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Il management del paz metastatico
Alberto Sobrero
IRCCS San Martino IST
Genova
TRIBE
Toward the definition of the overall benefit of antineoplastic agents in advanced CRC
DRUG 1° line other lines ‘overall’
FU
IRI
OXALI
ANGIO
CET
PANI
Extd RAS
REGO
6.0, 6.0, 2.2 5
2.0, 3.1, 3.2 2.7, 2.3 3
1.5, 3.1, 4.5 3
4.7, 1.3, 3.7, 3.9, 4.9 2.1, 1.4, 1.4 5
3.5 ,4.3,-0.7,-0.7 0.7, 4.7 4
4.2 2.0, -0.1, 0.5 4
1.4 1.4
1.5, 4.7, 3.8 4
mCRC simplified 1 line treatment strategy
FOLFIRI/FOLFOX CET
or FOLFOX PANI
RAS
MUT or not available
WT
Shrinkage needed?
NO YES
Doublet plus
bevacizumab
(or triplets lus bev)
Capecitabine or doublet
plus bevacizumab
FOLFOXIRI BEV / CALGB
● Difficile trovare uno spazio per FOLFOXIRI BEV nei
RAS wt ( non importa cosa dira’ il CALGB)
● Nei RAS mut FOLFOXIRI BEV diventa il competitor di
FOLFOX BEV o FOLFIRI BEV
● Nei B-raf mut FOLFOXIRI BEV si conferma la scelta
piu’ efficace
mCRC treatment strategy (make it simple)
FOLFIRI/FOLFOX CET
or FOLFOX PANI
RAS
MUT or not available
WT
Shrinkage needed?
Doublet
plus bevacizumab
or aflibercept
Regorafenib
NO YES
Doublet plus
bevacizumab
(or triplets lus bev)
Capecitabine or doublet
plus bevacizumab
Doublet
plus bevacizumab
or aflibercept
Regorafenib
Potential II Line Treatment Strategies
COMBINATION STUDY
BEV + IRI or oxali-based CT E32001 and TML2
CET + IRI EPIC3
PANI + IRI PICCOLO4
PANI + FOLFIRI 1815
AFLIB + FOLFIRI VELOUR6
BEV-bevacizumab; CET-cetuximab; IRI-irinotecan; PANI-panitumumab; AFLIB-aflibercept
1. Arnold D, et al. J Clin Oncol. 2012;30(15S): Abstract CRA3503; 2. Giantonio BJ, et al. J Clin Oncol.
2007;25:1539-1544. 3. Sobrero AF, et al. J Clin Oncol. 2008;26(14):2311-2319. 4. Seymour et al.
Lancet Oncol. 2013. 5. Sobrero AF, et al. J Clin Oncol. 2012;30(suppl 4): Abstract 387. 6. Van Cutsem
E, et al. J Clin Oncol. 2012;30:3499-3506.
E 3200 Overall Survival
Alive Dead Median Total
A:FOLFOX4 + bevacizumab10 289 246 43 12.9
B:FOLFOX4 290 257 33 10.8
C:bevacizumab 243 216 27 10.2
Pro
ba
bilit
y
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OS (months)
0 3 6 9 12 15 18 21 24 27 30 33 36
HR = 0.76
A vs B: p=0.0018
B vs C: p=0.95
RR: 9 vs 22%
PFS 0.64 (2.4)
Giantonio BJ, et al. ASCO 2005; J Clin Oncol. 2007;25:1539-1544
TML: OS, ITT Population
OS
esti
mate
Time (months)
1.0
0.8
0.6
0.4
0.2
0
0 6 12 18 24 30 36 42 48
No. at risk
CT 410 293 162 51 24 7 3 2
0
BEV + CT 409 328 188 64 29 13 4 1
0
CT (n=410)
BEV + CT (n=409)
9.8 mo 11.2 mo
Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)
p=0.0062 (log-rank test)
aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose
of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)
Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)
RR: 4 vs 5%
PFS 0.68 (1.6)
Arnold D, et al. J Clin Oncol. 2012;30(15S): Abstract CRA3503
PR
OP
OR
TIO
N A
LIV
E
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MONTHS
0 3 6 9 12 15 18 21 24 27 30 33 36 39
HR = 0.975
(95.03% CI = 0.854 – 1.114)
CETUXIMAB + IRINOTECAN; N = 648
Median OS = 10.71 mo
IRINOTECAN; N = 650
Median OS = 9.99 mo
STRATIFIED LOGRANK P-VALUE = 0.7115
EPIC: Overall Survival
RR: 4 vs 16%
PFS 0.69 (1.4)
Sobrero AF, et al. J Clin Oncol. 2008;26(14):2311-2319
Seymour MT, et al. Lancet Oncol. 2013;14:749-759.
PICCOLO: Overall Survival Median OS
10.5 mo
10.4 mo
HR=0.91 (95% CI 0.73-1.14)
P=0.44
RR OR 4.12 (p<0.0001)
PFS HR 0.78 (p=0.015)
GICS 2012
181: Overall Survival
Months
Pmab + FOLFIRI (n=303)
FOLFIRI alone (n=294)
WT
0
20
40
60
80
100 P
rop
ort
ion e
ve
nt fr
ee
(%
)
Events n (%)
Median (95% CI),
months
Pmab + FOLFIRI 267 (88) 14.5 (13.0, 16.1)
FOLFIRI alone 256 (87) 12.5 (11.2, 14.2)
Hazard ratio (95% CI): 0.92 (0.78, 1.10)
P-value: 0.37
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 48 45
RR: 10 vs 35%
PFS 0.82 (1.7)
Sobrero AF, et al. J Clin Oncol. 2012;30(suppl 4): Abstract 38
VELOUR: Overall Survival in ITT Population
Van Cutsem E et al. JCO. 2012;30:3499-3506
Pro
ba
bili
ty o
f S
urv
iva
l (%
)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Median follow-up = 22.28 months
Placebo/FOLFIRI
Aflibercept/FOLFIRI
Placebo: Median = 12.06 months
Aflibercept: Median = 13.50 months
Stratified HR=0.817 [95.34% CI, 0.713-0.937]
Log-rank p = 0.0032
Δ=1.4 months
614 485 286 131 51 14
612 498 311 148 75 33 Number At Risk
79.1% 50.3% 30.9% 18.7% 12.0%
81.9% 56.1% 38.5% 28.0% 22.3% Survival
Probability
Time (months)
13
VELOUR Post Hoc Analysis: OS by Timing of First-Line Disease Progression
9,76 9
10,63
15,15
11,86
9,92
12,48
17,35
0
2
4
6
8
10
12
14
16
18
20
1L PFS <3mo 1L PFS 3-6mo 1L PFS 6-9mo 1L PFS ≥9mo
Med
ian
OS
, m
o
FOLFIRI + Placebo FOLFIRI + Aflibercept
14 Mitchell et al. WCGIC 2014. Abstract and poster xx.
HR=0.701
(0.451, 1.09)
Δ=2.1 mo HR=0.704
(0.504, 0.984)
Δ=.92 mo
HR=0.822
(0.619, 1.093)
Δ=1.85 mo
HR=0.883
(0.712, 1.096)
Δ=2.2 mo
Bennouna et al. Lancet Oncol. 2013;14:29-37.
ML18147: Impact of First-Line PFS on Second-Line OS with Bevacizumab Subgroup Analysis*
*Pre-specified subgroup analysis.
CONCLUSIONS
16
ANTI EGFR weak in II line
ANTIANGIO II LINE aflibercept continued divergence of OS curves
aflibercept benefit maintained despite inclusion of
patients with unfavorable prognostic factors
bev BP when 1°- line PFS > 9 months
Aflibercept
• Strengths
• Best trial in CRC
• Rationale
• Shrinking agent
• Late effects on OS
• ‘prezzo’….!
• Weaknesses
• Limited benefit in median OS
• Toxicity
• The trial Affirm