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
60
80
100
Surviva
l 30303030CTCTCTCT
Benefit of systemic therapy in mCRCLessons learned from phase III
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20
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60
0 1 2 3 4 5Years
Surviva
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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
ty
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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