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OPTIMIZACIÓN TRATAMIENTO
ANTI-EGFR
Ruth Vera
Oncología Médica
OPTIMIZACIÓN TRATAMIENTO anti-EGFR
• OPTIMIZAR quiere decir:
• Buscar los mejores resultados
• Planificar una actividad para obtener los
mejores resultados
• Mejorar
• …
Type of tumor Tumors with EGFR
expression
Head and neck 90–100%
Colon 75–89%
Pancreas Up to 95%
Breast Up to 91%
Renal Up to 90%
NSCLC Up to 80%
Ovary Up to 77%
Bladder Up to 72%
Glioma Up to 63%
Lung
(NSCLC)
Colorectal
Head and neck
EXPRESIÓN DE EGFR
Importancia de la vía del EGFR en el Cáncer colorrectal
Survival
(anti-apoptosis)
Gene transcription
Cell cycle progression
MYC
MYC Cyclin D1
FOS JUN
P P
Cyclin D1
Angiogenesis Invasion and
metastasis
Chemotherapy/
radiotherapy resistance
Proliferation/
maturation
MAPK
RAS RAF SOS GRB2
PTEN AKT
STAT
PI3K pY
pY
Ligand AREG/EREG
EGFR-TK
pY
MEK
Meyerhardt JA & Mayer RJ. N Engl J Med 2005;352:476–487;
Venook A. Oncologist 2005;10:250–261
CRYSTAL study: OS
OS
est
imate
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
1. Ciardiello F, et. al. ASCO 2014 (Abstract No. 3506)
2. Van Cutsem E, et. al. J Clin Oncol 2011; 29:2011–2019
3. Douillard J-Y, et al. N Engl J Med 2013;369:1023–1034
4. Douillard JY, et. al. Ann Oncol 2014;25:1346–1355
Study Biomarker n OS HR (95% CI)
CRYSTAL1,2 KRAS 666 0.80 (0.67–0.95)
Anti-EGFR
+ CT vs CT
RAS 367 0.69 (0.54–0.88)
PRIME3,4 KRAS 656 0.83 (0.70–0.98)
RAS 512 0.78 (0.62–0.99)
1.0 2.0 0.1
Benefit with anti-EGFR Benefit without anti-EGFR
Choice of targeted therapy: A growing body of
evidence
Phase III studies in 1st line mCRC: OS
anti-EGFR vs anti-VEGF
FIRE-3 study: OS
KRAS exon 2 wt
population RAS wt population (84%)
1. Adapted from Heinemann V, et al. Lancet Oncol 2014;15:1065–1075
OS
est
imate
28.7
months
25.0
months
0.75
1.0
0.50
0.25
0.0
12 24 36 48 60 72
Months
HR 0.77
p=0.017
0
Cetuximab + FOLFIRI (n=297)
Bevacizumab + FOLFIRI (n=295)
Cetuximab + FOLFIRI (n=171)
Bevacizumab + FOLFIRI (n=171)
33.1
months
25.6
months
0.0
12 24 36 48 60 72
0.7
5
1.0
0.5
0
0.2
5
0.0
OS
est
imate
Months
HR 0.70
p=0.011
0
0
20
40
60
80
100
90
70
50
30
10
Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster).
*Stratified Cox proportional hazards model; No formal hypothesis testing
was planned; WT RAS, WT KRAS & NRAS exons 2/3/4
WT KRAS exon 2
Pro
po
rtio
n e
ve
nt-
fre
e (
%)
Months
0 36 4 8 12 16 28 32 20 24 40
HR* = 0.84 (95% CI, 0.64–1.11)
P = 0.22
WT RAS
Pro
po
rtio
n e
ve
nt-
fre
e (
%)
Months
HR* = 0.66 (95% CI, 0.46–0.95)
P = 0.03
0
20
40
60
80
100
90
70
50
30
10
0 32 4 8 12 16 20 24 28 36 40
Events n (%)
Median (95% CI) months
Panitumumab + mFOLFOX6 (n = 142)
100 (70) 10.9 (9.7–12.8)
Bevacizumab +
mFOLFOX6 (n = 143)
108 (76) 10.1 (9.0–12.0)
Events n (%)
Median (95% CI) months
Panitumumab + mFOLFOX6 (n = 88)
57 (65) 13.0 (10.9–15.1)
Bevacizumab + mFOLFOX6 (n = 82)
66 (80) 10.1 (9.0–12.7)
PEAK study: PFS
Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster).
*Stratified Cox proportional hazards model; No formal hypothesis testing
was planned; WT RAS, WT KRAS & NRAS exons 2/3/4;
NR, not reached
WT KRAS exon 2
Months
Pro
po
rtio
n a
live
(%
)
0
20
40
60
80
100
90
70
50
30
10
0 36 4 8 12 16 28 32 20 24 40
HR* = 0.62 (95% CI, 0.44–0.89)
P = 0.009
44
Events n (%)
Median (95% CI) months
Panitumumab + mFOLFOX6 (n = 142)
52 (37) 34.2 (26.6–NR)
Bevacizumab +
mFOLFOX6 (n = 143)
78 (55) 24.3 (21.0–29.2)
Events n (%)
Median (95% CI) months
Panitumumab + mFOLFOX6 (n = 88)
30 (34) 41.3 (28.8–41.3)
Bevacizumab + mFOLFOX6 (n = 82)
40 (49) 28.9 (23.9–31.3)
WT RAS
Months
Pro
po
rtio
n a
live
(%
)
HR* = 0.63 (95% CI, 0.39–1.02)
P = 0.058
0 32 4 8 12 16 20 24 28 36
0
20
40
60
80
100
90
70
50
30
10
44 40
PEAK study: OS
Phase III 80405 Trial: PFS
Lenz H et al. ESMO, 2014.
Lenz H et al. ESMO, 2014.
Phase III 80405 Trial: OS
Khattak et al. Clin Colorectal Cancer 2015
Summary of results
Khattak et al. Clin Colorectal Cancer 2015
ORR with RAS
Khattak et al. Clin Colorectal Cancer 2015
PFS with RAS
Khattak et al. Clin Colorectal Cancer 2015
OS with RAS
Circulating free DNA as biomarker and source for mutation detection in metastatic colorectal cancer. Spindler KL
RAS mutations vary between lesions in synchronous primary colorectal cancer: testing only one lesion is not sufficient to guide anti-EGFR treatment decisions. Oncoscience. 2015 Feb 9;2(2):125-30
Mutational analysis of circulating tumor cells from colorectal cancer patients and correlation with primary tumor tissue. PLoS One. 2015 Apr 22;10(4):e0123902
DETERMINACIÓN RAS: DÓNDE Y CUÁNDO ?
Se puede OPTIMIZAR mas el
tratamiento con anti-EGFR ?
• Además de la selección por RAS …
Como podemos OPTIMIZAR mas el
tratamiento con anti-EGFR ?
• Mut PI3K
• Pérdida expresión PTEN
• Amplif MET
• Amplif HER2
• Sobreex HER3
• Mut adquiridas
• Sobreex Ligandos EGFR
• …
Anti-EGFR + …
CONCLUSIONES
• “RAS story” como el mejor ejemplo de OPTIMIZACIÓN
• COMO y CUANDO ?
• Otros Biomarcadores
• Combinación con otros fármacos en pacientes con
mutaciones
• Manejo de Toxicidad cutánea