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