Diapositiva 1 - Abordaje Multidisciplinar del Cáncer

Transcripción

▼ Panitumumab
(▼) Este medicamento está sujeto a seguimiento adicional, es prioritaria la notificación de sospechas de reacciones adversas asociadas a este
medicamento.
Mejora de la supervivencia
en CCRm con
Panitumumab: de la
evidencia a la práctica cínica
Pilar García Alfonso
Jefe de Sección Oncología Médica
H.G.U. Gregorio Marañón
In the past 3 decades, advances in the treatment of
mCRC have led to improved OS…
Median OS
Time (months)
30
20
10
0
1980s
1990s
2000s
2010
BSC
5-FU
Irinotecan1
Capecitabine2
Oxaliplatin3
Bevacizumab4
Cetuximab5,6
*Not approved by the EMA or for use in the Czech Republic
1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 2004; 3. Rothenberg, et al. JCO 2003
4. Hurwitz, et al. NEJM 2004; 5. Cunningham, et al. NEJM 2004; 6. Van Cutsem, et al. NEJM 2009
7. Van Cutsem, et al. JCO 2007; 8. Van Cutsem, et al, JCO 2012; 9. Grothey, Van Cutsem, et al. Lancet 2012
Panitumumab7
Aflibercept8
Regorafenib9*
Examples of predictive biomarkers in oncology
Tumour type
Biomarker
Drug
Breast cancer
HER-2 overexpression
Trastuzumab1, lapatinib2
Gastric cancer
HER-2 overexpression
Trastuzumab1
CML
BCR/ABL fusion gene
Imatinib3
GIST
c-KIT mutation
Imatinib3
NSCLC
EGFR mutation
Gefitinib4, erlotinib5
mCRC
RAS mutation status
Panitumumab6, cetuximab7
Melanoma
BRAF V600
Vemurafenib8
NSCLC
ALK positive
Crizotinib9
1-9: European Public Assessment Reports, available at www.ema.europa.eu for:
1. Herceptin®; 2. Tyverb®; 3. Glivec®; 4. Iressa®; 5. Tarceva®; 6. Vectibix®;
7. Erbitux®; 8. Zelboraf®; 9. Xalkori®.
RAS, KRAS & NRAS exons 2/3/4
EGFR activation may involve downstream
signalling pathways that include RAS proteins
EGF
EGFR
TGF-α
EGFR Homodimer
EGF
EGFR
RAS
GTP
RAS
GDP
RAF
Nck
MEK
PI3K
Rac
PAK
PLCγ
PTEN
AKT
JNKK
ERK
JNK
PKC
S6K
Proliferation
Anti-apoptosis
Angiogenesis
Survival
Metastasis
mTOR
Myc
Elk
Jun
Fos
Berg M, Soreide K. Discovery medicine 2012; 14:207-14; Di Fiore F, et al. Br J Cancer 2010; 103:1765-72;
Han W, Lo HW. Cancer Lett 2012; 318:124-34; Herbst RS, Shin DM. Cancer 2002; 94:1593-611.
©2007 Amgen Inc. All rights reserved
Panitumumab – a fully human anti-EGFR mAb
inhibits ligand binding and EGFR dimerisation
Panitumumab
Fully human, monoclonal IgG2 antibody
Binds with high affinity and specificity to the
extracellular domain of the human EGFR
Dissociation constant: KD=0.05 nM1
Inhibits receptor activation of all known EGFR
ligands2
EGFR
Inhibits EGFR-dependent activity including
cell activation and cell proliferation in various
tumours2-5
1. Freeman D, et al. J Clin Oncol 2008; 26(15S):14536;
2. Yang XD et al. Cancer Res 1999; 59:1236-43;
3. Foon KA, et al. Int J Radiat Oncol Biol Phys 2004; 58:984-90;
4. Hecht JR, et al. Proc Am Soc Clin Oncol 2004; 22:A3511;
5. Crawford J, et al. Proc Am Soc Clin Oncol 2004; 22:A7083.
RAS signalling pathways
determine proliferation and
survival
EGFR homodimer
KRAS
GDP NRAS
GDP HRAS NF1
GDP
GRB2
Other
effector
pathways
Gab
GAP
SOS1
SHC
SHp2
KRAS
GTP
NRAS
GTP
HRAS
GTP
RAS effector pathways
Calcium
signalling
Cytoskeletal
organization
Schubbert S, et al. Nat Rev Cancer 2007; 7:295-308.
Proliferation
Survival
Vesicle
trafficking
RAS signalling pathways:
differential effects of KRAS and
NRAS
EGFR homodimer
KRAS
GDP NRAS NF1
GDP
GRB2
Other
effector
pathways
Gab
GAP
SOS1
SHC
SHp2
KRAS
GTP
NRAS
GTP
Proliferation
Schubbert S, et al. Nat Rev Cancer 2007; 7:295-308;
Wolfman JC, et al. Mol Cell Biol 2002; 22:1589-606.
Survival
KRAS
RAS
Incremento
Eficacia
PRIME study
FOLFOX4 ± panitumumab in 1stline treatment of metastatic CRC
FOLFOX4 (Q2W) +
panitumumab 6 mg/kg
(Q2W)
Metastatic
CRC
(n = 1183)
R
1:1
FOLFOX4
(Q2W)
Disease assessment every 8 weeks
E
n
d
o
f
t
r
e
a
t
m
e
n
t
L
o
n
g
t
e
r
m
f
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w
u
p
• Study endpoints: PFS (1°); OS, ORR, safety, HRQoL
• KRAS status was prospectively analysed
www.amgentrials.com; protocol ID: 20050203; ClinicalTrials.gov identifier: NCT00364013.
HRQoL, health-related quality of life
PRIME study KRAS exon 2 analysis
Efficacy data (primary, final & updated
OS analyses)
WT KRAS exon 2
Primary analysis1
Pmab +
FOLFOX
(n = 325)
OS events, %
Median OS, months
(95% CI)
Odds ratio
(95% CI)
Pmab +
FOLFOX
(n = 325)
82
23.9
(20.3–27.7)
FOLFOX
(n = 331)
19.7
23.8
19.4
(17.6–22.7)
(20.0–27.7)
(17.4–22.6)
0.83
0.88
0.83
(0.67–1.02)
P = 0.072
(0.73–1.06)
P = 0.17
(0.70–0.98)
P = 0.03
(9.2–11.1)
(95% CI)
(95% CI)
(17.6–22.6)
8.0
10.0
8.6
(7.5–9.3)
(9.3–11.4)
(7.5–9.5)
9.6
Hazard ratio
ORR*, %
19.7
(20.3–28.3)
FOLFOX
(n = 331)
Updated OS analysis3
68
23.9
(95% CI)
(95% CI)
Pmab +
FOLFOX
(n = 325)
54
Hazard ratio
Median PFS, months
FOLFOX
(n = 331)
Final analysis2
0.80
0.80
(0.66–0.97)
P = 0.02
(0.67–0.95)
P = 0.01
(n = 323)
(n = 317)
(n = 324)
55
48
57
48
(50–61)
(42–53)
(51–63)
(42–53)
P = 0.068
NA
NA
(n = 317)
1.35
NA
NA
NA
NA
NA
1.47
(1.07–2.04)
P = 0.02
1. Douillard JY, et al. J Clin Oncol 2010; 28:4697-705;
*Included only patients with baseline measurable disease per central
2. Douillard JY, et al. J Clin Oncol 2011; 29(suppl):abstract 3510 (and oral presentation);
review; WT KRAS, WT KRAS in codons 12/13;
3. Douillard JY, et al. N Engl J Med 2013; 369:1023-34.
pmab, panitumumab; NA, not available
PRIME study RAS analysis
KRAS, NRAS and BRAF
mutation hotspots
EXON 1
EXON 2
12
12
KRAS
EXON 2
12
EXON 1
12 1313
4%
EXON 15
600600
BRAF
9%
EXON 4
61
61
59
59
40%
EXON 1
NRAS
13
13
EXON 3
117117
146146
5%
6%
EXON 3
EXON 4
59
59
61
61
117
146146
117
4%
0%
EXON 16
Overall RAS
ascertainment rate: 90%
Overall RAS and BRAF
Among WT KRAS exon 2 patients, an additional 17% of tumours
with RAS mutations were found
Based on Douillard JY, et al. N Engl J Med 2013; 369:1023-34;
Oliner KS, et al. EJC 2013; 49 (suppl 3):abstract 2275 (and poster).
Percentages have been rounded; 7 patients harboured either KRAS or
NRAS codon 59 mutations
RAS status – prevalence of RAS mutations
among 1,060 evaluable patients
PRIME RAS analysis
(refinement of patient population by RAS mutation status)
PRIME (KRAS exon 2)
MT KRAS (exon 3,
4) n = 60/641
(9.4%)
n = 440/1,096
(40.1%)
n = 656/1,096
(59.9%)
MT
WT
Douillard JY, et al. N Engl J Med 2013; 369:1023-34.
n = 548/1,060
(51.7%)
n = 512/1,060
(48.3%)
MT NRAS (exon 2, 3, 4)
n = 48/641
(7.5%)
MT KRAS exon 3 (codon 61) & exon 4 (codons 117/146);
MT NRAS exon 2 (codons12/13), exon 3 (codon 61) & exon 4
(codon117/146)
PFS (primary analysis)
WT KRAS exon 21
WT RAS2
100
100
90
80
70
60
50
40
30
20
10
0
HR = 0.72 (95% CI, 0.58–0.90)
P = 0.004
80
Proportion event-free (%)
90
HR = 0.80 (95% CI, 0.66–0.97)
P = 0.02
70
60
50
40
30
20
10
0
0
2 4
Months
6
8
10 12 14 16 18 20 22 24
Events
n (%)
Median (95% CI)
months
Panitumumab +
FOLFOX4 (n = 325)
199 (61)
9.6 (9.2–11.1)
FOLFOX4 (n = 331)
215 (65)
8.0 (7.5–9.3)
1. Douillard JY, et al. J Clin Oncol 2010;28:4697-705;
0
2 4
Months
6
8
10 12 14 16 18 20 22 24
Events
n (%)
Median (95% CI)
months
Panitumumab +
FOLFOX4 (n = 259)
156 (60)
10.1 (9.3–12.0)
FOLFOX4 (n = 253)
170 (67)
7.9 (7.2–9.3)
WT RAS, WT KRAS & NRAS exons 2/3/4
(includes 7 patients harbouring KRAS/NRAS codon 59 mutations)
OS (primary analysis)
WT RAS2
WT KRAS exon 21
100
100
90
80
70
70
60
60
50
40
30
20
10
0
HR = 0.78 (95% CI, 0.62–0.99)
P = 0.043
80
Proportion alive (%)
90
HR = 0.83 (95% CI, 0.67–1.02)
P = 0.072
50
40
30
20
10
0
0
4
8
Months
12
16
20
24
28
32
36
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)
1. Douillard JY, et al. J Clin Oncol 2010;28:4697-705;
0
4
8
Months
12
16
20
24
28
32
36
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)
OS (primary analysis)
WT KRAS exon 2 / MT
other RAS
100
90
100
90
HR = 1.29 (95% CI, 0.79–2.10)
P = 0.305
80
70
70
60
60
50
40
30
20
10
0
HR = 1.25 (95% CI, 1.02–1.55)
P = 0.034
80
MT RAS
50
40
30
20
10
0
0
4
8
Months
12
16
20
24
28
32
36
Events
n (%)
Median (95% CI)
months
Panitumumab +
FOLFOX4 (n = 51)
35 (69)
17.1 (10.8–19.4)
FOLFOX4 (n = 57)
33 (58)
18.3 (13.0–23.2)
Douillard JY, et al. N Engl J Med 2013; 369:1023-34, supplements at:
http://www.nejm.org/doi/suppl/10.1056/NEJMoa1305275/suppl_file/nejmoa1305275_appendix.pdf.
0
4
8
Months
12
16
20
24
28
32
36
Events
n (%)
Median (95% CI)
months
Panitumumab +
FOLFOX4 (n = 272)
187 (69)
15.6 (13.4–17.9)
FOLFOX4 (n = 276)
175 (63)
19.2 (16.7–21.8)
MT RAS, MT in any KRAS or NRAS exon 2, 3, or 4
(excludes 7 patients harbouring KRAS/NRAS codon 59 mutations)
OS subgroup analysis
(primary analysis)
WT RAS
Factors
All patients
Western Europe / Canada / Australia
Rest of the world
ECOG: 0 or 1
ECOG: 2
Primary tumour: colon
Primary tumour: rectal
Number of sites: 1
Number of sites: 2
Number of sites: ≥3
Location of site: liver
Location of site: other
Baseline LDH <1.5 x ULN
Baseline LDH ≥1.5 x ULN
Baseline LDH <2 x ULN
Baseline LDH ≥2 x ULN
Male
Female
White / Caucasian
Other
N
HR
95% CI
512
302
210
479
32
335
177
105
187
218
88
424
336
154
382
108
331
181
468
44
0.78
0.78
0.74
0.74
1.34
0.84
0.61
0.73
0.90
0.68
0.70
0.79
0.81
0.77
0.82
0.73
0.80
0.72
0.79
0.57
0.62–0.99
0.57–1.05
0.51–1.08
0.57–0.95
0.63–2.89
0.63–1.12
0.40–0.94
0.41–1.33
0.61–1.34
0.48–0.97
0.35–1.39
0.61–1.01
0.59–1.10
0.52–1.13
0.62–1.09
0.46–1.15
0.59–1.08
0.49–1.05
0.61–1.01
0.25–1.27
Favours panitumumab
0.1
Douillard JY, et al. N Engl J Med 2013; 369:1023-34, supplements at:
http://www.nejm.org/doi/suppl/10.1056/NEJMoa1305275/suppl_file/nejmoa1305275_appendix.pdf.
Favours FOLFOX4
1.0
10.0
Hazard ratio (panitumumab + FOLFOX4 vs. FOLFOX4)
Refinement of patient population by WT RAS
status (primary analysis)
WT KRAS exon 21
Median PFS, months
Panitumumab +
FOLFOX4
(n = 325)
9.6
Hazard ratio
(P-value)
Median OS, months
(P-value)
ORR*, %
(95% CI)
FOLFOX4
(n = 331)
Panitumumab +
FOLFOX4
(n = 259)
FOLFOX4
(n = 253)
8.0
10.1
7.9
0.80
0.72
(P = 0.02)
(P = 0.004)
23.9
Hazard ratio
WT RAS2,3
19.7
26.0
20.2
0.83
0.78
(P = 0.072)
(P = 0.043)
55
48
59
46
(50–61)
(n = 175)
(42–53)
(n = 154)
(52–65)
(n = 149)
(40–53)
(n = 114)
1. Douillard J-Y, et al. J Clin Oncol 2010;28:4697-70;
2. Douillard J-Y, et al. N Engl J Med 2013;369:1023-34;
3. Vectibix EPAR Assessment report. 2013; EMA/CHMP/367675/2013.
*By central radiological assessment;
WT RAS, WT KRAS and NRAS exons 2/3/4
PRIME study RAS analysis. Summary of
adverse events (primary analysis)
WT RAS
Adverse event
Patients with any AE, n (%)
Panitumumab +
FOLFOX4
FOLFOX4
(n = 256)
(n = 250)
MT RAS
Total
(n = 506)
Panitumumab +
FOLFOX4
Total
FOLFOX4
(n = 268)
(n = 275) (n = 543)
256 (100)
248 (99)
504 (100)
266 (99)
273 (99)
539 (99)
Worst grade of 3
146 (57)
124 (50)
270 (53)
153 (57)
146 (53)
299 (55)
Worst grade of 4
71 (28)
51 (20)
122 (24)
63 (24)
55 (20)
118 (22)
Worst grade of 5
14 (5)
16 (6)
30 (6)
19 (7)
10 (4)
29 (5)
Any serious AE
110 (43)
92 (37)
202 (40)
121 (45)
84 (31)
205 (38)
AE leading to permanent
discontinuation of any
study drug
65 (25)
40 (16)
105 (21)
60 (22)
37 (13)
97 (18)
Not serious
48 (19)
28 (11)
76 (15)
50 (19)
24 (9)
74 (14)
Serious
24 (9)
15 (6)
39 (8)
17 (6)
14 (5)
31 (6)
(includes 7 patients harbouring KRAS/NRAS codon 59 mutations);
AE, adverse event
Douillard JY, et al. N Engl J Med 2013; 369:1023-34.
PRIME trial RAS primary analysis
BRAF mutations appeared to be
ognostic
Panitumumab
+ FOLFOX4
FOLFOX4
WT RAS/WT BRAF, n
228
218
Median PFS, months
10.8
9.2
0.68
(9.4–12.4)
(7.4–9.6)
(0.54–0.87)
28.3
20.9
0.74
(23.7–NE)
(18.4–23.8)
(0.57–0.96)
WT RAS/MT BRAF, n
24
29
Median PFS, months
6.1
5.4
0.58
(3.7–10.7)
(3.3–6.2)
(0.29–1.15)
10.5
9.2
0.90
(6.4–18.9)
(8.0–15.7)
(0.46–1.76)
(95% CI)
Median OS, months
(95% CI)
(95% CI)
Median OS, months
(95% CI)
HR
P-value
0.002
0.02
0.12
0.76
NE, not estimable.
Predefined retrospective analysis;
Includes 7 patients harbouring KRAS/NRAS codon 59 mutations.
Douillard J-Y, et al. N Engl J Med 2013;369:102334.
Selección de pacientes con RAS
Resection rates and
survival in patients with
WT RAS mCRC and liver
metastases:
the PRIME study
Resection rates and survival (unresectable CLM
patients)
WT RAS CLM patients (n=89)
Panitumumab +
FOLFOX4
(n = 48)
FOLFOX4
(n = 41)
P-valuec
34 (79)*a
18 (51)*b
0.015
Metastasectomy, n (%)
15 (31)
9 (22)
0.349
Complete resection, n (%)
14 (29)
7 (17)
0.216
40.7
33.4
≥30% tumour shrinkage at week 8, n (%)
Median OS, months
Hazard ratio (95% confidence intervals)
3-year OS rate, %
0.71 (0.43–1.16)
55
0.174
44
*Patients assessed at baseline and Wk 8; aN=43; bN=35; cDescriptive p-value.
Panitumumab+FOLFOX resulted in conversion of almost 1/3 of
initially unresectable CLM patients.
Peeters M, et al. Markers in Cancer: A joint meeting by ASCO, EORTC and NCI 2013 (Brussels, November 7-9).
EJC 2013;49:Suppl 4:S17-18:Abstract MC13-0022. Available at
http://www.eortc.be/temp/EJC%20abstract%20book.pdf Accessed 30 October 2013.
CLM (colorectal cancer liver metastases);
OS (overall survival).
PFS, OS (LLD patients, updated analysis)
PFS
OS
100
100
90
90
HR = 0.75 (95% CI, 0.48–1.19)
P = 0.2223
80
80
70
Kaplan-Meier estimate
70
HR = 0.71 (95% CI, 0.43–1.16)
P = 0.1737
60
50
40
30
20
10
0
60
50
40
30
20
10
0
0
4 8 12 16 20 24 28 32 36 40 44 48 52
Months
Events
n (%)
Median (95% CI)
months
Panitumumab +
FOLFOX4 (n = 48)
38 (79)
11.3
FOLFOX4 (n = 41)
37 (90)
9.9
Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC13-0022 (and poster).
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64
Months
Events
n (%)
Median (95% CI)
months
Panitumumab +
FOLFOX4 (n = 48)
32 (67)
40.7
FOLFOX4 (n = 41)
31 (76)
33.4
PFS, progression-free survival; OS, overall survival; LLD, liver-limited disease
Conclusiones de Prime RAS nativo en metástasis hepáticas
FOLFOX/Panitumumab en pacientes RAS nativo con
metástasis hepáticas exclusivas obtiene una rápida
reducción tumoral y potencial resección curativa en
un tercio de los pacientes
CASO CLINICO
- Mujer de 41 años que debuta con alteración del tránsito intestinal de 8
meses de evolución con episodios de diarrea alternados con
estreñimiento . Emisión de heces con restos de moco y sangre. Pérdida de
8-10 kg de peso.
COLONOSCOPIA:
A 15 cm del margen anal se identifica una lesión estenosante,
mamelonada y ulcerada.
Biopsia:
ADENOCARCINOMA BIEN
DIFERENCIADO
MARCADOR TUMORAL: CEA 283 ug/L (0,5 - 7).
RMN pélvica:
Tumoración de recto
superior T3 con
implantes y datos de
infiltración vascular e
infiltración de la fascia
mesorrectal posterior.
Adenopatías
mesorrectales en un
número aproximado
de 5.
ESTUDIO DE EXTENSIÓN:
TC TAP:
PET-TC:
• Incremento
patológico
En hígado dos
lesiones del metabolismo compatible con actividad
tumoral
en proceso
neoformativo
en unión rectosigma, en adenopatía
hipodensas,
de bordes
mal
interaortocava
y en lesiones
metastásicas hepáticas.
definidos, compatibles
con
metástasis.
Entre los segmentos V, VI y
ANÁLISIS
KRAS: RAS NATIVO.
VII deMUTACIONAL
5,5 x 5,3 x7,5cm
Entre los segmentos VII y
JD: Adenocarcinoma
de recto localmente avanzado con
VIII de 2,5cm.
metástasis hepáticas, con RAS nativo
PREGUNTA nº 1
Cuál SERÍA LA PRIMERA ESTRATEGIA TERAPEUTICA QUE
APLICARÍA?
a.
Cirugía del primario y quimioterapia paliativa
b.
Radioterápia pélvica seguida de cirugía y
quimioterapia
c.
Quimioterapia sistémica con anticuerpo
monoclonal seguida RT y de rescate quirúrgico
Quimioterapia sistémica con anticuerpo
monoclonal seguida RT y de rescate
quirúrgico
FOLFOX/ PANITUMUMAB
FOLFOX/Panitumumab con rápida
respuesta clinica
Respuesta después 5 ciclos:
CEA : 23,2 ug/L (previo 283)
TC TAP: Respuesta parcial.
• Disminución del engrosamiento
de la pared el recto con un diámetro
máximo de 2cm desapareciendo
el efecto masa en la pared.
• Notable disminución del tamaño de
las metástasis hepáticas.
- Segmento VII: 7,5cm 4,2cm
- Segmento VI: 2,5cm  0,8 cm
RMN pélvica:
Mejoría de la afectación tumoral local y adenopática de en torno al 50%.
• 8 ciclos de FOLFOX6-PANITUMUMAB
CEA 2,2 ug/L
TC TAP:
• Evolución radiológica favorable de
las metástasis hepáticas.
- Segmento VII: 4,2cm  3,2cm
- Segmento VI: 0,8cm  1,2 cm
• Engrosamiento parietal en región
rectosigmoidea de 1,1 cm con
disminución de tamaño respecto al
estudio previo.
Planificación de CIRUGÍA del tumor primario y de las metástasis
hepáticas.
Previo a la intervención se realiza RADIOTERAPIA CORTA
Irradiación externa sobre la cavidad pelviana administrando una dosis
total de 25Gy (5Gy por fracción; 5 sesiones)
CIRUGIA: Resección anterior recto y mesorrecto subtotal + Ileostomía
lateral.
Anatomía patológica:
Adenocarcinoma de recto con presencia de neoplasia residual en
submucosa y muscular propia. Ausencia de metástasis en los 18
ganglios aislados (ypT2N0).
Cambios fibrosos post-tratamiento con regresión tumoral extensa
(TRG3).
Control post-cirugía
• Desde el punto de vista clínico la paciente está asintomática, ha
ganado 2 kilos de peso.
• Mantiene neuropatía periférica grado I.
TC TAP:
• Cambios postquirúrgicos en
pelvis menor.
• Diminución del tamaño de las
lesiones hepáticas.
- Segmento VII: 3,2cm 1,9 cm
- Segmento VI: Disminución en
grosor y retracción del contorno
hepático.
CEA 10,6 ug/L
• Se decide continuar con el mismo esquema de quimioterapia
durante 2 meses y programar la cirugía de las metástasis hepáticas.
• Recibe 4 ciclos de FOLFOX6-PANITUMUMAB
(los 3 últimos sin oxaliplatino por neuropatía grado II- III).
Hallazgo: Metástasis en SVII (2,2cm); SVI (9mm); SV (3mm).
Técnica: Sectorectomía posterior. Metastasectomía SV.
Anatomía patológica:
Parénquima hepático sin signos de infiltración neoplásica en los fragmentos remitidos
como correspondientes a segmento VI y V.
En pieza de sectorectomía posterior se identifica una formación nodular irregular,
blanquecina, bien delimitada y de consistencia firme de 2,4x1,5 cm de ejes
mayores compatible con metástasis hepática por adenocarcinoma
moderadamente diferenciado con patron morfologico compatible con un origen
colorrectal primario con afectación focal del margen de resección
Impact of postprogression anti-VEGFcontaining therapy on
survival in mCRC
patients:
the PRIME study
Chemotherapy backbones used in PPT (updated analysis)
WT RAS
1st-line
therapy
Panitumumab
+ FOLFOX4
(n = 169)
FOLFOX4
(n = 177)
- anti-VEGF
(n = 114)
+ anti-VEGF
(n = 55)
- anti-VEGF
(n = 132)
+ anti-VEGF
(n = 45)
Irinotecan based
72 (63)
33 (60)
90 (68)
34 (76)
Oxaliplatin based
10 (9)
3 (5)
11 (8)
1 (2)
Both
17 (15)
17 (31)
16 (12)
10 (22)
Unknown
15 (13)
2 (4)
15 (11)
0 (0)
2nd-line
therapy
Type of chemotherapy, n (%)
- anti-VEGF, not containing anti-vascular endothelial growth factorcontaining therapy; + anti-VEGF, containing
anti-VEGF-containing therapy; PPT, post-progression therapy
OS (patients receiving PPT, updated analysis)
Overall
With Panitumumab + FOLFOX4
100
100
HR = 0.63 (95% CI, 0.48–0.81)
P = 0.0004
90
100
HR = 0.64 (95% CI, 0.44–0.94)
P = 0.0211
90
80
70
70
60
60
60
40
30
20
10
0
0
4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64
Months
Received
anti–VEGF (n = 100)
No anti–VEGF
treatment (n = 246)
80
70
50
50
40
30
20
10
0
0
4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64
Months
Events
n (%)
Median (95% CI)
months
80 (80)
38.1
Received
23.6
No anti–VEGF
treatment (n = 114)
208 (85)
HR = 0.62 (95% CI, 0.44–0.89)
P = 0.0101
90
80
FOLFOX4
50
40
30
20
10
0
0
4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64
Months
Events
n (%)
Median (95% CI)
months
39 (71)
40.0
26.0
91 (80)
Events
n (%)
Median (95% CI)
months
Received
41 (91)
36.2
No anti–VEGF
treatment (n = 132)
117 (89)
20.6
Data are from an exploratory analysis, data cut-off: January 24, 2013;
OS, overall survival; PPT, post-progression therapy
OS (updated analysis)
WT RAS
Post-PD anti-VEGF therapy
Panitumumab +
FOLFOX4
Yes
No
Yes
No
Patients, n
55
114
45
132
Events, n
39
91
41
117
22.8
11.5
22.6
9.4
FOLFOX4
From PD on 1st-line therapy
Median OS, months
Yes vs. no anti-VEGF therapy
Hazard ratio
(95% CI)
Descriptive p-value
0.55
0.59
(0.37–0.80)
0.0018
(0.41–0.85)
0.0043
From start of 1st-line therapy
Median OS, months
40.0
26.0
Yes vs. no anti-VEGF therapy
Hazard ratio
(95% CI)
Descriptive p-value
36.2
20.6
0.64
0.62
(0.44–0.94)
0.0211
(0.44–0.89)
0.0101
OS, overall survival; PD, progression; VEGF, vascular endothelial growth factor
OS (patients receiving PPT, updated analysis)
PPT including anti-VEGF therapy
100
90
Events
n (%)
Median (95%
CI) months
Panitumumab +
FOLFOX4 (n = 55)
39 (71)
40
FOLFOX4 (n = 45)
41 (91)
36.2
80
HR = 0.64 (95% CI, 0.41–
1.00)
P = 0.0494
70
60
50
40
30
20
10
0
0
4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68
Months
OS, overall survival; PPT, post-progression therapy; VEGF, vascular
endothelial growth factor
Conclusions
Treatment of WT RAS mCRC patients with pmab + FOLFOX4 followed by an
anti-VEGF agent produced a median OS of 40 months in these exploratory
analyses
Study limitations
Patients were not randomised to 2nd-line treatment
Patients who died or could not continue in the study until 1st-line PD were not
considered, in accordance with earlier reports1
Patients unable to tolerate 2nd-line anti-VEGF therapy were not considered
Confirmation of this treatment strategy in prospective clinical trials may be of
value to clinical practice
Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC13-0024 (and poster);
1. Bennouna J, et al. Lancet Oncol 2013;14:29-37.
VEGF, vascular endothelial growth factor
PREGUNTA nº 2
Cuál es el principal objetivo que se valora en el momento de
decidir qué anticuerpo monoclonal se utiliza en el tratamiento del
paciente WT en primera línea de mCRC?
a.
OS
b.
PFS
c.
ORR
d.
Ninguno de los anteriores
PREGUNTA nº 3
En qué se basaría el tratamiento de elección en
primera línea para un paciente mCRC WT?
a. Tratamiento basado en anti-EGFR
b. Tratamiento basado en anti-VEGR
c. Quimioterapia sola
Cross-trial comparisons have
limitations – are head-to-head trials
available?
CALGB 80405
(phase III)
Bevacizumab +
FOLFOX or FOLFIRI
PD
Primary endpoint: OS
Cetuximab +
FOLFOX or FOLFIRI
PD
FIRE III
(phase III)
Bevacizumab +
FOLFIRI
PD
Cetuximab +
FOLFIRI
PD
Bevacizumab +
mFOLFOX6
PD
Panitumumab +
mFOLFOX6
PD
Untreated
KRAS WT mCRC
(n=1,100)
Untreated
KRAS WT
mCRC
(n=520)
R
R
Primary endpoint: ORR
PEAK
(phase II)
Primary endpoint: PFS
Untreated,
unresectable
KRAS WT mCRC
(n=285)
R
FIRE-3 study design
Stintzing S, et al. Journal of clinical oncology 2014 32(suppl 3):abstr 445. Pres. at ASCO GI 2014
FIRE-3 study results
Evaluation of OS
CALGB 80405 QoL analysis, comparing 1L cetuximab vs
Bevacizumab, in combination with FOLFOX/FOLFIRI
Bevacizumab +
FOLFOX/FOLFIRI
Previously untreated KRAS
WT mCRC
(n=2,900)
R
(n=518 in QoL analysis)
Cetuximab +
FOLFOX/FOLFIRI
• Phase III
• Primary endpoint: QoL at 3 months
• QoL was assessed at baseline, 6 weeks, and 3, 6 and 9 months post-randomisation, using the
EORTC QLQ-30 and the Dermatology- Specific Quality of Life (DSQL) scales
• As the QoL analysis enrolled the first 518 patients randomised to CALGB 80405, the majority
were enrolled prior to a protocol amendment eliminating the dual biologic arm and restricting
participation to patients with KRAS WT tumours
Naughton, et al. ASCO 2013
PEAK study: mFOLFOX6 + panitumumab or bevacizumab in 1stline treatment of WT KRAS exon 2 mCRC
mFOLFOX6 (Q2W) +
panitumumab 6 mg/kg
(Q2W)
Metastatic
CRC
WT KRAS exon 2
(n = 285)
R
1:1
mFOLFOX6 (Q2W) +
bevacizumab 5 mg/kg
(Q2W)
S
a
f
e
E
n
d
o
f
t
r
e
a
t
m
e
n
t
t
y
30 days
(+ 3 days)
f
o
l
l
o
w
u
p
Tumour Assessment Q8W (±7 days);
Treatment administered until
disease progression, death,
or withdrawal from study
P
o
s
t
t
r
e
a
t
m
e
n
t
f
o
l
l
o
w
E
n
d
o
f
s
t
u
d
y
u
p
Every 3 months (±28 days)
until end of study
• Study endpoints: PFS (1°); OS, ORR, safety, exploratory biomarker analysis
• No formal hypothesis testing was planned
Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster);
Protocol ID: 20070509; ClinicalTrials.gov identifier: NCT00819780.
ORR, objective response rate; mFOLFOX6, modified FOLFOX6
PEAK study: Efficacy data (primary & longer follow-up analyses)
WT KRAS exon 2
Primary analysis1
Panitumumab +
mFOLFOX6
(n = 142)
OS events, n (%)
Median OS, months
(95% CI)
25.4
(28.8–NR)
(22.9–29.5)
34.2
24.3
(26.6–NR)
(21.0–29.2)
0.72
0.62
(0.47–1.11)
P = 0.14
(0.44–0.89)
P = 0.01
10.1
10.9
10.1
(9.4–13.0)
(9.0–12.6)
(9.7–12.8)
(9.0–12.0)
(95% CI)
(95% CI)
Bevacizumab +
mFOLFOX6
(n = 143)
10.9
Hazard ratio*
ORR*, %
Panitumumab +
mFOLFOX6
(n = 142)
46
NR
(95% CI)
(95% CI)
Bevacizumab +
mFOLFOX6
(n = 143)
31
Hazard ratio*
Median PFS, months
Longer follow-up analysis1,2
0.87
0.84
(0.65–1.17)
P = 0.35
(0.64–1.11)
P = 0.22
58
54
58
54
(49–66)
(45–62)
(50–67)
(45–62)
1. Schwartzberg L, et al. J Clin Oncol 2013; 31 (suppl):abstract 3631 (and poster);
2. Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster).
*Stratified Cox proportional hazards model;
No formal hypothesis testing was planned; NR, not reached
PEAK study RAS analysis
KRAS, NRAS and BRAF mutation hotspots
EXON 1
KRAS
EXON 1
NRAS
EXON 1…
EXON 2
EXON 3
12 13
59 61
N/A#
4%
EXON 2
EXON 3
12 13
59 61
5%
6%
EXON 15
117
146
7%
EXON 4
146
117
0%
EXON 16…
600
BRAF
EXON 4
6%
1. Schwartzberg L, et al. J Clin Oncol 2013; 31 (suppl):abstract 3631 (and poster);
2. Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster).
Overall RAS
ascertainment
rate: 82%
Percentages have been rounded; #WT KRAS exon 2 tumour status
was defined in the trial eligibility criteria; N/A, not applicable
PEAK study RAS
analysis: PFS
PEAK study RAS analysis: OS
Objective response
Overall summary of AEs (longer follow-up analysis)
WT KRAS exon 2 /
MT other RAS
WT RAS
Pmab +
mFOLFOX6
(n = 86)
Bev +
mFOLFOX6
(n = 80)
Pmab +
mFOLFOX6
(n = 24)
Bev +
mFOLFOX6
(n = 27)
86 (100)
80 (100)
24 (100)
27 (100)
Worst grade of 3
60 (70)
43 (54)
13 (54)
16 (59)
Worst grade of 4
17 (20)
15 (19)
7 (29)
8 (30)
Worst grade of 5
4 (5)
7 (9)
1 (4)
1 (4)
Serious adverse events
37 (43)
32 (40)
9 (38)
13 (48)
Leading to permanent
discontinuation of any study drug
25 (29)
24 (30)
9 (38)
7 (26)
Adverse event, n (%)
Patients with any adverse event
WT RAS, WT KRAS & NRAS exons 2/3/4; AE, adverse event;
pmab, panitumumab; bev, bevacizumab
Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster).
PEAK study RAS analysis: Conclusions
In this updated analysis of the 1st-line estimation study of
previously untreated patients with WT RAS* mCRC, data
suggest PFS and OS HR favoured panitumumab + mFOLFOX6
relative to bevacizumab + mFOLFOX6
PFS HR = 0.66 (95% CI, 0.46–0.95; P = 0.03) for OS in favour of pmab
OS HR = 0.63 (95% CI, 0.39–1.02; P = 0.06) in favour of pmab
The magnitude of improvement in PFS and OS in patients with
WT RAS tumours treated with panitumumab is clinically
relevant in the mCRC population
*WT RAS, WT KRAS & NRAS exons 2/3/4; No formal hypothesis testing
was planned; AE, adverse event; pmab, panitumumab
Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster).
Incremental improvements in OS in mCRC over the past
decade
Saltz1, 2000
5-FU/LV bolus
Douillard2, 2000
12.6
5-FU/LV infusion
Saltz1, 2000
14.1
IFL
14.8
Douillard2, 2000
FOLFIRI (de Gramont or AIO)
Goldberg3, 2004
FOLFOX
Hurwitz4, 2004
19.5
IFL + bevacizumab
Saltz5, 2008
17.4
20.3
XELOX/FOLFOX + bevacizumab
Falcone6, 2007
21.3
FOLFOXIRI
Van Cutsem7, 2011
22.
623.5*
FOLFIRI + cetuximab
Douillard8, 2013
FOLFOX + panitumumab
Douillard9, 2013
FOLFOX + panitumumab
0
5
23.8*
26.0#
10
15
20
Overall survival (months)
1. N Engl J Med 2000; 343:905-14; 2. Lancet 2000; 355:1041-7;
3. J Clin Oncol 2004; 22:23-30; 4. N Engl J Med 2004; 350:2335-42;
5. J Clin Oncol 2008; 26:2013-9; 6. J Clin Oncol 2007; 25:1670-6;
7. J Clin Oncol 2011; 29:2011-9; 8. J Clin Oncol 31, 2013 (suppl; abstr 3620, and poster); 9. N Engl
J Med 2013;369:1023-34.
25
30
Informal comparison as these are not head-to-head clinical trials;
*WT KRAS; #WT RAS, WT in KRAS & NRAS exons 2/3/4
Panitumumab
in 2nd-line
mCRC
The 20050181 study:
Panitumumab + FOLFIRI
treatment in WT RAS mCRC
20050181 study: FOLFIRI ± panitumumab in 2nd-line treatment of
metastatic CRC
FOLFIRI (Q2W) +
panitumumab 6 mg/kg
(Q2W)
Metastatic
CRC
(n = 1186)
R
1:1
FOLFIRI
(Q2W)
Disease assessment every 8 weeks
E
n
d
o
f
t
r
e
a
t
m
e
n
t
L
o
n
g
t
e
r
m
f
o
l
l
o
w
u
p
• Study endpoints: PFS and OS (1°), ORR, safety
Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).
ORR, objective response rate
20050181 study KRAS exon 2 analysis: Efficacy in patients with WT
KRAS tumours
Median PFS, months
Panitumumab + FOLFIRI
(n = 303)
FOLFIRI
(n = 294)
5.9
3.9
Hazard ratio
0.73
(P = 0.004)
(P-value)
Median OS, months
14.5
Hazard ratio
0.85
(P = 0.12)
(P-value)
ORR, n (%)
(95% CI)
Peeters M, et al. J Clin Oncol 2010; 28:4706-13.
12.5
(35)
(10)
(30–41)
(n = 297)
(7–14)
(n = 285)
By central review;
*P < 0.001 (descriptive); exact test of odds ratio
stratified by randomisation factors
20050181 study RAS analysis: Mutation hotspots
EXON 1
EXON 2#
12
KRAS
EXON 1
12
13
13
44.9%
EXON 2
12
NRAS
EXON 3
12 1313
2.2%
EXON 4
59
61
59 61
4.4%
EXON 3
59
117
146
117 146
7.7%
EXON 4
61
59 61
5.6%
117
117
146146
0%
Overall RAS
18% (107/597) of WT KRAS exon 2 tumours have RAS mutations
Prevalence is defined as mutations detected in a population of
WT KRAS exon 2 patients whose tissues were deemed evaluable
for RAS testing; #The KRAS exon 2 data is from the overall population;
WT RAS, KRAS & NRAS exons 2/3/4
20050181 study RAS analysis: PFS (primary analysis)
WT RAS
100
90
Events
n (%)
Median (95% CI)
months
Panitumumab +
FOLFIRI (n = 204)
117 (57)
6.4 (5.5–7.4)
FOLFIRI (n = 211)
138 (65)
4.4 (3.7–5.5)
HR = 0.695 (95% CI,
0.536–0.903)
Log-rank p-value = 0.006
80
70
60
50
40
30
20
10
0
0
2
4
6
8
Months
10
12
14
16
18
RAS ascertainment rate: 85%;
20050181 study RAS analysis : OS (primary analysis)
WT RAS
Events
n (%)
100
90
Median (95% CI)
months
Panitumumab +
FOLFIRI (n = 204)
127 (62) 16.2 (14.5–19.7)
FOLFIRI (n = 211)
141 (67) 13.9 (11.9–16.1)
HR = 0.803 (95% CI, 0.629–
1.024)
Log-rank p-value = 0.08
80
70
60
Proportion alive %
50
40
30
20
10
0
0
2
4
6
8
10
12
14
16
Months
18
20
22
24
26
28
30
32
34
RAS ascertainment rate: 85%;
20050181 study RAS analysis
Refinement of WT
patient
by WT
KRAS exonpopulation
2
WT RASRAS
status
Panitumumab +
Panitumumab +
FOLFIRI
FOLFIRI
FOLFIRI
FOLFIRI
(primary analysis)
(n = 303)
(n = 294)
(n = 204)
(n = 211)
1
Median PFS,
months
5.9
Hazard ratio
(P-value)
Median OS, months
(P-value)
(95% CI)
6.4
4.4
0.73
0.695
(P = 0.004)
(P = 0.006)
14.5
Hazard ratio
ORR, %
3.9
2
12.5
16.2
13.9
0.85
0.803
(P = 0.12)
(P = 0.08)
35
10
41
10
(30–41)
(n = 297)
(7–14)
(n = 285)
(32–48)
(n = 200)
(6–15)
(n = 205)
1. Peeters M, et al. J Clin Oncol 2010; 28:4706-13;
2. Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).
20050181 study RAS analysis; Refinement of patient population
by MT RAS status. (primary analysis)
MT KRAS exon 21
Median PFS,
months
Panitumumab +
FOLFIRI
(n = 238)
5.0
Hazard ratio
(P-value)
Median OS, months
(P-value)
ORR, %
(95% CI)
FOLFIRI
(n = 248)
Panitumumab +
FOLFIRI
(n = 299)
FOLFIRI
(n = 294)
4.9
4.8
4.0
0.85
0.861
(P = 0.14)
(P = 0.14)
11.8
Hazard ratio
MT RAS2
11.1
11.8
11.1
0.94
0.914
(P = *ND)
(P = 0.34)
13
14
15
13
(9–18)
(n = 232)
(10–19)
(n = 237)
(11–20)
(n = 292)
(9–17)
(n = 282)
1. Peeters M, et al. J Clin Oncol 2010; 28:4706-13;
2. Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).
*ND, not done;
CASO CLINICO
Paciente de 77 años con AP de DMNID en tratamiento
con metformina e HTA
Diagnosticado de adenocarcinoma de recto
moderadamente diferenciado con metástasis
hepáticas en ambos lóbulos irresecables de entrada
con afectación de la grasa mesorrectal no
obstructivo.
Elevación del CEA: 10 ug /l
RAS NATIVO
Se propone QT dentro de Ensayo Clínico MO18725B17.
FOLFOXIRI/ BEVACIZUMAB
Después de 8 ciclos de FOLFOXIRI/BEVA
RP> 50%
TOX:
- Neutropenia g 4,
trombopenia g 2, diarrea
y mucositis grado 2
CEA: 1 ng/l
Cirugia radical del primario y de las metástasis hepáticas pero en la valoración
postquirurgica han aparecido metástasis hepáticas recientes
Inicia 2ª línea de tratamiento con QT:
Irinotecan – panitumumab, con RC
PREGUNTA nº 4
¿En relación con la secuencia de los esquemas
terapéuticos en pacientes con cáncer colorrectal
metástasico RAS nativo, cual de las siguientes
afirmaciones es correcta?
1. Después de progresar a un esquema de quimioterapia con anti-EGFR en
primera línea, los anti-VEGF asociado a la quimioterapia incrementan la
supervivencia global
2. Después de progresar a un esquema de quimioterapia con anti-VEGF los
anti-VEGF no aportan beneficio a la quimioterapia
3. Los anti-EGFR y los anti-VEGF no aportan beneficio a la quimioterapia en
2º línea
Multi-Line Therapy Trial in Unresectable
Metastatic Colorectal Cancer (STRATEGIC-1)
Folfiri+ Cetuximab
1L
2L
QT basada en
OXALI+Beva
3L
OPTMOX + BEVA
QT basada en IRI+
Bevacizumab
Anti-EGFR +/IRINOTECAN
Objetivo 1ºDuración de Control de la enfermedad desde el inicio hasta
la última estrategia
2º: Calidad de vida, PFS, OS, RR, T Fallo estraegias
ClinicalTrials.gov Identifier:NCT01910610
Código: TTD-12-03/ULTRA
Diseño
Objetivos
• Ensayo clínico fase II, no comparativo
• Pauta: FOLFIRI+panitumumab
• Tratamiento hasta PE o retirada por
otras causas
Pacientes
WT RAS
con CCRM y
resistentes
QT basada
irinotecán
Técnicas alta
sensibilidad
genotipo
ampliado:
RAS
PIK3Ca
BRAF
NRAS
• Tasa de respuesta objetiva (principal)
• Supervivencia libre de progresión
Supervivencia global
• Perfil de seguridad
N=45
FOLFIRI
+Pmab
N=82
experimental
No mutado
N=37
paralelo
Mutado
N=82
Coordinadores: Dr. Ramón Salazar y Gabriel Capellá
CONCLUSIONES
1.-La determinación del estado mutacional de RAS debe
realizarse en los pacientes que sean candidatos a recibir
un tratamiento con anti-EGFR
2.- El factor predictivo RAS ha permitido aumentar la
eficacia de Panitumumab, consiguiendo un incremento en
la supervivencia global.
3. La combinación de FOLFOX con Panitumumab
representan una alternativa terapéutica útil y segura en
primera línea.
4. Los estudios de secuenciación permitiran establecer la
secuencia adecuada de los biológicos
¡ Muchas Gracias!
[email protected]

Diapositiva 1 - Abordaje Multidisciplinar del Cáncer

Transcripción

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