Optimal strategy in patients with potentiel resectable mCRC

ØGC seminar 2014

Per PfeifferProfessor in Clinical Oncology

Dept of Oncology, OUH, DenmarkInstitute of Clinical Research, USD, Denmark

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Surviva

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Benefit of systemic therapy in mCRCLessons learned from phase III

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BSC 5-FU Combination SurgeryCT + CT

6666 12121212 18181818 24242424

SurgerySurgerySurgerySurgery

Five-year survival of English CRC patients1998–2004 (n=114,155)

1

0.9

0.8

0.7

0.6

0.5

Surv

ival pro

babili

ty

All patients

All stage 4 resected n=3116

3%

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

0.5

0.4

0.3

0.2

0.1

0

Surv

ival pro

babili

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Years

Stage 4, no resection

All stage 3

Morris EJA, Forman D, Thomas JD, Quirke P, Taylor EF, Fairley L, Cottier B, Poston G. Brit J Surg 2010; 97: 1110-8

9%

46%

Author, year Regimen No CR/RR(%)

Median PFS (months)

Median OS(months)

Double vs doubleTournigand et alJCO 2004

FOLFOX 111 5/54 8.5 20.620.620.620.6FOLFIRI 111 3/56 8.0 21.521.521.521.5

Goldberg et alJCO 2004

IFL 264 ?/31 6.9* 15.0*15.0*15.0*15.0*FOLFOX 267 ?/45* 8.7 19.519.519.519.5

Glimelius et alAnn Oncol 2008

FLIRI 281 4/35 9.4 19.419.419.419.4FOLFIRI 286 5/49* 9.0 19.019.019.019.0Ann Oncol 2008 FOLFIRI 286 5/49* 9.0 19.019.019.019.0

Cassidy et alJCO 2008

XELOX 1017 ?/47 8.0 19.819.819.819.8FOLFOX 1017 ?/48 8.5 19.619.619.619.6

Porchen et alJCO 2007

XELOX 241 2/48 7.1 16.816.816.816.8FUFOX 233 6/54 8.0 18.818.818.818.8

Díaz-Rubio et alJCO 2007

XELOX 171 5/37 8.9 18.118.118.118.1FUOX 171 5/46 9.5 20.820.820.820.8

5/505/505/505/50 8888 20202020

Life expectancy in mCRC

BSC Optimal therapyOS CR/RR Resection PFS OS

All mCRC

Alberts et al, JCO 2005; 23: 9243Poston et al, JCO 2008; 26: 4828

Adam et al, AS 2004; 240: 644Stangl et al, Lancet 1994; 343: 1405

Wagner et al AS 1984; 199: 502-8

All mCRCAll mCRC in trial 6 5/50 8 20Liver-onlyPotentiel resectableResectable

BSC Optimal therapyOSmo

CR/RR%

Resection%

PFSmo

OSmo

All mCRC 3 < 5 6 12

Life expectancy in mCRC

Alberts et al, JCO 2005; 23: 9243Poston et al, JCO 2008; 26: 4828

Adam et al, AS 2004; 240: 644Stangl et al, Lancet 1994; 343: 1405

Wagner et al AS 1984; 199: 502-8Sørbye, et al, Cancer 2009; 115: 4678

All mCRC 3 < 5 6 12All mCRC in trial 6 5/50 < 10 8 20Liver-only 10 5/70 30 12 26 Potentiel resectable 16 5/70 30 15 30Resectable 20 > 50 ~ 100 18 48

mCRCmCRC

ResectableResectable“Solitary“ LM“Solitary“ LM

Group 2 and 3Group 2 and 3Never resectableNever resectable

Palliative CTPalliative CT

Group 1Group 1ResectableResectable

after after responseresponse

Treatment strategy in mCRCMDT very important

Group 0Adjuvant ?

Neoadjuvant ?

Palliative CTPalliative CTafter after responseresponse

Resection ?

Group 1Preop CT

Triple or double+TT

Group 2SymptomsDouble±TT

Group 3No symptoms

Single

Schmoll et al, ESMO Guidelines, Ann Oncol 2012

ESMO approach: Grouping of patients

Liver / Lung limited disease Definitely unresectable

Curative approach Palliative therapy

resectable unresectable symptomatic asymptomatic

ESMO Group 0 ESMO Group 1 ESMO Group 2 ESMO Group 3

Supported by randomised trials Not supported by randomised trials

Is the current treatment algorythm inESMO 2012 guidelines useful?

Schmoll H-J, et al. Ann Oncol 2012;23:2479–2516

Treatment guidelines in mCRCmCRC patient - ESMO group 1 (and 2)

Ras wt Ras mut

1st line Cetuximab + FOLFIRIFOLFIRI + Bev

CapOx + Bev

May 2014

1st line

2nd line

3rd line

Cetuximab + FOLFIRI

Anti-EGFR + FOLFOXCapOx + BevFOLFOXIRI

FOLFOX + Bev

FOLFIRI + AfliberceptFOLFOX + Bev

FOLFIRI + Aflibercept

Regorafenib

Phase I/IIRechallenge with Cx

RegorafenibPhase I/II

Sequential approach in frail or „low-tumor-burden“

Targeted therapy in mCRCWhat do we know ?

• Presently mainly 2 classes of TT in mCRC– Anti-EGFR are active through all lines

• KRAS status predicts for resistance to EGFR– Anti-angiogenic drugs are active through all lines

• Presently no useful clinical predictive biomarkers

Schmoll et al, ESMO Guidelines, Ann Oncol 2012

EGFR pathway as an example

Ciardiello F & Tortora G. EGFR Antagonists in Cancer Treatment. NEJM 2008;358:1160-74.

Study, first authorPaper Regimen No Resection CR/RR

(%)Median PFS

(months)Median OS(months)

CRYSTAL, van Cutsem NEJM 2009, JCO 2011

FOLFIRI 350 5% 0/40 8.4 20.0FOLFIRI+Cx 316 8% 1/57 9.9 23.5

OPUS, BokemeyerAnn Oncol 2011

FOLFOX 97 8% 1/34 7.2 18.5FOLFOX+Cx 82 7% 4/57 8.3 22.8

PRIME, Douillard FOLFOX 331 8% ?/48 8.0 19.4

EGFR inhibitors as 1st line therapy in mCRCEfficacy in KRAS wt – which chemo-backbone ?

PRIME, DouillardNEJM 2013

FOLFOX 331 8% ?/48 8.0 19.4FOLFOX+Pa 325 7% ?/55 9.6 23.8

COIN, MaughanLancet 2011

“Ox” 367 3% ?/57 8.6 17.9“Ox”+Cx 362 4% ?/64 8.6 17.0

Nordic VII, TveitJCO 2012

FLOX 97 13% ?/47 8.7 22.0FLOX + Cx 97 14% ?/46 7.9 20.1FLOX + Cx 109 5% ?/51 7.5 21.4

mCRCmCRC

ResectableResectable“Solitary“ LM“Solitary“ LM

Group 2 and 3Group 2 and 3Never resectableNever resectable

Palliative CTPalliative CT

Group 1Group 1Resectable Resectable

after responseafter response

Treatment strategy in mCRCMDT very important

Group 0Adjuvant ?

Neoadjuvant ?

Palliative CTPalliative CTafter responseafter response

Resection ?

Group 1Preop CT

Triple or double+TT

Group 2SymptomsDouble±TT

Group 3No symptoms

Single

Schmoll et al, ESMO Guidelines, Ann Oncol 2012

Group 0: Resectable metastases (10%)Group 0: Resectable metastases (10%)Group 0: Resectable metastases (10%)Group 0: Resectable metastases (10%)Aim: Increase cure ratePeri-operative FOLFOX3 + 3 months Recommendation BAdjuvant 5-FU (capecitabine) after R0 resection6 months Recommendation B

Treatment strategy in mCRC

6 months Recommendation B

5 y DFS: 37%

5 y DFS: 28%

Nordlinger et al, Lancet 2008 Mitry et al, JCO 2008

EORTC 40983 - EPOCPeri-operative chemotherapy

PFS

Only pre-op chemo in patients with elevated CEA and PS 0

PFS

Sorbye et al, AS 2012; 255: 534-9

New EPOC study

Neoadjuvant FOLFOX +/- Cetuximab in LLD

Group 0

Resectablemetastases

Primrose et al. Lancet Oncol 2014

Group 2 and 3Never resectable

Palliative CT

mCRCmCRC

Resectable“Solitary“ LM

Group 1Group 1Resectable Resectable

after responseafter response

Treatment strategy in mCRCMDT very important

Palliative CT

Group 3No symptoms

Single

Group 2SymptomsDouble±TT

Group 0Adjuvant ?

Neoadjuvant ?

after responseafter response

Resection ?

Group 1Preop CT

Triple or double+TT

Schmoll et al, ESMO Guidelines, Ann Oncol 2012

Resection and response to chemotherapyStudies with neoadjuvantfocus(„liver metastases“)r=.96, p=.002

Studies met. CRC

Resection r

ate ,6

,5

,4

,3Studies met. CRCr=.74, p<.001

Phase III Studiesmetast. CRCr=.67, p=.024, p=.024

Folprecht, Ann Oncol 2005

Response rate

,9,8,7,6,5,4,3

,3

,2

,1

0,0

Study Regimen n R0 resection (%)Phase III, ”unselected” pts with mCRCCrystal FOLFIRI 599 1.5

FOLFIRI + cetuximab 599 4.3 *OPUS FOLFOX 168 2.4

FOLFOX + cetuximab 169 4.7Falcone FOLFIRI 122 5.7

Resection rate in patients with mCRCData from randomized studies evaluating ”triple” therapy

Falcone FOLFIRI 122 5.7FOLFOXIRI 122 14.8 *

Souglakos FOLFIRI 146 3.4FOLFOXIRI 137 8.8

NO16966 FOLFOX 701 6.3FOLFOX + bevacizumab 699 4.9

Phase II, highly selected pts with limited mCRCCELIM FOLFOX + cetuximab 53 38

FOLFIRI + cetuximab 53 30

Study, first authorPaper Regimen No Resection CR/RR

(%)Median PFS

(months)Median OS(months)

CRYSTAL, van Cutsem NEJM 2009, JCO 2011

FOLFIRI 350 5% 0/40 8.4 20.0FOLFIRI+Cx 316 8% 1/57 9.9 23.5

OPUS, BokemeyerAnn Oncol 2011

FOLFOX 97 8% 1/34 7.2 18.5FOLFOX+Cx 82 7% 4/57 8.3 22.8

PRIME, Douillard FOLFOX 331 8% ?/48 8.0 19.7

EGFR inhibitors as 1st line therapy in mCRCEfficacy in KRAS wt – which chemo-backbone ?

PRIME, DouillardJCO 2010

FOLFOX 331 8% ?/48 8.0 19.7FOLFOX+Pa 325 7% ?/55 9.6 23.9

COIN, MaughanLancet 2011

“Ox” 367 3% ?/57 8.6 17.9“Ox”+Cx 362 4% ?/64 8.6 17.0

Nordic VII, TveitJCO 2012

FLOX 97 13% ?/47 8.7 22.0FLOX + Cx 97 14% ?/46 7.9 20.1FLOX + Cx 109 5% ?/51 7.5 21.4

Falcone; n = 244, JCO 2007 FOLFIRI FOLFOXIRINo pts 122 122Response rate 41 % 66 %*Median PFS (months) 6.9 9.8*R0 surgery (liver only) 6% (12%) 15% (36%)*

GONOmCRC - 1st line therapy

R0 surgery (liver only) 6% (12%) 15% (36%)*Median survival (months) 16.7 22.6*

Falcone et al, JCO 2007; 25: 1670-6

Resectable liver metastases

Situations

Potentially resectable metastases

Non-resectable, palliative therapy

CRYSTAL: Resection rates according to country

X 11…10.1%

9.4%

6.9%

13.0%

15.6%

6.2%

10.0%

8%

10%

12%

14%

16%

No. Pts 106 103 89 85 80 73 64 58 58 54 54 49 32 32 27 10

Resections 4 3 9 2 3 1 6 1 4 7 1 1 5 2 1 1

Country

3.8%

2.9%2.3%

3.7%

1.4% 1.7%

6.9%

1.9%2.0%

6.2%

3.7%

0%

2%

4%

6%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

DoubletsDoubletsDoubletsDoubletsFOLFOX or FOLFIRI

DoubletsDoubletsDoubletsDoubletsFOLFOX or FOLFIRI

RRRRAAAANNNNDDDDOOOO138 patients

Randomized study in mCRC Group 1mCRC - 1st line therapy

Doublets + CxDoublets + CxDoublets + CxDoublets + CxDoublets + CxDoublets + CxDoublets + CxDoublets + Cx

OOOOMMMMIIIISSSSAAAATTTTIIIIOOOONNNN

138 patients18-75 years

PS 0-2Pot Res mCRC

KRASwt

Ye et al, JCO 2013; 31: 1931-8

Ye, JCO 2013, n = 138 Doublets Doublets + CxNo pts 68 70Response rate 29 % 57 %*R0 resection rate 7% 26%*Median PFS (months) 5.8 10.2*

Randomized study in mCRC Group 1mCRC - 1st line therapy

Median PFS (months) 5.8 10.2*Median survival (months) 21.0 30.9*

Ye et al, JCO 2013; 31: 1931-8

mCRC

Nordic 8mCRC, RASwt and BRAFwt - 1st line therapy

FOLFIRI+ Cx

FOLFIRI+ Cx

FOLFIRI+ Cx

FOLFIRI+ Cx

ESMO group 1 → ESMO group 1-3

mCRC

RASwtBRAFwt

N = 90 x 2 patientsAim: RR 70%

FOLFIRI+ Cx

FOLFOX+ Cx

FOLFIRI+ Cx

FOLFOX+ Cx

Nordic 8 (new)Inclusion criterias

• RAS wildtype mCRC• Candidate for combination therapy• ESMO group 1, 2 or 3 • Measurable disease (RECIST)• 1st line therapy• Performance status 0-1• Adequate hematological, hepatic, and renal function• > 18 years• Register ESMO group at baseline• Register deepness of response

• NORDIC 8 – change of inclusion criterias– Decrease number of patients (- 15% ?)

• KRAS exon 2 WT → RAS WT, BRAF ?

Nordic 8 Amendment

– Increase number of patients (+ 200% ?)• ESMO Group 1 → ESMO Group 1 - 3

Treatment algorythm in mCRCmCRC patient (ESMO gruppe 1 og 2)

Ras wt Ras mut

1st line Cetuximab + FOLFIRIFOLFIRI + Bev

CapOx + Bev

May 2014

1st line

2nd line

3rd line

Cetuximab + FOLFIRICapOx + BevFOLFOXIRI

FOLFOX + Bev FOLFOX + Bev

FOLFIRI + Aflibercept

Phase I/II

Rechallenge with CxRegorafenibPhase I/II

Sequential approach in frail or „low-tumor-burden“

Treatment guidelines in mCRCmCRC patient - ESMO gruppe 1 (og 2)

Ras wt Ras mut

1st line Cetuximab + FOLFIRIFOLFIRI + Bev

CapOx + Bev

May 2014

1st line

2nd line

3rd line

Cetuximab + FOLFIRI

Anti-EGFR + FOLFOXCapOx + BevFOLFOXIRI

FOLFOX + Bev

FOLFIRI + AfliberceptFOLFOX + Bev

FOLFIRI + Aflibercept

Regorafenib

Phase I/IIRechallenge with Cx

RegorafenibPhase I/II

Sequential approach in frail or „low-tumor-burden“

mCRCmCRC

ResectableResectable“Solitary“ LM“Solitary“ LM

Group 2 and 3Group 2 and 3Never resectableNever resectable

Palliative CTPalliative CT

Group 1Group 1ResectableResectable

after after responseresponse

Treatment strategy in mCRCMDT very important

Group 0Adjuvant ?

Neoadjuvant ?

Palliative CTPalliative CTafter after responseresponse

Resection ?

Group 1Preop CT

Triple or double+TT

Group 2SymptomsDouble±TT

Group 3No symptoms

Single

Include pts in Nordic 8 Include pts in Nordic 8 Include pts in Nordic 8 Include pts in Nordic 8

Final slide

Thank you for your attentionattention

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