Michel DUCREUX, MD, PhD Gustave Roussy Cancer Centre, Grand … · 2018. 5. 31. · 6 mois 1-an 2-ans 3-ans 4-ans Grade 1 Grade 2 Grade 3 Evaluable patients n=976 4-year Grade 0 85.5%

ESMO Preceptorship Programme

Adjuvant treatment of colon cancer

Michel DUCREUX, MD, PhD

Gustave Roussy Cancer Centre, Grand Paris, FRANCE

Colorectal – Valencia – 18-19 May 2018

ESMO PRECEPTORSHIP PROGRAM

DISCLOSURE SLIDEParticipation to advisory boards:

ROCHE

MERCK SERONO

AMGEN

NOVARTIS

SANOFI

BAYER

SIRTEX

LILLY

SERVIER

IPSEN

2

Speaker in symposiums:

ROCHE

MERCK SERONO

NOVARTIS

IPSEN

LILLY

AMGEN

Research funding:

ROCHE

MERCK SERONO

PFIZER

My wife is the Head of The Oncology Business Unit in Sandoz Company (French Affiliate)


▪ Adjuvant chemotherapy is indicated for stage III (N+)

▪ FOLFOX / CapeOx ; 3 months vs 6 months

▪ Capecitabine or (inf.) FU/LV as an option for some patients

▪ FOLFOX / CapeOx for patients < 70y, use with caution for pts > 70y

▪ Antibodies (EGFR, VEGF) are not indicated

▪ The decision for an adjuvant treatment should balance the risk of

cancer mortality and that of comorbidities

▪ Specific problems

▪ Stage II

▪ Role of biological markers

Aims of the talk

STAGE III (N+)…


Sargent D, J Clin Oncol 2009Moertel et al NEJM 1990

10.3%

First positive study: 5FU +

levamisole…


X’Act trial (Capecitabine vs FuFol Mayo) Overall survival

Twelves C, N Engl J Med 2005

Non infériority < 0,001

Superiority 0,05Stage III colon

(n= 1987)


2004 combination chemotherapy!

FOLFOX new standard stage III


MOSAIC studyMain endpoint: Disease-Free Survival (3-years)

Secondary endpoint: tolerance, overall survival (6-years)

n=2246

Inclusion:

Oct 1998–Jan 2001 (146 centres;

20 countries)

• Colon cancer, complete resection

• Stage II, 40%; Stage III, 60%

• Age 18–75 years

• KPS ≥60

• No previous CT

RLV5FU2

FOLFOX4(LV5FU2 + oxaliplatin 85 mg/m²)

(n=1123)

(n=1123)

A. de Gramont et al., ASCO 2003 / T. André et al. NEJM 2004

ESMO PRECEPTORSHIP PROGRAMA. de Gramont et al., ASCO 2007 / T. André et al. JCO 2009

Data cut-off: January 2007 months

Pro

bab

ility

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

Events

FOLFOX4 243/1123 (21.6%)

LV5FU2 279/1123 (24.8%)

HR [95% CI]: 0.84 [0.71–1.00]

p=0.046

2,5%

FOLFOX4

LV5FU2

MOSAIC: Long-term results

Overall survival ITT


Long-term Tolerance

(% patients)

FOLFOX

5.5

LV5FU2

6.1

0

10

20

30

40

50

60

Pendant

Tx

6 mois 1-an 2-ans 3-ans 4-ans

Grade 1

Grade 2

Grade 3

Evaluable patients

n=976 4-year

Grade 0 85.5%

Grade 1 12.0%

Grade 2 2.8%

Grade 3 0.7%

Data cut-off: January 2007

Second cancer

Peripheral

Neuropathy


A. de Gramont et al., ASCO 2007 / T. André et al. JCO 2009Data cut-off: January 2007

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Months

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

HR [95% CI]

Stade II 1.00 [0.70–1.41]

Stade III 0.80 [0.65–0.97]

0.1%

4.2%

p=0.986

p=0.023

Overall survival Stage II / III


Stage III colon

cancer•No previous CT

• Resection ≤ 8 weeks

n=1886

n=944

n=942

RANDO MISATION

XELOX vs 5-FU/LV:

NO16968 (XELOXA) Phase III trial

Bolus 5-FU/LV (6 months) Mayo Clinic [n=664]*oru

Roswell Park [n=278]**

XELOX (6 months) Capecitabin 1000mg/m2

BID D1 to 14

(1 week rest)

+ oxaliplatin 130 mg/m2 IV D1

every 3 weeks

8 cycles

Main endpoint

Better DFS


Absolute difference at 3-year 4%

HR=0.80 (IC 95% : 0.69–0.93)

p=0.0045

1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6 years

71 %

67 %

XELOX n=944 5-FU/LV n=942

Surv

ie s

ans

mal

adie

Schmoll et al. J Clin Oncol 2015;33:3733-40

Xelox, a valid option

Confirmed at 7 years : 63% vs 56%


1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

HR=0.87 (IC 95% : 0.72–1.05)

p= 0.1486

Years

78 %

74 %

XELOX n=9445-FU/LV n=942

Mean follow-up : 59 months

Surv

ie g

lob

ale

ITT population

Overall survival Xelox vs Fufol

Schmoll et al. J Clin Oncol 2015;33:3733-40Confirmed with longer follow-up: 73 vs 67%


64%CapecitabineX-ACT, 2005

65%LV5FU2MOSAIC 2004

61%LV5FU2André, 2003

66%FUFOL ou RPMIXELOXA, 2010

63%FUFOLINT0089, 2005

62%FUFOLIMPACT 1994

44%SurveillanceIMPACT 1993

52%SurveillanceMoertel 1990

3-y DFSTreatmentStudy

Monotherapy

73%

71%

FOLFOX4

XELOX

MOSAIC 2004

XELOXA, 2010

Poly CT

The last 15 years

A LITTLE BIT MORE

COMPLICATED…


Fluoropyrimidine ± Oxaliplatin Stage III

HR for DFS

P value DFS ∆ (%) HR for OS P valueOS ∆ (%)

MOSAIC (FOLFOX)

0.78CI, 0.65-0.93

@ 5 year

0.005∆ 7.5%

58.9% vs 66.4%@ 5 year

0.80CI, 0.65-0.97

@ 6 year

0.023∆ 4.2%

68.7% vs 72.9%@ 6 year

NSABP C-07(FLOX)

0.78CI, 0.68-0.90

@ 5 year

0.0007 ∆ 6.6 %57.8% vs 64.4%

@ 5 year

0.85CI, 0.72-1.00

@ 5 year

0.052∆ 2.7%

73.8% vs 76.5%@ 5 year

XELOXA(XELOX)

0.80CI, 0.69-0.93

@ 3 year

0.0045∆ 4.4%

66.5% vs 70.9%@ 3 year

0.87CI, 0.72-1.05

@ 5 year

0.1486∆ 3.4%

ND(57 months FU)

1 André T, J Clin Oncol. 2009

2 Yothers G, J Clin Oncol 2011

3 Haller D, J Clin Oncol 2011


Fluoropyrimidine ± Oxaliplatin Stage III HR for

DFSP value DFS ∆ (%) HR for OS P value

OS ∆ (%)

MOSAIC (FOLFOX)

0.78CI, 0.65-0.93

@ 5 year

0.005∆ 7.5%

58.9% vs 66.4%@ 5 year

0.80CI, 0.65-0.97

@ 6 year

0.023∆ 4.2%

68.7% vs 72.9%@ 6 year

NSABP C-07(FLOX)

0.78CI, 0.68-0.90

@ 5 year

0.0007 ∆ 6.6 %57.8% vs 64.4%

@ 5 year

0.85CI, 0.72-1.00

@ 5 year

0.052∆ 2.7%

73.8% vs 76.5%@ 5 year

XELOXA(XELOX)

0.80CI, 0.69-0.93

@ 5 year

0.004∆ 5 %

62% vs 67%@ 3 year

0.83CI, 0.70-0.99

@ 5 year

0.04∆ 3.0%74% vs. 77%

(@ 5y)

X-ACTFU/FA bolus vs.

Capecitabine

0.87CI, 0.75-1.00

@ 3y

0.0528∆ 3.6%

60.6% vs. 64.2%@ 3y

0.84 CI: 0.69–1.01

@3y

p=0.07∆ 3.7%

77.6% vs. 81.3%@3y

1 André T, J Clin Oncol. 2009

2 Yothers G, J Clin Oncol 2011

3 Haller D, J Clin Oncol 2011

4 Schmoll HJ, J Clin Oncol 2016


N 1-3

N > 3

Andre et al. JCO 2015

Overall survival stage III

pT3-4 N+

A ROLE FOR TARGETEDTHERAPIES?


Bevacizumab

3 large negative studies (>6000 pts)

- NSABP- C08- AVANT- QUASAR 2


NSABP C-08 trial

Phase III study

NSABP-C-08

Stage II/III

m FOLFOX 6 – 6 months

+ Bevacizumab -1 year

(n=1 335)

m FOLFOX 6 – 6 months

(n=1 338)

C. Allegra et al., ASCO 2011, A#3508

Stage II = 24.9%

Main endpoint: 3-year DFS

Median follow-up: 55 months

RR


NSABP-C-08: bevacizumab, no effect

C. Allegra et al., ASCO 2011, A#3508

100%

viv

ants

80

60

40

20

0

0 1 2 3 4 5

Years

1268

1289

1205

1233

1135

1163

942

950

204

204

mFF6 1341 Pts, 224 deaths

mFF6+Bev 1337 Pts, 218 deaths

HR=0.96, 95% CI (0.79-1.15)

p= 0.64

SG

Allegra C et al 2013;31:359-64


Cetuximab

2 large negative studies (>6000 pts)

- N0147- PETACC 8


KRAS WT

0

10

20

30

40

50

60

70

80

90

100

% S

urv

ivants

sans m

ala

die

0 6 12 18 24 30 36

Time (Months)

Folfox

Folfox + Cmab

Arm3 Year Rates

(95% CI)HR

(95% CI)P

Folfox

n=902

75.8%(72.1%-79.6%)

1.2(0.96-1.5)

0.22

Folfox+ Cmab

n=945

72.3%(68.5%-76.4%)

KRAS MT

0

10

20

30

40

50

60

70

80

90

100

% S

urv

ivants

sans m

ala

die

0 6 12 18 24 30 36

Time (Mointh)

Arm3 Year Rates

(95% CI)HR

(95% CI)P

Folfox

n=374

67.2%(61.4%-73.5%)

1.2(0.9-1.6)

0.13

Folfox+ Cmab

n=343

64.2%(58.7%-70.2%)

Folfox

Folfox + Cmab

NO 147: Folfox +/- cetuximab

Alberts et al. JAMA 2012;307:1383-93


FOLFOX4 + cetuximab

791 699 505 356 132 2 0

FOLFOX4811 732 527 381 131 4 0

PETACC8 : PFS : Wt KRAS

Years

DFS

rat

e

FOLFOX4 + CetuximabN = 791

FOLFOX4N = 811

No, events 190 179

S3-year PFS[95%CI], %

75.1[71.7; 78.1]

78.0[74.8; 80.8]

HR pour SSR [95% CI]p-value (log-rank)

1.047 [0.853; 1.286]O.6562

Taieb J et al Lancet Oncol 2014;15:862-73


Meta-analysis: nothing….

NEW DATA: A CHANGE IN THE

STANDARD OF CARE?


Heinemann, et al. ASCO 2014

*tumors of the transversum were excluded from

further analysis

3%*

44%

20%

77%

33%

Stage III

Stage IV

Stage II

Schrag et al. ASCO 2016

Prognostic role of tumour site

ESMO PRECEPTORSHIP PROGRAMSinicrope et al. Clin Cancer Res 2015

KRAS/BRAF wt

KRAS mut

BRAFmut

Biological features: a prognostic role

ESMO PRECEPTORSHIP PROGRAMSinicrope et al. Clin Gastroenterol Hepatol 2016;14:651–658

Interaction with MMR status


Role of the 4 classes of

molecular consensus???

Guinney et al. Nat Med 2015


Dienstmann R et al. Ann Oncol 2017;28:1023-31

Beyond TNM system??

• 8904 patients

• TNM, clinico-pathological featurs and biological determination of

Ras and Raf

• Training set: NO147 and PETACC 3

• Validation set: observational studies

Conclusion: Incorporation of MSI, BRAF and KRAS mutations improves the ability

to prognosticate in stage II and stage III cc patients, but only modestly increases

prediction accuracy in multivariate models that include clinicopathological

features, particularly in chemotherapy-treated patients…

3 MONTHS VERSUS 6

MONTHS… THE IDEA STORY…


IDEA Trials Summary


Non-inferiority Hypothesis Testing


Global IDEA study: toxicityAdverseEvents

FOLFOX CAPOX

G0 – 1 G2 G3 – 4 p-value G0 – 1 G2 G3 - 4 p-value

Global


Disease-free survival: primary

endpoint not met

Grothey A et al. 2018;378:1177-88


Primary DFS Analysis (mITT), cont.

Presented By Qian Shi at 2017 ASCO Annual Meeting


DFS in different subgroups of

patients

Grothey A et al. 2018;378:1177-88


DFS Forrest-plot….

Grothey A et al. 2018;378:1177-88

Grothey A et al. 2018;378:1177-88


3-year DFS (%)HR / CT

and subgroups

CT

XELOX FOLFOX XELOX/FOLFOX combined

SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI) 3 m 6 m 3 m 6 m 3 m 6 m

Subgroups

Low risk(T1-3 N1)

~60%

High risk (T4 and / or N2)

~40%

Combined

Non-inferior Uncertain Inferior



and subgroups

CT


SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI)


Subgroups

Low risk(T1-3 N1)

~60%


~40%

62.7(60.8-64.4)

64.4(62.6-66.4)

1.12(1.03-1.23)

Combined




and subgroups

CT


SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI)


Subgroups

Low risk(T1-3 N1)

~60%


~40%

64.1(61.3-67.1)

64.0(61.2-67.0)

1.02(0.89-1.17)

61.5(58.9-64.1)

64.7(62.2-67.3)

1.20(1.07-1.35)

62.7(60.8-64.4)

64.4(62.6-66.4)

1.12(1.03-1.23)

Combined




and subgroups

CT


SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI)


Subgroups

Low risk(T1-3 N1)

~60%

83.1(81.8-84.4)

83.3(82.1-84.6)

1.01(0.90-1.12)


~40%

64.1(61.3-67.1)

64.0(61.2-67.0)

1.02(0.89-1.17)

61.5(58.9-64.1)

64.7(62.2-67.3)

1.20(1.07-1.35)

62.7(60.8-64.4)

64.4(62.6-66.4)

1.12(1.03-1.23)

Combined




and subgroups

CT


SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI)


Subgroups

Low risk(T1-3 N1)

~60%

85.0(83.1-86.9)

83.1(81.1-85.2)

0.85(0.71-1.01)

81.9(80.2-83.6)

83.5(81.9-85.1)

1.10(0.96-1.26)

83.1(81.8-84.4)

83.3(82.1-84.6)

1.01(0.90-1.12)


~40%

64.1(61.3-67.1)

64.0(61.2-67.0)

1.02(0.89-1.17)

61.5(58.9-64.1)

64.7(62.2-67.3)

1.20(1.07-1.35)

62.7(60.8-64.4)

64.4(62.6-66.4)

1.12(1.03-1.23)

Combined




and subgroups

CT


SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI)


Subgroups

Low risk(T1-3 N1)

~60%

85.0(83.1-86.9)

83.1(81.1-85.2)

0.85(0.71-1.01)

81.9(80.2-83.6)

83.5(81.9-85.1)

1.10(0.96-1.26)

83.1(81.8-84.4)

83.3(82.1-84.6)

1.01(0.90-1.12)


~40%

64.1(61.3-67.1)

64.0(61.2-67.0)

1.02(0.89-1.17)

61.5(58.9-64.1)

64.7(62.2-67.3)

1.20(1.07-1.35)

62.7(60.8-64.4)

64.4(62.6-66.4)

1.12(1.03-1.23)

Combined 75.9(74.2-77.6)

74.8(73.1-76.6)

0.95(0.85-1.06)

73.6(72.2-75.1)

76.0(74.6-77.5)

1.16(1.06-1.26)

P-value interaction test:CT: 0.0061

Risk-groups : 0.11



CT

XELOX FOLFOX

Riskgroups

Low-risk(T1-3 N1)

~60%3 months

High-risk(T4 et/ou N2)

~40%6 months

IDEA : Recommandations



CT

XELOX FOLFOX

Riskgroups

Low-risk(T1-3 N1)

~60%3 months (3-) 6 months

High-risk(T4 et/ou N2)

~40%3 (-6) months 6 months

IDEA : Recommandations


STAGE II DISEASE…. !!!!


Stage II

Small benefit (3%) with 5FU

No clear improvement with FOLFOX

Is-t possible to define a subgroupthat could benefit from FOLFOX?


Some Stage II tumours with poor

prognosis

0102030405060708090

100

5yr real OS (%)

Gunderson et al, JCO 2009

Stage II Stage III


QUASAR – old study, small benefit

ESMO PRECEPTORSHIP PROGRAMTournigand C et al. J Clin Oncol 2015;33:4176-87

MOSAIC : FOLFOX vs LV5FU2, all

stage II patients: no difference

ESMO PRECEPTORSHIP PROGRAMTournigand C et al. J Clin Oncol 2015;33:4176-87

Low risk High risk

MOSAIC late follow-up and Stage II

disease


Stage II

No risk factor

Stage II

Any risk

factor

O‘Connor et al. JCO 2011

Stage III

High risk stage

II and SEER


Overall 5-year survival

1950 colon cancer

– Groupe 1, occlusion without perforation n=120 33%

– Groupe 2, occlusion + perforation tumour n=35 50%

– Groupe 3, occlusion + proximal perforation n=13 33%

– Groupe 4, no occlusion, no perforation n=1682 51%

Do we even know how to select high

risk patients?

Chen et al, 2000


Low number of lymph nodes remains

not good… 134 567 pT3N0

< 12 LN analysed

– 23.3% of the patients

• 46.8% in 2003 – 12,5% en 2012

– 5-year overall survival : 66.8%

• 69.8% > 12 LN versus 58.7% p< 0.001

– 16.7% of adjuvant CT if less than 12 LN:

• OS with CT 78.4% versus 54.7% without, p< 0.001

Wells KO et al. Dis Colon Rectum 2017


Role of perineural invasion US National Database: 21,488 patients:

– 55.2% T3, 23.1% T2, 14.4% T1, 7.3% T4 disease

– 4.6% (n = 987) had PNI

– 86.8% no PNI and no CT; 8.7% no PNI and CT; 3.7% (n = 785) PNI and no

CT, and 0.9% (n = 202) PNI and CT

– Patients with PNI who had CT: younger, private insurance, fewer comorbidities greater T stage

– PNI and CT improved OS in T3-4 disease (P


No benefit in Stage III patients, could be even deleterious in stage II

patientsSargent DJ et al. J Clin Oncol. 2010;28:3219

MSI(n=165)

MSS(n=863)

Stage II Stage III

MSI + tumours, no benefit from 5FU

based CT


Coloprint, useful to select patients??


Immunoscore: an hope


Immunoscore and stage II disease:

DFSStage II (n=1433) - High/int/low

100

20

0

San

s re

chu

te (

%)

0 1 2 3 4 5 6

years7 24

375

694

364

p


Stage II colon cancer

Age < 70y Advanced age or

comorbidities

pT4 pT3

pMMR / MSS dMMR / MSI-H

Consider adj. CTx No adj. CTx

Additional marker:

less than 12 LN / PNI ? /

Gene signature / Immunoscore?

Algorithm of decision in stage II

disease


Stage III diseaseComplete resection

Reference

Folfox4 or Xelox

pT3N1 3 monthsXELOX

PT3N2 6 monthsXELOX or FOLFOX

> 70 y:

Capecitabine or LV5FU2

Options

CI oxaliplatin: LV5FU2 or cap

DPD measurebefore tmt

Adjuvant CT has to bediscussed

Documents

Michel DUCREUX, MD, PhD Gustave Roussy Cancer Centre, Grand … · 2018. 5. 31. · 6 mois 1-an 2-ans 3-ans 4-ans Grade 1 Grade 2 Grade 3 Evaluable patients n=976 4-year Grade 0 85.5%