1. Trattamento del mCRC
Prof Giovanni Brandi
Dimes
University of Bologna

2. Different strategies for metastatic CRC
Intensive
Cure
Surgery /CHT
Conservative
Increase OS
CHT

3. Overall survival (OS) = Result of several treatments
#=metastasectomy
I line
II line
III line #
CHT “adiuvant” # # # t
Continuum of care of mCRC

4. CHT Oxaliplatin 5-FU Capecitabine Irinotecan – (CPT-11) OXA 5-FU CAPE
Eloxatin®
5-FU
Capecitabine
Xeloda®
5-FU
OXA
Class:
analogues of Pt
CAPE
Class:
prodrug of 5-FU
(per OS)
Class:
antimetabolites
Pirimidine antagonist
(uracile)
OXA
HFS syndrome
Irinotecan – (CPT-11)
Campto® S1
Mitomicina C
Tomudex
IRI
Class:
inhibitors of topoisomerase I (camptotecine)

5. MABs or TKis Panitumumab Bevacizumab Cetuximab Ramucirumabb
Humanized IgG
anti EGFR
IgG chymeric
anti EGFR
Humanized IgG
anti VEGF
Others … failed.
Aflibercept
Regorafenib
Ramucirumabb
Cediranib
Sunitinib
Vatalanib
Brivanib

6. The most recent CHT TKI PD-1 BLOCKING Dabrafenib Trametinib
TAS-102
PEMBRO
DABRA
TRAME
DABRA
TRAME
Trifluridine +
tipiracil hydrochloride
Dabrafenib
Trametinib
Pembrolizumab

7. Targets and Therapies in CRC
AFLIBERCEPT
(VEGF-trap)
CETUXIMAB
PANITUMUMAB
VEGF-B
VEGF-A
BEVACIZUMAB
VEGF-A
PIGF
EGFR
RAMUCIRUMAB
VEGFR3
VEGFR2
VEGFR1
PDGFR P P P P P P P P
EGFR phosphorylation P P P P P P P P
Ras
Dabrafenib
PI3K
Raf
AKT
Mek
REGORAFENIB
CHEMOTHERAPY
Trametinib
mTOR
Erk
DNA synthesis

8. FOLFIRI = FOLFOX Colucci JCO 2005 CAPOX = CAPIRI Grothey 2004
FOLFIRI or FOLFOX6 First-Line?
Tournigand C et al. J Clin Oncol. 2004;22: A B
FOLFIRI >FOLFOX6
FOLFOX6 > FOLFIRI
(n = 109)
(n = 81)
(n = 111)
(n = 69)
Median combined PFS (months)
14.2
10.9
Median OS (months)
21.5
20.6
Median PFS (months)
8.5
4.2
8.0
2.5
RR (%)
56.0
15.0
54.0
4.0
(p = .64)
(p = .99)
in sequence A more patients received second-line therapy (74% vs 62%)
FOLFOX6 showed better outcomes (15% vs 4%) in second-line setting compared with FOLFIRI

9. Infusional 5-FU vs Oral fluoropirimidins
XELOX vs FUOX - Diaz-Rubio et al , JCO 2007
348 pts
RR: 37% v 46% p=0.539
mTTP: 8.9 v 9.5 m p= 0.153
mOS: 18.1 v 20.8 m p= 0.145
toxicity similar
CAPOX vs FUFOX ( AIO) Porschen et al , JCO 2007
474 pts
RR: 48% vs 54%
mPFS: 7.1 vs 8.0 m p=0.117
mOS: 16.8 v 18.8 m p=0.26
XELOX* vs FOLFOX-4* Cassidy JCO 2008
2 034pts
RR: 47% vs 48%
mPFS: 8.0 m vs 8.5 m p= n.s.
mOS:19.8 v 19.6m p= n.s.
≠ type toxicity: diarrhea vs febrile neutropenia

10. strong differences for dosage, age and PS
Doublet Vs Triplet
FOLFOXIRI vs FOLFIRI
Study
Drug
RR %
R0 %
mPFS
mOS
Souglakes BJC 2006
Folfoxiri (n=137) 43 10
8,4
21,5
Folfiri (n=146)
33,6 4
6,9
19,5 p
0,168
0,08
0,17
0,337
Falcone
JCO 2007
Folfoxiri (n=122) 60 15
9,8
22,6
Folfiri (n=122) 34 6
16,7
0,0001
0,033
0,0006
0,032
strong differences for dosage, age and PS

11. Exposure to as Many Agents as Possible Prolongs OS30
BIOLOGICS
OS (months) = (3 drugs % x 0.1), R2 = 0.85
Infusional 5-FU/LV + irinotecan
Infusional 5-FU/LV + oxaliplatin
Bolus 5-FU/LV + irinotecan
Irinotecan + oxaliplatin
Bolus 5-FU/LV
LV5FU2
First-Line Therapy
Median OS (months)
Patients with 3 Drugs (%)
2007 22 21 20 19 18 17 16 15 14 13 12
p=0.0001
FOLFOXIRI
CAIRO
We know that exposure to multiple chemotherapy agents is associate with prolonged OS
Using multiple lines of therapy across a patient’s disease enables several different agents to be used
Figure adapted from Grothey & Sargent

12. WHICH CHT with TT in mCRC? META-ANALYSIS
PRISMA 2009 method for systematic review and metanalysis (22 studies included)
OUTCOMES for EGFR-I by CHT backbone OS
PFS
Chan DL et al, PLOSone 2015

13. WHICH CHT with TT in mCRC? META-ANALYSIS
PRISMA 2009 method for systematic review and metanalysis (22 studies included)
Chan DL et al, PLOSone 2015

14. WHICH CHT with TT in mCRC? META-ANALYSIS
PRISMA 2009 method for systematic review and metanalysis (22 studies included)
OUTCOMES for anti-angiogenetic agents by CHT backbone OS
PFS
Chan DL et al, PLOSone 2015

15. Folfiri/Folfoxiri + Bev (and mainteinence 5-FU/LV+Bev) -TRIBE
Falcone , ASCO 2013 R
508 mCRC pts
1st line
unresectable
stratified by
center
PS 0/1-2
adjuvant CT
FOLFIRI+bev
(up to 12 cycles)
FOLFOXIRI+bev
5-FU/LV +Bev PD
G3/4 adverse events,
% patients
FOLFIRI + bev
N=254
FOLFOXIRI + bev
N=250 p
Diarrhea 11 19
0.012
Stomatitis 4 9
0.048
Neutropenia 20 50
<0.001
TEV 6 7
0.593
Primary endpoint: PFS
Secondary endpoint: OS (preliminary)
The intensification of chemotherapy with FOLFOXIRI plus BEVA increases PFS (12.1 vs 9 months, p=0.003) HR= 0,75 when compared with folfiri plus beva
TRIPLET plus BEVA increases RECIST RESPONSE RATE (65% vs 53%, p=0.006) and OS (31 vs 25.8 months, p=0.054)
FOLFOXIRI plus BEVA improves EARLY TUMOR SHRINKAGE (62.7% vs 51.9%, p=0.025) and DEPTH OF RESPONSE (43.4% vs 37%, p=0.003)
Median follow up: 32.3 mos
FOLFIRI + bev: N = 256 / Died = 155
FOLFOXIRI + bev: N = 252 / Died = 131
FOLFIRI + bev, median OS : 25.8 mos
FOLFOXIRI + bev, median OS : 31.0 mos
Unstratified HR: 0.83 [ ]
p=0.125
Stratified HR: 0.79 [ ]
p=0.054

16. OS stratified by RAS/BRAF mutational status
TRIBE study
Cremolini C, .. Falcone A
Lancet Oncol 2015
252 vs. 256 pz
Median OS
OS stratified by RAS/BRAF mutational status
29.8 months
25.8 months

17. Crystal trial: FOLFIRI +/- Cetuximab
Van Cutsem et al. NEJM ‘09
KRAS wt pts (348)
ITT 1198 pts
pfs .
OS (m)
ITT 1198 HR
0.87 P
0.04
Kras wt 666
0.79
0.009
Kras m 387
1.03
0.75
Folfiri
18.6m
20m
16.7m
+ Cetux
19.9m
23.5m
16.2m
Van Cutsem et al. J Clin Oncol ‘11

18. Panitumumab/Folfox vs Folfox - PRIME (JY Douillard et al)
JCO, 2010
NEJM,
Phase III First line Primary end point: PFS
1183 pts included
KRAS status were not required at entry
Analysis on 639 pts Kras WT exon 2
WT KRAS (exon 2)
Mutation rate increase up to 17%
656 pts
KRAS mut exon2
440 pts
In real WT-panitumab pts
PFS increase of 0,5 months
and OS of 2 months
MT KRAS (exon 2) 18

19. Cetuximab + FOLFIRI (n=297)
Wich Mab (Beva or anti-EGFR) should be coupled
to CHT in first line? FIRE III
Heinemann, et al. Lancet Oncol 2014 R
Previously
untreated
Unresectable
KRAS WT mCRC
(n=592)
Bevacizumab + FOLFIRI (n=295)
Cetuximab + FOLFIRI (n=297)
Trial aimed to superiority
of CETUX over BEVA in RR
Primary end point = RR
Secondary = PFS,OS
KRAS 12/13 wt
Negative study, but…….. OS HR p RR
1,18
0,18
PFS
1.06
0.54
Median OS RASwt
33 months
25.6 months

20. Deepness of response correlates with post-progression and overall survival ?
Data from the CRYSTAL trial indicate that tumor size reduction is more predictive for OS than PFS
Cetuximab + FOLFIRI
(n=315)
FOLFIRI
(n=348) p
Median DpR1 (95% CI)
50.9
(18.4–78.6)
33.3
(8.0–58.0)
p<0.0001
Median OS2
(95% CI)
23.5
(21.2–26.3)
20.0
(17.4–21.7)
p<0.0093
adapted from Mansmann et al, ASCO GI 2013 (Abstract No.427)
Despite their individual-level associations with PFS and OS, RBEs do not appear to be surrogate endpoints in first-line mCRC, given their poor predictive ability. E. Coart et al, ASCO GI 2015

21. Patients with untreated KRAS 12/13 wt mCRC
Wich Mab (Beva or anti-EGFR) should be coupled to CHT
in first line? PEAK (Phase II-R)
Schwartzberg L, ASCO 2013
Panitumumab + mFOLFOX6
Patients with untreated KRAS 12/13 wt mCRC
N=285 R
Primary endpoints: PFS
Bevacizumab + mFOLFOX6 21

22. CALGB 80405
Veenock , Asco 2014
Two third of CALGB patients received oxaliplatin, which is thought to be an inferior companion for cetuximab
Response to anti-EGFR agents might be deeper than with bevacizumab and this would translate in better OS even with no difference in PFS
Response rate is proven to be significantly higher with cetuximab than with bevacizumab (72% vs 52%; p=0.003 in FIRE 3 study; 67% vs 54%, p<0.01 in CALGB study), so an anti-EGFR should be the standard of care when tumor shrinkage is desiderable, such as symptomatic patients or patients inoperable upfront but poitentially resecable.
The median OS was beyond 30 months; however, there was no significant difference between the cetuximab and bevacizumab in combination with chemotherapy (32 months vs 31.2 months).
FOLFIRI/cetuximab and FOLFOX6/bevacizumab are equivalent in terms of overall survival (OS) in patients with previously untreated KRAS wild type (codons 12 and 13) metastatic colorectal cancer and that either regimen is appropriate in first-line treatment
There was no difference in the progression-free survival (11 months for both arms)
However, there was higher response acheived in the cetuximab arm in the expanded RAS population, 68.6% vs 53.6% (p < 0.01).
higher response acheived in the cetuximab arm in the expanded RAS population, 68.6% vs 53.6% (p < 0.01).

23. 2° line Ramucirumab/Folfiri vs Placebo/Folfiri (RAISE)
Tabernero J. – Lancet Oncology 2015
Primary endpoint: OS
Patients who relapsed/progressed within 6 months of completion of oxaliplatin, fluoropyrimidine and Bevacizumab first-line chemotherapy were eligible

24. CRC Last Lin: Panitumumab and cetuximab
Vs BSC
Vs cetuximab
999 pz
499 Panitumumab
500 Cetuximab
Price et al, Lancet Oncol 2014
Van Cutsem , JCO 2007

25. CONCUR CORRECT CRC Last Line Regorafenib vs BSC OS 8.8m 6.4 m 6.3m 5 m
Li J, et al. Lancet Oncol. 2015;
CORRECT
Grothey A, et al. Lancet. 2013
(R: 500 ptz) OS
(P: 253 ptz)
HR=0.55
8.8m
HR =0.77
6.4 m
6.3m
5 m N
HR (95% CI)
Time from first diagnosis of metastatic disease to randomization
<18 months
140
0.82 ( )
≥18 months
620
0.76 ( )
Prior anticancer treatment
F, Ox, Iri, Bev
375
0.83 ( )
F, Ox, Iri, Bev, anti-EGFR
385
0.71 ( )
Prior treatment lines for metastatic disease ≤3
395
0.79 ( )
>3
365
0.75 ( )
KRAS mutation status (historical)
299
0.65 ( ) Y
430
0.87 ( )
Favors regorafenib
Favors placebo
0.0
0.5
1.0
1.5
2.0
2.5
3.0 25

26. Has routine mismatch repair status determination a role?26

27. WES: mutation rate 25 times higher
Phase 2 trial with PEMBROLIZUMAB
41 pts 32 CRC
NEJM 2015
WES: mutation rate 25 times higher
in dMMR pts
G3-4 AES %

28. presence of F. nucleatum in ~ 330 cases of hepatic metastases from CRC
FUSOBACTERIUM NUCLEATUM AND CRC
Mima et al. Gut 2015
A collaboration with Harvard University is ongoing in order to assess the
presence of F. nucleatum in ~ 330 cases of hepatic metastases from CRC

29. Dabrafenib Trametinib
JCO 2015
43 pz with BRAF V600-mutation CRC
Dabrafenib
(BRAF inh)
Trametinib
(MEK inh)

30. ESMO Clinical Practice Guidelines: Strategic Scenarios in the Continuum of Care of mCRC
A: Scenario 1
B: Scenario 2
C: Scenario 3
First line
Cytotoxic doublet1+ bevacizumab
Cytotoxic doublet1 + bevacizumab
Cytotoxic doublet1 + anti-EGFR antibody2
Cytotoxic doublet1 + bevacizumab or afli or ramu3
Cytotoxic doublet1 + bevacizumab or aflibercept3
Second line
Cytotoxic doublet1 + anti-EGFR antibody2
Irinotecan or FOLFIRI + anti-EGFR antibody2
Third line
Regorafenib
Regorafenib
Fourth line
Regorafenib
Regorafenib
1Cytotoxic doublets: fluoropyrimidine + oxaliplatin or irinotecan; 2RAS WT; 3Aflibercept or ramucirumab only in combination with FOLFIRI.
1. Van Cutsem. 2014; 2. Van Cutsem

31. A change in surgical paradigm of liver metastases
La dernière partie de cette relation approche le role de la metastasectomie dans le traitement des patients.
En ce qui concerne la résection des métastases hépatiques, on est passé graduellement du concept du nombre de lésions qu’on peut réséquer avec bénéfice, à un concept qui va au delà de l’extension de la maladie.
En d’autres mots, une approche qui garde tout d’abord à la partie du foi qu’on peut sauvegarder après résection envisagée comme radicale.
Until about 2005:
Number of lesions
Position of lesions
Today:
Radically resectable disease, even with a two-stage approach
Adequate future remnant liver
Preservation of functional liver anatomy

32. Surgery of mets when possible!
1° metastasectomy
2° and 3° metastasectomy
At relapse after
1° metasectomy
Surgery ± CHT
OS=58,7 months (n=29)
CHT alone
OS=24.0 months (n=29)
European register of liver mets
Brandi et al, Langenbacks Arch 2012
This retrospective controlled study (n=60) suggests that surgery is superior to chemotherapy even in patients relapsed after first metastasectomy
Established!

33. Multimodality management of CRC liver mets
Conversion CHT
Unresectable liver mets
Conversion CHT
Unresectable liver mets
Neoadiuvant CHT
resectable liver mets
San Paolo’ Conversion
facilitate surgery
obtain predictive and prognostic information
early systemic therapy for poor-prognosis pts
allow R0 resection
via dowsizing

34. Conversion CHT/TT for unresectable liver mets
CHT alone
CHT + MAb
Pts
Author
Schedules
RR%
R0 Rate %
168
OPUS study*
FOLFOX 36 2
599
CRYSTAL study*
FOLFIRI 38 4 53
Wein
5-FU/FA 41 10
330
Bismuth
5-FU/FA +/- OHP 16 15
151
Giacchetti
5FU/FA + OHPchrono 69 20 47
Abad
FOLFOXIRI 23 44
Leonard
HAI-FUDR+ FOLFOX/FOLFIRI 40
Pozzo 31 74
Falcone 71 34
Pts
Author
Schedules
RR%
R0 Rate %
170
OPUS study*
FOLFOX + CETUX 46 5
599
CRYSTAL study*
FOLFIRI + CETUX 47 7 32
Fornaro
mFOLFOXIRI + PANITUM 89 21
138
Le-Chi
FOLFIRI/FOLFOX4 + CETUX 57 26
106
CELIM study
FOLFOX/FOLFIRI + CETUX
70 kras wt 31
508
Falcone
FOLFOXIRI + BEVA 65 41
OLIVIA study 80 49 43
POCHER study
Chrono FOLFOXIRI
+ CETUX 79 60 42
Assenat
FOLFIRINOX +CETUX 81 -
*: not as conversion planned studies

35. OS postmetastasectomy according the response to neoadiuvant cht
Les données qui dérivent d’un régistre européen des métastases hépatiques montrent que seulement les patients avec controle de la maladie par la chimiothérapie peuvent etre opérer avec bénéfice, tandis que ceux avec progression de la maladie obtiennent des résultats défavorables et non supérieurs à la chimiothérapie tout seule. RC
RP e SD PD
Source : LiverMetSurvey 2008

36. Resectable vs initially unresectable
Rescue Surgery of initially non resectable mets after CHT-induced downstaging
LiverMetSurvey:
Resectable vs initially unresectable
Il est important de souligner que meme les patients initialement non opérables, …. une foi obtenu une réponse et opérés radicalement, obtiennent un résultat de survie comparable à celui des patients opérés d’emblée.
A noter qu’environ 25 % de ces patients sont encore vivants après plus de 10 ans, probablement guéris.
Adam et al. Ann Surg 2004;240: 644–658)
Up to 25% of resected pts are living at 10 y !!

37. Clinical Colorectal Cancer 2013
DFS