the history of colorectal cancer. what have been achieved ... · there is an adjuvant therapy for...

The History of Colorectal Cancer. What have been achieved over the last 20 years?

June 23, 2018Aimery de Gramont

Franco-British InstituteLevallois-Perret

Disclosure

Unpaid member of Roche and Sanofi advisory boardsHonorarium Chugai and Yakult

Being old, it’s being younglonger than the other.

M1 median survival 6-10 months

Dukes C 5-year survival: 25%

When there was no 5FU…

5FU

5FU levamisole

5FU PALA

5FU ci

5FU short ci

LV5FUweekly FUFOL

FUFOLlow-dose

5FU IFN

5FU dipyr.

5FU cisplatin

5FU MTX0/1 0/20/1

5/8

1/4

1/51/35/9

4/7

0/1

4/6

5-Fluorouracil modulation

5FU levamisole

5FU ci

5FU PALA

5FU levamisole

5FU ci

5FU dipyr.5FU PALA

5FU levamisole

5FU ci

0/1

4/6

5FU dipyr.5FU PALA

5FU levamisole

5FU ci

0/20/1

4/6

5FU dipyr.5FU PALA

5FU levamisole

5FU ci

0/10/20/1

4/6

5FU dipyr.5FU PALA

5FU levamisole

5FU ci

LV5FUweekly

4/7

FUFOLLV5FUweekly

4/75/9

FUFOLLV5FUweekly

4/71/35/9

FUFOLLV5FUweekly

4/7

FUFOLlow-dose

1/35/9

FUFOLLV5FUweekly

4/7

Response rate benefit

5FU bolus

Adjuvant Therapy

There is an adjuvant therapy for colon cancer! The first step (1990)

5year OS Stage III

1970: 25%1990: 63%

There is an adjuvant therapy for colon cancer! The first step (1990)

5FU+lev

better safety

DFS

5FU bolus + LV

Francini 1994IMPACT 1995 NCCTG 1997NCCTG-NCIC 1998INT 0089 1998NSABP C04 1999QUASAR 2000

Moertel

Adjuvant Therapy (1990-2004)

6 months = 12 monthsLow dose leucovorinElderly patients

5FU+lev

better safety

DFS

5FU bolus + LV

Adjuvant Therapy

LV5FU2/5FU protracted

UK 2000-2004INTERGROUP 0153 2000GERCOR 2003PETTACC 2

Capecitabine

NSABPC06 Lambersky 2006

UFT+LV

X-Act Twelves 2005

Small motion or stagnation (1990-2004)

New drugs and negative trialsAlpha-interferonRaltirexedEdrecolomab targeting cell surface glycoprotein 17-1A

« a decade of decadence » by Norman Wolmark

When there was only 5FU….

M+Median survival 12 monthsStage III 5-year survival 50%

20 years ago…

IrinotecanOxaliplatin

New Drugs

Summary of Chemotherapy

Fluropyrimidines single agent first-line achieve up to 30% RR and 6 months PFS

Oxaliplatin and irinotecan are modestlyactive as single agent.

Fluropyrimidines are the backbone of the combination regimens with oxaliplatinand irinotecan

Doublets 50% RR and 9 months PFS Triplet 60% RR and 10 months PFS Combination regimens are less active in

second-line than in first-line

MayoLV5FU2

FOLFOX4

FOLFOX6FOLFIRI

OPTIMOX

PFS

RR

toxicity

20

40

60

% / wks

20

1991 1995 1997 2000

20 years ago…

0102030405060708090

100

0 20 40 60 80 100 120 140 160 Weeks

%

C91One line

C93C97

Two lines

C95C96

Three lines

Overall survival

20 years ago…

Strategy

20 years ago…

Multi-lines

Surgery of metastases

Stop and Go & Maintenance

Chemotherapy holidays

surgery

CR/PR

Stable

PD

FOLFOX

PR

Stable

PD

FOLFIRI

FOLFIRI FOLFIRI

FOLFIRI

PD

FOLFOX75% ITM

Algorithm in year 2000

20 years ago…

Adjuvant Therapy

The second step (2004)

2246 patients

The huge benefit of Oxaliplatin in stage IIIC

Stage III N2

André T et al, JCO 2015

15% absolute benefit

When there was onlychemotherapy…

M+ Median survival

Targeted therapies

Targeted therapies and Chemotherapy

First-line Trials

Beva

Cetux IrinoOxali Pmab

Cap

Cunningham, NEJM 2004

Irinotecan+Cetuximab

Cetuximab irinotecan

Cetuximab: BOND TrialEGFR+ tumors refractory to 5-FU/Irinotecan

RANDOMISATION

RR 22.9%PFS 126 d OS 8.6 months

RR 10.8% PFS 45 dOS 6.9 months

329/577 screened patients

The best example of synergy

RANDOMISATION

FOLFIRI + Aflibercept

N=612

Aflibercept Second-Line. VELOUR

FOLFIRI + Placebo

Tabernero. ESMO 2011, Van Cutsem JCO 2012

PFS 6.9m*OS 13.5 m*

N=614

PFS 4.7 mOS 12.1 m

Second-line

Endpoint OS

Grothey Lancet 2012

Regorafenib

Placebo

REGORAFENIB: CORRECT TrialRefractory to 5-FU/CPT-11/oxali/Bev/CetuxPmab

RANDOMISATI

ON

RR1.6%PFS 1.9 m HR 0.49* OS 6.4 m HR 0.77*

RR 0.4% PFS 1.7 mOS 5.0 m

N=255

N=505

3d or 4th-Line

RAISE Ramucirumab

FOLFIRI+BSC

Tumors refractory to 5- FU//oxaliplatin/Bev

RR 12.5%PFS 4.5m OS 11.7m

FOLFIRI+RAMRR 13.7% PFS 5.7m HR 0.79*OS 13.3m HR 0.84*

RRAANNDDOOMMIISSAATTIIOONN N=1072, primary objective >OS

Tabernero. ASCO GI 2015

N=536

N=536

Second-line Ramucirumab

Yoshino T. WGIC 2014

TAS 102

Placebo

TAS-102: RECOURSE TrialThird-line

RANDOMISATION

RR1.6% NSPFS 2.0 m HR 0.48* OS 7.1 m HR 0.68*

RR 0.4% PFS 1.7 mOS 5.3 m

N=266

N=534

3-4th-LineMayer RJ. NEJM 2015

Beva


Cap

Beva


Cap

AflibRegoRego TAS 102

SOUS-TITRE 1Texte de la diapositive

Should we follow mCRC treatment guidelines?

First line

Third line

FU FU + BevOptional first line (group 3 only)

Oxaliplatin-based first line Irinotecan-based first line Chemo-triplet

Fourth line

Regorafenib

Second line

FU/Ox FU/Ox/IriFU/Ox + BevFOLFOX +Pan or Cet

FOLFIRI + Pan/Cet

FU/Iri +Bev Fu/Iri

Pan/Cet ± Iri or FU/Bev

Pan/Cet ± Iri FU + Bev

FOLFIRI +Aflibercept

Regorafenib

FU/Iri +Cet FU/Iri FU/Iri + Bev

FU/Ox FOLFOX + Cet (Pan)


Regorafenib

Regorafenib Regorafenib

FU/Ox +Bev


Schmoll, et al. Ann Oncol 2012

SOUS-TITRE 1Texte de la diapositive

First line

Third line

FU FU + BevOptional first line (group 3 only)

Oxaliplatin-based first line Irinotecan-based first line Chemo-triplet

Fourth line

Regorafenib

Second line

FU/Ox FU/Ox/IriFU/Ox + BevFOLFOX +Pan or Cet

FOLFIRI + Pan/Cet

FU/Iri +Bev Fu/Iri

Pan/Cet ± Iri or FU/Bev



Regorafenib

FU/Iri +Cet FU/Iri FU/Iri + Bev

FU/Ox FOLFOX + Cet (Pan)


Regorafenib

Regorafenib Regorafenib

FU/Ox +Bev


Schmoll, et al. Ann Oncol 2012

Rationalising the complexity of treatment

http://homepage.mac.com/edandhelen/iblog/C605282913/E20051222053953/Media/einstein.jpg

Texte de la diapositive

Third line

Optional first line (group 3 only)

Chemo-triplet

Fourth line

Second line

Chemo A + Bev

PD

Chemo B + Bev

PD

Anti-EGFR

PD

RegorafenibSchmoll, et al. Ann Oncol 2012

Rationalising the complexity of treatment

http://homepage.mac.com/edandhelen/iblog/C605282913/E20051222053953/Media/einstein.jpg

KRAS wtN = 1025

Right 1°Median OS

(mos)

Left 1°Median OS

(mos)

Hazard Ratio95% CI

(adjusted*)P (adjusted*)

All pts 19.4 33.3 1.55 (1.32,1.82) P < 0.0001

Cet 16.7 36.0 1.87 (1.48, 2.32) P < 0.0001

Bev 24.2 31.4 1.32 (1.05, 1.65) P = 0.01

*Adjusted for biologic, protocol chemotherapy, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary, liver metastases

19.3 MONTHS IS A BIG DIFFERENCE !!

80405: Sidedness is Prognostic

Venook ASCO 2016

NCCN Guidelines

« Until that time, only patients whoseprimary tumors originated on the left sideof the colon (splenic flexure to rectum) should be offered cetuximab or panitumumab in the first-line treatment of metastatic disease. »

NCCN Guidelines Version 2.2017 – Colon cancer

Adjuvant Therapy

2007-2018: Another decade of decadence ? ?

New drugs and negative trialsBevacizumab: NSABP C08 - AVANTCetuximab: NO 147 - PETACC8

SubpopulationsElderlyStage II

No because of better staging and new biomarkers

Lymph node status

5 year OS Stage III

1970: 25%1990: 63%2004: 76%2015: 85%

André A et al. JCO 2015

LV5FU2 FOLFOX4

Left and Right Colon

Survival after relapse

MOSAIC

KRAS/BRAF and MS status

Taieb J et al, JAMA Oncol 2016

MSSKRAS

MSSBRAF

MSIKRAS

MSIBRAF

MSS poor pc of mutations

MSI good pc of mutations

Aspirin in mutant PIK3CA

Liao X. NEJM 2012

Prognostic Biomarkers

ct-DNARecurrence scoreColoprintGUCY2C expression in LNImmunoscoreCDX2CMS…

Biomarkers

• We need predictive biomarkers to better define:

1 stage II patients who should be treated2 stage III patients who should not be treated3 patients who could benefit from oxaliplatin4 patients who could benefit from new therapies

mFOLFOX6/XELOX

mFOLFOX6/XELOX

12/8 cyclesR

stage III 6/4 cycles

SCOT

Non inferiority trial (HR

IDEA Clinical Consensus: Risk-based approach to adjuvant chemotherapy in stage III colon cancer

ASCO 2017 Presented by: Qian Shi, PhD on behalf of IDEA collaborators; NEJM 2018

Risk group Recommended duration of adjuvant therapy

T1-3 N1

T4 and/or N2

3 months

Duration of therapy determined by- tolerability of therapy- patient preference- assessment of risk of recurrence- Regimen (CAPOX vs FOLFOX)

6 months

(~60% of stage III)

(Or other high-risk factors)

IDEA Clinical Consensus: Risk-based approach to adjuvant chemotherapy in stage III colon cancer

ASCO 2017 Presented by: Qian Shi, PhD on behalf of IDEA collaborators; NEJM 2018

Risk group Recommended duration of adjuvant therapy

T1-3 N1

T4 and/or N2

3 months

Duration of therapy determined by- tolerability of therapy- patient preference- assessment of risk of recurrence- Regimen (CAPOX vs FOLFOX)

6 months

(~60% of stage III)

(Or other high-risk factors)Duration of therapy determined by- efficacy of FOLFOX in this setting- superiority of FOLFOX 12 vs 6 cycles- non inferiority non demonstrated for CAPOX

Per protocol resultsReassessement when overall survival is mature

0 1 2 3 4 5 6

Years from Randomization

0

10

20

30

40

50

60

70

80

90

100

6 Months

3 Months

Duration

0 1 2 3 4 5 6

Years from Randomization

0

10

20

30

40

50

60

70

80

90

100

Per

cent

Wit

hou

t E

vent

6 Months

3 Months

Duration

6424 5446 4464 3000 1609 826 3216410 5530 4477 3065 1679 873 334

Primary DFS Analysis (mITT)

Duration 3-yr DFS

3m 74.6 %

6m 75.5 %

3-yr DFS diff. = -0.9%, 95% CI, (-2.4 to 0.6%)

N PatientsAt risk

DFS HR = 1.0795% CI, 1.00 to 1.1

p= 0.11

Shi et al. ASCO 2017, Grothey NEJM 2018

Non Inferiority

InvestigatorStatistician

Risk of 3-year recurrence +7%Risk of 3-year grade 2+ neuropathy -3%

In 2018…M+ Median survival~30 monthsStage III 5-year survival 85%

New concepts: Evolution and Revolution

RAS wtRAF

wt

MSI


RAS wtRAF

wt

MSI


Slide Number 1DisclosureSlide Number 3Slide Number 4Slide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Summary of ChemotherapySlide Number 20Slide Number 21Slide Number 22Slide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27Slide Number 28Slide Number 29Slide Number 30The huge benefit of Oxaliplatin in stage IIICSlide Number 32Targeted therapiesSlide Number 34Slide Number 35Slide Number 36Slide Number 37Slide Number 38Slide Number 39Slide Number 40Slide Number 41Slide Number 42Slide Number 43Slide Number 44Slide Number 45Slide Number 46Slide Number 47Slide Number 48Should we follow mCRC treatment guidelines?Rationalising the complexity of treatment Rationalising the complexity of treatment 80405: Sidedness is PrognosticNCCN GuidelinesSlide Number 54Slide Number 55Slide Number 56Left and Right ColonKRAS/BRAF and MS statusAspirin in mutant PIK3CAPrognostic BiomarkersBiomarkersSlide Number 62IDEA Clinical Consensus: Risk-based approach to adjuvant chemotherapy in stage III colon cancer IDEA Clinical Consensus: Risk-based approach to adjuvant chemotherapy in stage III colon cancer Primary DFS Analysis (mITT)Slide Number 66Slide Number 67Slide Number 68Slide Number 69Slide Number 70

the history of colorectal cancer. what have been achieved ... · there is an adjuvant therapy for...

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