,5]

[Fracción molar] [1:0,5]

• El hidrocloruro de tipiracilo (TPI) es un

inhibidor de la timidina fosforilasa y evita la

degradación de la FTD

• Se emplea para aumentar la concentración

efectiva in vivo de FTD

TAS-102

La inhibición de la timidilato sintasa es el principal mecanismo de acción cuando FTD se administra

por vía intravenosa.

FTD es el

componente

activo

• Trifluridina (FTD) es un nucleósido basado

en la timidina, que se incorpora al ADN de

las células tumorales tras su fosforilación

(es el componente activo)

64

Mayer RJ et al. NEJM 2015

OS m: TAS-102 7.1 m

Placebo 5.3 m

RECOURSE: Overal Survival and PFS

Control enfermedad 44% vs 16%, p<0.001

RR: 1,6% vs 0.4%

TAS-102 2.0 m

Placebo 1.7 m

1. Mayer RJ, et al. N Engl J Med. 2015; 372:1909

RECOURSE: Perfil de seguridad

RECOURSE: Onset of neutropenia predicts outcomes with TAS-102 in patients with mCRC

Ohtsu A, et al. ASCO 2016. Abstract 3556 (poster presentation).

Grade ≥3 neutropenia was associated with longer OS for TAS 102 vs placebo, irrespective of timing of onset

Outcome

Earliest onset of grade ≥3 neutropenia

Cycle 1 Cycle 2 (L) or ≥2 (P) Cycle ≥3 No grade ≥3 neutropenia

LONSURF (n=75)

Placebo (n=265)†

LONSURF (n=86)

Placebo (n=215)

LONSURF (n=39)

Placebo (n=48)

LONSURF (n=333)

Placebo (n=265)†

Median OS, months 9.7 5.3 8.7 6.3 16.4 10.2 5.5 5.3

HR 0.48 (95% CI: 0.32, 0.64) HR 0.56 (95% CI: 0.41, 0.78) HR 0.36 (95% CI: 0.17, 0.75) HR 0.97 (95% CI: 0.81, 1.16)

Median PFS, months 3.7 1.7 3.7 1.8 6.5 3.7 1.9 1.7

HR 0.35 (95% CI: 0.25, 0.48) HR 0.34 (95% CI: 0.25, 0.46) HR 0.32 (95% CI: 0.18, 0.56) HR 0.69 (95% CI: 0.58, 0.82)

Consistent treatment benefit was observed for OS and PFS regardless of cycle of onset of grade ≥3 neutropenia

HR, adjusted HR for LONSURF vs placebo.

†All placebo patients

Objective: Post-hoc analysis of the RECOURSE study to explore the association between the onset of grade ≥3 neutropenia and OS/PFS, in mCRC patients treated with LONSURF or placebo

OS for patients with onset of grade ≥3 neutropenia at cycle 1

OS for patients with no neutropenia onset

0 2 4 6 8 10 12 14 16 18 20

TAS 102 Placebo

Time (months)

0

0.2

0.4

0.6

0.8

1.0

OS

esti

mat

e

2 4 6 8 10 12 14 16 18 20

TAS 102 Placebo

Time (months) 0

0

0.2

0.6

OS

esti

mat

e

0.4

0.8

1.0

Secuencia de Regorafenib vs TAS 102

Regorafenib TAS 102

TAS 102 Regorafenib

Mutations in RAS emerge during anti-EGFR treatment

and decline when treatment is suspendend

RAS

RAS

wt

Response to treatment Progression to treatment

wt RAS wt

Off treatment

Basal RAS wt tumor

Cetuximab rechallenge

Limited evidence for treatment with cetuximab

Rechallenge with anti-EGFR therapy

Cetuximab + FOLFIRI

R

FIRE-4 (Phase III, n=550)

Bevacizumab + FOLFOX/XELOX

Cetuximab + irinotecan/FOLFIRI

Regorafenib Cetuximab + FOLFIRI

R

1st line 2nd line 3rd line

Liquid biopsy to track/identify resistance

• Primary endpoint: OS after randomization 2 • Results expected: January 2022

RAS wt

mCRC Bevacizumab + FP maintenance

Targeted therapy in clinical development for mCRC

Slide 32

Presented By Dirk Arnold at 2016 ASCO Annual Meeting

TARGET TRIAL

Exposure to as many agents as possible prolongs OS

Adapted from Grothey & Sargent. JCO 2005

OS (months) = 13.2 + (3 drugs % x 0.1), R2=0.85

Infusional 5-FU/LV + irinotecan

Infusional 5-FU/LV + oxaliplatin

Bolus 5-FU/LV + irinotecan

Irinotecan + oxaliplatin

Bolus 5-FU/LV

LV5FU2

First-line therapy

Me

dia

n O

S (m

on

ths)

Patients with 3 drugs (%)

2007

22

21

20

19

18

17

16

15

14

13

12

0 10 20 30 40 50 60 70 80

p=0.0001

FOLFOXIRI

CAIRO

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