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