2013 ASCO GI Winterhalder

8/11/2019 2013 ASCO GI Winterhalder

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A CC 2013

, 04. A 2013


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C C C /

G . J C 2011


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C C C /

A . . 3501


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C C C /

A . . 3501


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C C C /

A . . 3501


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C C C /

A . . 3501


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C C C /

A . . 3501

C / :1.

2. E E


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Primary endpoint: PFS2

Secondary endpoints: OS, TTP2 (time to progression or death

after PS1)

Phase III CAIRO-3: Bevacizumab + CT

maintenance vs observation

UntreatedmCRC

(N=635)

CR

PR

SD

Bevacizumab+ XELOX PD2

Bevacizumab+ capecitabine

PD1

PDnot eligible

PFS2PFS1

Bevacizumab+ XELOX

Observation

Rn=558

Koopman M, et al. ASCO 2013 (Abstract No. 3502)


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C C CA 3

A . . 3502

2 D


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C C CA 3

A . . 3502


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C C CA 3

A . . 3502


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C C CA 3

A . . 3502


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C C CA 3

A . . 3502


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Phase III CAIRO-3: Bevacizumab + CT

maintenance vs observation

*Primary endpoint Koopman M, et al. ASCO 2013 (Abstract No. 3502)

Maintenance treatment with bevacizumab + capecitabine significantly increased PFS1and PFS2 compared with observation

There was no significant increase in OS

Bev + CT maintenance Observation

Median PFS1, mo 8.5 4.1

HR (95% CI), p-value HR 0.44 (95% CI 0.360.53), p


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C C CA 3

A . . 3502

:1. F 1, F 2 2 D

2.


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C C CA 3

A . . 3502


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Bevacizumab continuation versusno continuation after first-line

chemo-bevacizumab therapy in patients with metastatic

colorectal cancer:a randomized phase III non-inferiority trial

Koeberle D, Betticher D, von Moos R, Dietrich D, Brauchli P,Baertschi D, Matter K, Winterhalder R, Borner M, Anchisi S,Moosmann P, Kollar A, Saletti P, Roth A, Frueh M, Kueng M,Popescu R, Schacher S, Hess V, Herrmann R

Swiss Group for Clinical Cancer Reseach


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Non-inferiority study hypothesis: no bevacizumab vs bevacizumab

Non-inferiority design based on bevacizumab maintenance as control arm

Primary endpoint: TTP Secondary endpoints: PFS, OS (both from start of 1st line treatment),

time to 2nd line treatment, safety, costs

Phase III SAKK 41/06: No bev vs bev

maintenance in 1st line mCRC

Koeberle D, et al. ASCO 2013 (Abstract No. 3503)

Untreated

mCRC(Per-protocol:N=262)

Bevacizumab +CT

(46 months)

Bevacizumab7.5 mg/kg q3 wks

Observation

Maintenance therapy

Until PDRNoPD


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Study design

First-line chemo-therapy + BEVfor 4-6 months

NoPD

Randomization1: 1

BEV continuation(7.5 mg/kg q 3 w)

until PD

No antitumor treatment(no BEV) until PDStratification factors:

Best response during first-line chemotherapy + BEV (CR/PR vs SD) Duration of first-line chemotherapy + BEV (16-20 vs 21-24 weeks) Type of chemotherapy (Irinotecan + 5-FU vs Oxalipaltin + 5-FU vs

Fluoropyrimidine mono) Disease burden (metastases in one organ vs multiple organs) Center

Study conducted in 26 sites in Switzerland (accrual period 2007-2012)


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SAKK 41/06: No bev vs bev maintenance

*Primary endpoint Koeberle D, et al. ASCO 2013 (Abstract No. 3503)

Study failed to demonstrate non-inferiority of no bevacizumab(observation alone)

Bevacizumabmaintenance Observation

Median PFS, mo 9.5 8.5HR (95% CI), p-value HR 0.75 (95% CI 0.580.96), p=0.021

Median TTP*, mo 4.1 2.9

HR (95% CI), p-value HR 0.74 (95% CI 0.570.95), p=0.47Median OS, mo 25.1 22.8

HR (95% CI), p-value HR 0.83 (95% CI 0.611.12), p=0.218


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TTP subgroup analysis

0.5 0.727 1.0 1.5

BEV better no BEV better

allage < 60age > 60femalemaleWHO 0WHO 1FL CR/PRFL SD

FL dur 16-20FL dur 21-24FL iri + fluoFL oxa + fluoFL fluo mono1 organ>1 organs

Hazard Ratio (95% CI)

FL = First-line


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Cost analysis

Included resource use Base case 1) Low (-30%) High (+30%)

BEV continuation USD 5.58/mgBEV administration USD 372

Control visit to oncologist USD 165 115 215

In-patients USD 1600/day 1120/day 2080/day

CT-scan USD 663MRI USD 735

1) Swiss prices and Swiss health system

Not included costs: Laboratory tests, out-patient AE treatments,other out-patient treatments/care


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Cost analysis

BEV NO

BEV


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Summary

Non-inferiority could not be demonstrated

The difference in median TTP between BEVcontinuation versus no treatment after randomizationis 5 weeks

Overall survival in both arms is not significantlydifferent

Utility of BEV continuation needs to be balancedwith significantly higher treatment costs


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A . . 3506


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Primary endpoint: ORR

Secondary endpoints: PFS, OS, TFS, DpR, secondary resection rate,safety

Statistics: Designed to detect a difference of 12% in ORR induced by

FOLFIRI + cetuximab (62%) vs FOLFIRI + bevacizumab (50%)

284 evaluable patients needed to achieve 80% power for one-sidedFishers exact test at an alpha level of 2.5%

Patients with untreatedKRAS wt mCRC

N=592

FIRE-3: Head-to-head study of cetuximab + FOLFIRI vs

bevacizumab + FOLFIRI in 1st line mCRC

R

Cetuximab + FOLFIRI

Bevacizumab + FOLFIRI

Open-label, randomized, multicenter Phase III

DpR: deepness of response; TFS: time to failure of strategyKRAS wt: codons 12/13 Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)


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A . . 3506


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FIRE-3: Evaluation of ORR

Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)

FOLFIRI +cetuximab

FOLFIRI +bevacizumab Odds ratio

(95% CI) p-value*ORR % 95% CI % 95% CI

ITT population(n=592) **

62.0 56.267.5 58.0 52.163.7 1.18(0.851.64) 0.183

Assessable forresponse

(n=526)72.2 66.277.6 63.1 57.168.9 1.52(1.052.19) 0.017

*Fishers exact test (one-sided)

** Unconfirmed response, investigator assessment Predefined per protocol: 3 cycles of chemotherapy and 1 CT scan following baseline


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297295

Numbersat risk

10099

1915

106

54

3

P r o

b a

b i l i t y o

f s u r v

i v a

l

Eventsn/N (%)

Median(months)

95% CI

FOLFIRI + cetuximab 250/297(84.2%)

10.0 8.810.8

FOLFIRI + bevacizumab 242/295(82.0%) 10.3 9.811.3

HR 1.06 (95% CI: 0.881.26)Log-rank p=0.547

FIRE-3: PFS (ITT)


0.75

1.0

0.50

0.25

0.012 24 36 48 60 72

Months since start of treatment


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297295

Numbersat risk

218214

111111

6047

2918

92

0.75

1.0

0.50

0.25

0.0

P r o

b a

b i l i t y o

f s u r v

i v a

l

FIRE-3: OS (ITT)


12 24 36 48 60 72Months since start of treatment

Eventsn/N (%)

Median(months)

95% CI


28.7 24.036.6


HR 0.77 (95% CI: 0.620.96)Log-rank p=0.017


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297295

Numbersat risk

218214

111111

6047

2918

92

0.75

1.0

0.50

0.25

0.0

P r o

b a

b i l i t y o

f s u r v

i v a

l

FIRE-3: OS (ITT)


12 24 36 48 60 72Months since start of treatment

Eventsn/N (%)

Median(months)

95% CI


28.7 24.036.6


HR 0.77 (95% CI: 0.620.96)Log-rank p=0.017

HR 1.0

HR 1.0HR !!!


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malefemale

Gender:

1>1

Number ofmetastatic sites:

65>65

Age:

colonrectum

Localization:

noyes

Liver-limited disease:

yesno

Synchronous mets:


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A . . 3506


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A . . 3506


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FIRE-3 is the first head-to-head comparison of FOLFIRI + cetuximabversus FOLFIRI + bevacizumab in KRAS wild-type mCRC patients

The primary endpoint was not met : ORR favored FOLFIRI + cetuximabbut did not reach the level of significance within the ITT population

1st line treatment with FOLFIRI + cetuximab resulted in a clinicallymeaningful difference in median OS of 3.7 months (HR 0.77) whencompared with FOLFIRI + bevacizumab

Toxicity profiles were as expected and manageable for bothcombinations

FIRE-3: Conclusions



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Head-to-head trials of targeted agents in1st line mCRC

1. Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506);2. Naughton MJ, et al. ASCO 2013 (Abstract No. 3611); 3. NCT00265850;

4. Schwartzberg LS, et al. ASCO GI 2013 (Abstract No. 446); 5. Schwartzberg LS, et al. ASCO 2013 (Abstract No. 3631)

FIRE-3 1

CALGB 80405 2,3

PEAK4,5


N=592R

Cetuximab + FOLFIRICetuximab + FOLFIRI

Bev + FOLFIRIBev + FOLFIRI


N~1200(after trial modification)

Cetuximab +FOLFOX/FOLFIRI

Cetuximab +FOLFOX/FOLFIRI

Bev +FOLFOX/FOLFIRI

Bev +FOLFOX/FOLFIRI

Bev + cetuximab +FOLFOX/FOLFIRI*Bev + cetuximab +FOLFOX/FOLFIRI*

*Arm closed to accrual as of 09/10/2009


N=285R

Pani + mFOLFOX6Pani + mFOLFOX6

Bev + mFOLFOX6Bev + mFOLFOX6

R


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A F F 6 + B 1 2 C C ( , 2)

, . J C 31, 2013 ( ; 3631).

C C( =285)

A 8 ( 7 );

, ,

1:1

6 ( 2 ) +

6 /( 2 )

6 ( 2 ) + 5 /

( 2 )

: F * (1 ); , , , ,

D

A

A

AD

D

30 (+ 3 )

3 ( 28 )


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EA B A

F 2 C C

, . J C 31, 2013 ( ; 3631).

Eventsn (%)

Median (95% CI)months

Panitumumab +mFOLFOX6 (n=142)

90 (63) 10.9 (9.413.0)

Bevacizumab +mFOLFOX6 (n=143)

94 (66) 10.1 (9.012.6)

Eventsn (%)

Median (95% CI)months

Panitumumab +mFOLFOX6 (n=88)

50 (57) 13.0 (10.915.1)


60 (73) 9.5 (9.012.7)

A 2 ( ) A : 2,3,4 A / A

( % )

0

20

40

60

80

100

( % )

0

20

40

60

80

100

90

70

50

30

10

90

70

50

30

10

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32


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EA B A

2 C C

, . J C 31, 2013 ( ; 3631).

Events

n (%)

Median (95% CI)

MonthsPanitumumab +mFOLFOX6 (n=142)

52 (37) 34.2 (26.6NR)


78 (55) 24.3 (21.029.2)

Events

n (%)

Median (95% CI)

monthsPanitumumab +mFOLFOX6 (n=88)

30 (34) 41.3 (28.841.3)


40 (49) 28.9 (23.931.3)

A 2 ( ) A ( 2,3,4 A / A )

( % )

( % )

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3834 36 40 42 44 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3834 36 40 42

0

20

40

60

80

100

90

70

50

30

10

0

20

40

60

80

100

90

70

50

30

10


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C :1. C

2. C


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+

H . A C 2013, A .4005-1825.

+


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+

H . A C 2013, A .4005-1825.

+

342 861

61 62

EC G 0 37% 100 16%

1 62% 90 42%2 0.6% 80 35%

70 7%

39% 44%

16% 19%

88% 85%

+


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+

H . A C 2013, A .4005-1825.

+

46% 38%

F . 5% 3%

9% 13%D 13% 6%

F 24% 17%

9% 17%

+


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+

G

H . A C 2013, A .4005-1825.

+

G A

171 430

9% 7%

D ( + D) 51% 33% ( ) 6.8 6.7

1 21% 22%

18 6% 9%

F ( ) 3.3 3.7

+


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+

A

H . A C 2013, A .4005-1825.

+

342 861

32% 23%

D ( + D) 70% 48%

( )(H )

11.1(0.57)

8.5(0.72)

1 48.4% 35%

F ( )(H )

6.4(0.47)

5.5(0.69)

G ? ?

G ? ?


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G . 2010

Documents

2013 ASCO GI Winterhalder