Gastrolearning II modulo/1a lezione Terapia del cancro colorettale - Gestione oncologica Prof. C. Barone - Università Cattolica Sacro Cuore (Roma).

1. Terapia del cancro colorettale
Carlo Barone
Oncologia Medica
Università Cattolica del S. Cuore
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2. Argomenti
• Terapia adiuvante del cancro del colon
• Terapia del cancro del retto
• Terapia della malattia metastatica
– Metastasi epatiche (± polmonari)
– Metastasi multiple

3. Trials with Oxa: Adjuvant Setting
Trial
Pts
Treatment
Data
MOSAIC
224
6
FOLFOX-4 x 6 mos
5-FULV2 x 6 mos
5-y DFS
6-y OS
Safety
FLOX x 6 mos
Bolus 5-FULV w x 6 mos
5-y DFS
Safety
XELOX x 6 mos
Bolus 5-FULV w/q4w x 6
mos
5-y-DFS
Safety
(NEJM 2004,
ASCO 2005,
ASCO 2007)
NSABP C-07 2407
(JCO 2007)
ASCO 2008
ROCHE
NO16968
(JCO 2007)
1886

4. MOSAIC: 5-yrs DFS Updated
3.8
7.5
André T, et al. JCO 2009

5. MOSAIC Updated: OS – 6 years
2.5
André T, et al. JCO 2009

6. MOSAIC OS Updated: 6 yrs, by stage
p=0.996
0.1%
p=0.029
4.4%
André T, et al. JCO 2009

7. X-ACT updated: 5-Year DFS and OS
Xeloda
5-FU/LV
0.8
0.6
Absolute difference
at 5 years: 4.1%
4
0
1
2
3
4
5
Years
HR = 0.86 (95% CI 0.74-1.01)
p = 0.0600
0.8
0.6
Absolute difference
at 5 years: 3.1%
4
6
7
5-year OS (%)
71.4
68.4
1.0
HR = 0.88 (95% CI 0.77-1.01)
p = 0.0682
OS estimate
DFS estimate
1.0
5-year DFS (%)
60.8
56.7
(n = 1,004)
(n = 983)
8
0
Twelves C, et al. ASCO GI 2008. Abstract 274.
1
2
3
4
5
Years
6
7
8

8. NO16968 XELOXA Trial
Primary endpoint: DFS
XELOX
5-FU/LV
1.0
0.8
0.6
0.4
HR=0.80 (95% CI: 0.69–0.93)
p=0.0045
0.2
0.0
0
1
2
3
Years
ITT population
4
5
6

9. 3-year DFS: benefit with XELOX
maintained over time
3-year
DFS
XELOX
5-FU/LV
1.0
70.9%
66.5%
0.8
Δ at 3 years: 4.5%
0.6
0.4
0.2
0.0
0
1
2
3
Years
ITT population
4
5
6

10. 4-year DFS: benefit with XELOX
maintained over time
3-year
DFS
70.9%
66.5%
XELOX
5-FU/LV
1.0
4-year
DFS
68.4%
62.3%
0.8
Δ at 3 years: 4.5%
0.6
Δ at 4 years: 6.1%
0.4
0.2
0.0
0
1
2
3
Years
ITT population
4
5
6

11. 5-year DFS: benefit with XELOX
maintained over time
3-year
DFS
1.0
5-year
DFS
70.9%
66.5%
XELOX
5-FU/LV
4-year
DFS
68.4%
62.3%
66.1%
59.8%
0.8
Δ at 3 years: 4.5%
0.6
Δ at 4 years: 6.1%
0.4
Δ at 5 years: 6.3%
0.2
0.0
0
1
2
3
Years
ITT population
4
5
6

12. NO16968 (XELOXA) and MOSAIC:
DFS in stage III disease
FOLFOX4
DFS
(%)
(%)
3-yr 1
NO16968
LV5FU2
72.2
65.3
XELOX
70.9
3-yr3
5-yr
66.4
2
XELOX
NO16968
5-yr3
66.1
1.
ITT population
5-FU/LV
66.5
58.9
HR
(95% CI)
0.76
(0.62–0.92)
0.80
(0.69–0.93)
p=0.0045
0.78
(0.65–0.93)
p=0.005
5-FU/LV
59.8
André et al. NEJM 2004; 2. André et al. 2009;
3. Haller et al. ESMO 2009

13. NO16968 (XELOXA) and MOSAIC:
DFS in stage III disease
Estimated probability
1.0
NO16968 (XELOXA)1*
XELOX
MOSAIC2,3**
FOLFOX4
3-yr DFS
5-yr DFS
(n=944)
70.9%
66.1%
(n=672)
72.2%
66.4%
0.8
0.6
0.4
0
1
*Median observation time: 57.0 months
**Median follow-up: 71.3 months
Cross-trial comparison
ITT population
2
3
Years
4
5
6
1. Haller et al. ESMO 2009
2. André et al. NEJM 2004
3. André et al. JCO 2009

14. Oxaliplatin with Fluoropyrimidine
Conclusion
•
•
•
Significantly improved DFS
Neurologic toxicity is an issue
Previous analyses have demonstrated
surrogacy of 3yr DFS for 5yr OS
• Long term survival benefit now demonstrated
in stage III
• Both FOLFOX and XELOX are acceptable

15. Should patients with stage II colon cancer
receive adjuvant therapy?
Meta-analyses
Direct evidence from randomized
trials
Identification of “high risk” patients

16. To B or Not To B?

17. QUASAR: Study design
Colon or rectal cancer
• Stage I-III
• Complete resection
with no evidence of
residual disease
2x2
randomization to
5-FU with low- or
high-dose LV and
Lev or placebo
Clear indication for
chemotherapy
(n = 4320)
No clear indication
for chemotherapy
(n = 3239)
* Prior to 10/1997 chemotherapy patients were randomized as in
clear indication arm; after 10/1997 patients received 5-FU/low-dose LV.
R
A
N
D
O
M
I
Z
E
Observation
(n = 1617)
Chemotherapy
(n = 1622)*
Gray et al. ASCO 2004. Abstract 3501. At: http://www.asco.org/ac/1,1003,_12-002511-00_18-0026-00_19-0010698,00.asp.
Accessed November 2004.

18. The QUASAR Trial
100
Observation (n=1622)
Chemotherapy (n=1617)
% of Patients
80
60
40
P = .02
5-year OS, Obs = 77.4% vs CT = 80.3%
Relative risk = 0.83 (95% CI, 0.71-0.97)
20
0
0
1
2
3
4
5
Years
QUASAR group Lancet 2007
6
7
8
9
10

19. DFS: High-Risk Stage II Patients only
1.0
0.9
0.8
FOLFOX-4 n = 286
Probability
0.7
LV5FU2
5.0
n = 290
0.6
0.5
3-year
5-year
0.4
FOLFOX-4
85.4%
82.1%
0.3
LV5FU2
80.4%
74.9%
HR [95% CI]: 0.74 [0.52-1.06]
0.2
7.2
0.1
High-risk stage II – defined as at least
one of the following:
T4, tumor perforation, bowel
obstruction, poorly differentiated
tumor, venous invasion, <10 lymph
nodes examined
Data cut-off: June 2006
0
0
6
12
18
24
30
36
42
48
54
Disease-Free Survival (months)
60
66
72

20. MOSAIC OS Updated: 6 yrs, by stage
p=0.996
0.1%
p=0.029
4.4%
André T, et al. J Clin Oncol 2009;27:3109-16.

21. OXA in stage II
Pooled data from recent NSABP colon trials
Estimates by Risk Group
Endpoint
5-FU/Lv
5-FU/Lv +
Oxa
Increase
with Oxa
86.7
90.2
+ 3.5
89.2
91.7
+ 2.5
DFS - HiRisk
76.3
80.7
+ 4.4
- LoRisk
80.6
83.6
+ 3.0
- HiRisk
84.0
89.2
+ 5.2
- LoRisk
89.0
91.6
+ 2.9
- Risk Group
OS
- HiRis
- Lo Risk
TTR

22. CONCLUSION
The best estimate of the magnitude of survival
benefit from AC, if it exists, is an absolute
improvement of 2-4% in 5-year survival

23. Should Stage II Pts Receive Adj Therapy?
A Statistical Perspective
Number of patients needed to detect a realistic
treatment benefit assuming a true relative risk
reduction of 18% with a power of 90% (two sided)
Survival
ARR
No. of
patients
At 3 years
85%
2.5%
8000
At 4 years
80%
3.3%
5800
At 5 years
75%
4.0%
4700
Buyse M, Piedbois P. Semin Oncol 2001;28(1 Suppl 1):20-4.

24. Stage II: Conclusions
The observed HR & KM estimates suggest a
trend for benefit from Oxa in stage II
Benefit of monotherapy
• 2-3% in 5 yr DFS/OS
• Clinically meaningful?
• Prior 12 LN era – still relevant?
Additional benefit of Oxaliplatin
• No benefit overall
• ≈ 3 % in high risk stage IIs
• Needed number to treat: ≈ 33
Should be considered stage II, but …
• Biomarker?

25. Shift of the Paradigm
Shift of the Paradigm
The role of adjuvant chemotherapy
The role of adjuvant chemotherapy
1975
Simpler
strategies
1990
More
complex
strategies
2005
Surgery
RT/CT + CT
RT
Surgery
CT
Surgery
CT + RT/CT + CT
RT+CT
Surgery
CT
The role of adjuvant CT is
The role of adjuvant CT is not
easily recognizable
easily recognizable

26. Two paradigms of RT:
Two paradigms of RT:
Different outcomes, different role for adjuvant CT
Different outcomes, different role for adjuvant CT
Radioterapia post-operatoria
Radioterapia post-operatoria
Obiettivi:
Obiettivi:
Sopravvivenza
Sopravvivenza
DFS
DFS
Controllo locale
Controllo locale
Radioterapia preoperatoria
Radioterapia preoperatoria
Obiettivi:
Obiettivi:
DFS
DFS
Ruolo della chirurgia: Primario
Ruolo della chirurgia: Primario
Ruolo della CT adiuvante: Chiaro e
Ruolo della CT adiuvante: Chiaro e
significativo. Tutti gli obiettivi
significativo. Tutti gli obiettivi
USA: L’evidenza del NCI
USA: L’evidenza del NCI
Consensus del 1990
ha
Consensus del 1990
ha
dominato la scena sino ai primi aa.
dominato la scena sino ai primi aa.
2000
2000
Controllo locale
Controllo locale
Retrostadiazione
Retrostadiazione
Chir. Conservativa
Chir. Conservativa
Sopravvivenza,
Sopravvivenza,
Ruolo della chirurgia: Comprimario
Ruolo della chirurgia: Comprimario
Ruolo della CT adiuvante: Difficile
Ruolo della CT adiuvante: Difficile
da definire. Quali obiettivi?
da definire. Quali obiettivi?
Europa: Sopravvivenza con RT
Europa: Sopravvivenza con RT
preoperatoria non inferiore a RCT
preoperatoria non inferiore a RCT
post-operatoria
post-operatoria

27. Randomized trials with post-operative CRT
Randomized trials with post-operative CRT
 La CRT adiuvante migliora la Sopravvivenza rispetto
 La CRT adiuvante migliora la Sopravvivenza rispetto
alla Chirurgia da sola, alla RT da sola o alla CT da sola
alla Chirurgia da sola, alla RT da sola o alla CT da sola
● GITSG 7175 (NEJM 1985)
● GITSG 7175 (NEJM 1985)
● NCCTG 79-47-51 (NEJM 1991)
● NCCTG 79-47-51 (NEJM 1991)
 Impatto meno chiaro sulla sopravvivenza
 Impatto meno chiaro sulla sopravvivenza
● NSABP R-01 (JNCI 1988)
● NSABP R-01 (JNCI 1988)
● NSABP R-02 (JNCI 2000)
● NSABP R-02 (JNCI 2000)

28. Neoadjuvant Chemoradiotherapy:
Neoadjuvant Chemoradiotherapy:
The Shift of Paradigm
The Shift of Paradigm
1975
1975-1990
1990
1990-2000
2004
2000-Oggi
1990
2005
USA CRT Post-op; Europa RT Pre-op
NCI Consensus: CRT adiuvante
Pre-op CRT
Trial Tedesco (Pre-op Standard)
Nuove combinazioni terapeutiche in Pre-op
Ruolo della terapia adiuvante
Nuove strategie

29. CAO/ARO/AIO-94 Study: The Shift
CAO/ARO/AIO-94 Study: The Shift
Adjuvant versus neoadjuvant RChT
Adjuvant versus neoadjuvant RChT
OP
5-FU (120h)
1000mg/m2
Rest 4-6
weeks
Bolus 5-FU
500mg/m2
Radiotherapy 50,4 + 5,4 Gy
Weeks 1
25
5-FU (120h)
1000mg/m2
5
9
ARM A
13
17
ARM B
OP
4-6 weeks
rest period
Radiotherapy 50,4 Gy
Sauer R, NEJM 351: 2004
21

30. CAO/ARO/AIO-94 Study: Local Failure
CAO/ARO/AIO-94 Study: Local Failure
Sauer R, NEJM 351: 2004

31. CAO/ARO/AIO-94: Distant Metastases
CAO/ARO/AIO-94: Distant Metastases
Sauer R, NEJM 351: 2004

32. CAO/ARO/AIO-94: Overall Survival
CAO/ARO/AIO-94: Overall Survival
76% CRT post
74% CRT pre
Post-operative CRT
Pre-operative CRT
Sauer R, NEJM 351: 2004
P= 0.80

33. FFCD-9203
FFCD-9203
Pre-operative radiotherapy vs radiochemotherapy
Pre-operative radiotherapy vs radiochemotherapy
Randomisation
762 pts
PreOp-RT
Resection
Regimen
PreOp-RT = 45 Gy in 5 weeks
Week 1 and 5: 5 days FU/FA: 350/20 mg/m²
4 x FU/FA
Gerard JP, ICO 2006
PreOp-RT+
2 x FU/FA
Resection
4 x FU/FA

34. FFCD-9203
FFCD-9203
Pre-operative radiotherapy vs radiochemotherapy
Pre-operative radiotherapy vs radiochemotherapy
Randomisation
762 pts
PreOp-RT
Resection
Regimen
PreOp-RT = 45 Gy in 5 weeks
Week 1 and 5: 5 days FU/FA: 350/20 mg/m²
4 x FU/FA
Gerard JP, ICO 2006
PreOp-RT+
2 x FU/FA
Resection
4 x FU/FA

35. FFCD-9203
FFCD-9203
Pre-operative radiotherapy vs radiochemotherapy
Pre-operative radiotherapy vs radiochemotherapy
Randomisation
762 pts
PreOp-RT
Resection
16.5%
Local Failure
8.0%
Regimen
PreOp-RT = 45 Gy in 5 weeks
Week 1 and 5: 5 days FU/FA: 350/20 mg/m²
4 x FU/FA
Gerard JP, ICO 2006
PreOp-RT+
2 x FU/FA
Resection
4 x FU/FA

36. FFCD-9203
FFCD-9203
Is there a role for adjuvant chemotherapy?
Is there a role for adjuvant chemotherapy?
Randomisation
762 pts
PreOp-RT
Resection
4 x FU/FA
Regimen
PreOp-RT = 45 Gy in 5 weeks
Week 1 and 5: 5 days FU/FA: 350/20 mg/m²
Does it increase OS or DFS ?
Does it increase only toxicity?
Gerard JP, ICO 2006
PreOp-RT+
2 x FU/FA
Resection
4 x FU/FA

37. FFCD-9203
FFCD-9203
Pre-operative radiotherapy vs radiochemotherapy
Pre-operative radiotherapy vs radiochemotherapy
RT
CT+RT
Gerard JP, JCO 2006

38. EORTC-study 22921
EORTC-study 22921
Randomisation
252 pts
253 pts
253 pts
253 pts
PreOp-RT
PreOp-RT+
2 x FU/FA
PreOp-RT
PreOp-RT+
2 x FU/FA
Resection
Resection
Resection
Resection
4 x FU/FA
4 x FU/FA
Regimen
PreOp-RT = 45 Gy in 5 weeks
180 pts
Week 1 and 5: 5 days FU/FA: 350/20 mg/m²
Bosset JF, NEJM 2006
189 pts

39. Pre-operative treatment: CT vs CRT
Pre-operative treatment: CT vs CRT
65.8%
64.8%
Bosset JF, NEJM 2006

40. Adjuvant CT: Yes or Not
Adjuvant CT: Yes or Not
Bosset JF, NEJM 2006

41. Post-operative treatment: Yes or not
Post-operative treatment: Yes or not
Progression free
Survival
Bosset JF, NEJM 2006

42. Local recurrence as first event
Local recurrence as first event
Bosset JF, NEJM 2006

43. Ca. Retto: Modalità di trattamento - 1
cT3 (MRF-) N0-2 M0

44. Ca. Retto: Modalità di trattamento - 2
cT3 (MRF+) N0-2 M0 o cT4 ogni N M0

45. Ca. Retto: Modalità di trattamento in
corso di valutazione

46. Ca retto localmente avanzato: RAPIDO trial
Rt Short
Rt +Chemo
Chemo
Restaging
Restaging
Surgery
Surgery
Chemo

47. Timing della CT: CRT o CT prima?

48. Timing della CT: CRT o CT prima?
3 years DFS
RT-CHEMO
SURGERY
CHEMO
68%
CHEMO
RT-CHEMO
SURGERY
70%
Fernandez-Martos C et Al - ASCO - 2011

49. Potenzialmente resecabile dopo CT?
No
Il pz può tollerare una CT intensiva?
Si
No
Il pz può tollerare una CH maggiore?
No
B
Sintomi presenti o imminenti?
Comportamento aggressivo del tumore?
No
C
Si
Si
Malattia molto avanzata o “bulky”
No
Si
Il pz può tollerare una CT intensiva?
No
Si
Gruppo 2: intermedio
Gruppo 3: non intensivo/”sequenziale
Si
Gruppo1:intensivo
A

50. Gruppi Clinici per la stratificazione del
trattamento di I linea (induzione)
• Gruppo 0
– Metastasi epatiche e/o polmonari chiaramente
resecabili R0
• Gruppo 1
– Solo metastasi epatiche e/o polmonari non resecabili
R0, che:
• Potrebbero divenire resecabili dopo CT di induzione
• Possono essere associate a metastasi limitate/localizzate in
altre sedi (es.: lfn)
• Si riferiscono a pazienti in grado di affrontare un intervento
chirurgico maggiore e terapia medica intensiva

51. Gruppi Clinici per la stratificazione del
trattamento di I linea (induzione)
• Gruppo 2
– Metastasi (o siti metastatici) multiple, con:
• Rapida progressione e/o
• Sintomi correlati al tumore e/o rischio di rapido
deterioramento
• Co-morbidità che richiede trattamento intensivo
• Gruppo 3
– Metastasi (o siti metastatici) multiple, con:
• Nessuna opzione per resezione chirurgica
• e/o assenza di sintomi maggiori o rischio di rapido
deterioramento
• e/o comorbidità serie (che escludono possibilità chirurgiche
e/o trattamento intensivo)

52. Obiettivi e Intensità del trattamento
Obiettiivo
Intensità del trattamento
Gruppo 0 Guarigione
Riduzione del rischio di
recidiva
Nessuna o Moderata
(FOLFOX)
Gruppo 1 Massima riduzione del tumore
Regime più attivo
Gruppo 2 Rapida riduzione tumorale
cliicamente rilevante
Controllo della progressione di
malattia
Combinazione attiva: almeno
doppietta
Gruppo 3 Prevenzione di ulteriore
progressione
Riduzione tumorale meno
rilevante
Bassa tossicità più rilevante
• “Watchful waiting”
(eccezionalmente)
• Approccio sequenziale
(inizio con agente singolo o
doppietta con bassa tox)
• Eccezionalmente triplette

53. Survival by year of diagnosis
Retrospective review of 2470 pts with MCRC who received their primay
treatment between 1990 and 2006 at M.D. Anderson and Mayo Clinic
2004-2006
2001-2003
1990-2000
Kopetz S et al, J Clin Oncol. 2009 Aug 1;27(22):3677-83

54. Improved use of medical treatments
*Compared with irinotecan use in 1998 and normalized by yearly patient volume
Kopetz S et al, J Clin Oncol. 2009 Aug 1;27(22):3677-83

55. Increased percentage of resected pts
Kopetz S et al, J Clin Oncol. 2009 Aug 1;27(22):3677-83

56. Hepatic surgery increases survival
• 2470 pts with mCRC undergone CHT (Mayo Clinic 1990-2006); 231 liver resections
• Landmark analysis of survival of pts alive 12 months after diagnosis (70% of initial
population)
mOS
(monthsi)
5 yrs
Surv
Resected
patients
65,3
55%
Not
resected
26,7
19,5%
HR
0,35
70% della popolazione inclusa
Error bars represent 95% CLs
Sensible increase of long-term survival:
Actual possibility of cure
Kopetz S et al. J.Clin.Onc. 2009;27:3677-3683

57. LiveMetSurvey: OS
14,744 pts
Resected vs
operated but not resected
Initially resectable vs
non resectable
http://www.livermetsurvey.org, June 2011.

58. Resection of CRC liver metastases
• Accepted standard practice despite lack of
randomized trial
• Due to substantial cure rate reported in initial
series1, 2
• Survival directly related to liver metastases
resectability
– 5-y OS = 40-58% following successful resection3
– As high as 71.5% following solitary resection4
• It follows that we accept resection as a realistic
standard of cure
From: 1. Kopetz S et al J Clin Oncol 27: 3677-83; Adam R et al Ann Surg 2010;
3. Vauthey JN, et al. Semin Oncol 2005;32:S118-22; 4. Aloia TA, et al. Arch Surg 2006;141:460-6;
.

59. Liver Resection - New Perspective
OLD
Required limited number of
metastases
Resectability determined
by “what comes out”
NEW
No. of mts no longer a decision
factor
Anticipated negative margins
≥30% liver mass and two
continuous segments preserved
Associated with a near zero
operative mortality rate
Resectability determined
by “what stays in”

60. Actual 10-y Survival after Resection of
CLM
612 pts resected from 1985 to 1994 at MSKCC with 10-year follow up
THE MAJORITY OF
PATIENTS are NOT
CURED!
10-y Survival: 17%
Tomlinson J, JCO’07

61. How reach a consensus on resectability of
CRC liver metastases in MDT
1.Appropriate Rx
margins
2.Up to 4 mts
3. No negative
prognostic factors
1. Rx margins not
appropriate
2. Negative prognostic
factors
3. Surgery possible only
after relevant tumour
shrinkage
Heterogenous group:
• Unresectable
extrahepatic
metastases
• Comorbidities
• Other …
15%
35%
50%
Easy resectable
Marginally or
Potentially
resectable
Unresectable
and never likely
to be resectable
Modified from Masi G et al, Future Oncol 2011 and from Nordlinger et al, Ann Oncol 2009

62. Multimodality Management of CRC
Liver Metastases
– Neoadjuvant/Perioperative chemotherapy
• Resectable liver metastases:
– Facilitate surgery
– Obtain predictive and prognostic information
– Early systemic therapy for poor-prognosis pts
– Conversion chemotherapy
• Unresectable liver metastases:
– Allow R0 resection via downsizing
– Postoperative (adjuvant) chemotherapy
• Hepatic arterial infusion (HAI)
• Systemic treatment

63. Bittoni, Giampieri et al, CROH 2012

64. EPOC study: Trial Design and Objectives
FOLFOX4
x 6 cycles
R
364 pts
Surgery
Surgery
FOLFOX4
x 6 cycles
• Potentially resectable (1-4) liver
metastases
• Primary endpoint:
to demonstrate a 40% increase in
mPFS (HR=0.71) with 80% power
and 2-sided significance level 5%
Nordlinger et al, Lancet 2008

65. Primary Endpoint
N pts N pts
CT
Surg
% absolute
difference
in 3-year PFS
Hazard
Ratio
(CI)
P-value
All Patients
182
182
+7.2%
(28.1% to 35.4%)
0.79
(0.62-1.02)
0.058
All eligible
Patients
171
171
+8.1%
(28.1% to 36.2%)
0.77
(0.60-1.00)
0.041
All resected
Patients
151
152
+9.2%
(33.2% to 42.4%)
0.73
(0.55-0.97)
0.025
MOSAIC: 3-yr DFS for stage III: +7.2%

66. EPOC trial
PFS in eligible patients
100
90
HR= 0.77; CI: 0.60-1.00,
p=0.041
80
70
60
50
+8.1% at 3 years
36.2%
40
30
20
28.1%
10
0
(years)
0
O N
134 182
126 182
1
2
3
4
Number of patients at risk :
86
62
47
34
118
78
59
47
Nordlinger et al, ASCO 2007, Lancet 2008
5
21
28
6
9
13
7
8
4
4
Treatment
Surgery
Pre&Postop CT

67. EPOC trial
OS update 2012
HR= 0.87; CI: 0.66 -1.14, p=0.303
100
90
80
Periop CT
52.4.% (55.0 months)
70
+8.7 months
in median OS
+4.1 %
at 5 years
60
50
40
Surgery only
48.3% (63.7 months)
30
20
10
0
(years)
0
O
2
N
Number of patients at risk :
Nordlinger et al, ASCO 2012
4
6
8
10
12
Treatment

68. Resectable liver metastases
“New EPOC” phase III study
Previously
untreated
patients
with
resectable
mCRC
R
Planned:
n=340
ERBITUX
+
oxaliplatin +
fluoropyrimidine
for 12 weeks
Oxaliplatin +
fluoropyrimidine
for 12 weeks
Protocol amendment
Patients with KRAS mutant
tumors excluded
Available at clinicaltrials.gov NCT00482222
R
E
S
E
C
T
I
O
N
Adjuvant
therapy for
12 weeks
(same schedule as
pre-operatively)
Started February 2007
PFS

69. Results: Overview
• Planned vs enrolled pts: 340 vs 271
• Planned vs enrolled events: 212 vs 96
• Amendments:
– 2008, recruitment restricted to KRAS wt
– 2010, CAPOX proscribed
– 2010, FOLFIRI allowed for all pts
PFS (m)
CR+PR (%) RR (%)
OS (m)
FP+Oxa+Cet
14.1
58.4
90
39.1
FP+Oxa
20.5
43.7
87
n.r.
HR
1.5
p
<.048

70. Concerns
• Inclusion of capecitabine
• Analysis with less than 50% of planned events
(96 vs 212)
• Most patients characteristics in favour of the B
arm (PS 2, G3, synchronous, CEA >30, size,
extrahepatic disease, not resected primary, prior
adj oxa)
• Unknown percentage of randomized patients
actually completing Cetuximab
• … waiting for definitive publication …

71. Bevacizumab+CT: only phase II studies
56 pts
39 pts

72. Suggestions from approximate comparison
do not make sense
Trial
Resp. R
(%)
Res. R
(%)
mPFS
(m)
mOS
(m)
-
84
≈ 12
48.3
43
83
≈ 18
55
58.4
90
14
39.1
CT
43.7
87
20.5
n. reach.
Gruenberger ’08
73.2
92.8
n. rep.
n. rep.
Nasti ‘13
66.7
84.6
14
38
EPOC
Surg
CT
New EPOC Surg

73. Adjuvant Chemotherapy
May reduce the risk of recurrence
• Focus on completed and current trials
– Hepatic artery infusion (HAI)
– Systemic chemotherapy

74. HAI plus Systemic Chemotherapy (Combined
Therapy) vs with Systemic Monotherapy Alone
Median: 68.4 months
2
Only
6%
ad
pt s h
of
ha
ore t
m
n
f
0% o
5
th
a
AI pl
eH
Median: 55.2 months
Kemeny, N. E. et al., NEJM 341:2039, 1999
NEJM 352:734, 2005
74 pts
o
ed d
nn
se
82 pts

75. HAI adj CT for pts having resection
or ablation of liver CRC mts
Lygidakis excluded
Cochrane Database Syst Rev 2006

76. HAI adj CT for pts having resection
or ablation of liver CRC mts
Cochrane Database Syst Rev 2006

77. HAI +/- adj sys CT vs +/- adj sys CT
after resection of liver metastases
Study
Pts
Surgery
HAI
Sys CT
4 yrs DFS
4 yrs OS
ECOG
Kemeny
2002
75
+
+
FUDR
5FU
25 vs 46%
p 0,04
52,7 vs
61,5%
p NS
Lorenz
1998
226
+
+
5FU/AF
-
13,7 vs 4,2
mesi
p NS
40,8 vs 34,5
mesi
p NS
MSKCC
156
Vauthey
2006;
Aloia 2006
+
+
FUDR
5FU/AF
5FU/AF
33 vs 48%
p 0,045
27 vs 41%*
p NS
Lygidakis
2001
+
+
Im/ ito/5FU
5FU/Mito/Im 33 vs 58%§
Mito/5FU
p 0,002
64 vs 78%§
p NS
122
* 10 years OS; §Estrapolated from Kaplan-Meier curve

78. Adj HAI + Sys CT +/- Bevacizumab
L
I
V
E
R
S
U
R
G
E
R
Y
HAI
HAI
+

Kemeny et al, J Clin Oncol 2011
Sys CT +
Bevacizumab
Sys CT alone

79. Adj HAI + Sys CT +/- Bevacizumab
HAI + Sys
CT + Bev
(n. 38)
HAI + Sys
CT
(N. 35)
p
4 yrs
RFS
37%
46%
0,4
4 yrs OS
81%
85%
0,5
Bilirubin
>3 mg/dl
38%
0
0,02
Biliary
stent
11,4%
0
0,05
Kemeny et al, J Clin Oncol 2011

80. Adjuvant Systemic Treatment after
Liver Resection
Power and Kemeny, JCO 2010

81. Mitry E, JCO 2008

82. Mitry et al, J Clin Oncol 2008

83. § Median DFS (A) in patients receiving
LV5FUs was 21.6 versus 24.7 months for
FOLFIRI [hazard ratio (HR) 0.89, log-rank
P = 0.44].
§ No significant differences were found in
OS (72% vs 73%) (B)
§ A trend was observed for improved DFS
in patients receiving FOLFIRI within 42
days of surgery (HR 0.75, P = 0.17)
Ychou M et al. Ann Oncol 2009;20:1964-1970

84. Adjuvant CT after resection of metastases
Study
n.
Treatment
Result
Lorenz et al ‘98
226
HAI 5FU/FA 6 months
vs Surgery alone
Kemeny N et al ‘99
and ‘05
156
Sys 5FU+ HAI Flox + Dex
vs Systemic 5FU
Improved DFS
Kemeny M et al ‘02
75
Sys 5-FU + HAI Flox
vs Surgery alone
Improved RFS
Langer et al ‘02
107
Systemic 5-FU/FA 6 courses
vs Surgery alone
Trend for improved
DFS and OS
Portier et al ‘06
173
Systemic 5-FU/FA 6 courses
vs Surgery alone
Improved DFS
Mitry et al ‘08
278
Systemic 5-FU/FA 6 months
vs Surgery alone
Trend for improved
DFS and OS
Ychou et al ‘09
306
Systemic 5-FU/FA 6 months
vs FOLFIRI 6 months
No difference in DFS
or OS
No improved DFS or
OS.

85. Post-operative, not pre-operative, CT impacts
survival in single metachronous liver mts
• Retrospective analysis of 1.471 pts from MetSurg International Registry
Surgery vs pre-operative CT
5 yrs OS: 60% vs 60%, p =.57
Adam et al, Ann Surg 2010
Surgery vs post-operative CT
5 yrs OS: 36% vs 58%, p =.04

86. Perioperative or Adjuvant Therapy for
Resectable Liver Mts - Conclusions
• Despite improvement of 3-yrs survival, EPOC
randomized phase III study failed to show a definite longterm OS advantage for neoadjuvant therapy
• Studies continue to draw attention to adjuvant therapy
• Value of HAI-based therapy to be assessed
• Conclusion:
– In patients with resectable liver metastases neoadjuvant CT
might be considered before surgery, but the possibility of
adjuvant CT only after surgery might be of value
• NCCN Guidelines
– “Patients who have completely resected liver metastases should
be offered 4 to 6 months of adjuvant chemotherapy…
observation or a shortened course of chemotherapy is
considered for patients who have completed neoadjuvant
chemotherapy.”

87. Treatment of CRC liver metastases
A sensible strategy for MDT
If a biological concern….
may be it is better to try to improve DFS and OS
may be pCR could affect survival
If a techical concern…..
may be it is better to improve RR to surgery

88. Strategies in resectable liver metastases

89. Conversion to Resection of CRC
Metastasis: an Optimal Treatment Goal
COLORECTAL CANCER
~50% will develop metastases (synchronous or metachronous)
30-35% liver only metastases
10-25%
candidate for surgery
Convert?
AIM: R0 RESECTION
Cure rate: 20-30%
5 yrs survival: 40-60%
75-90%
non candidates for surgery
PALLIATIVE THERAPY
70-80% relapse
within 2 years
Leonard JCO 2005; Chua Clin Colorectal Cancer 2006; Kemeny Oncologist 2007; Leichman Surg Oncol Clin N Am 2007;
Van Cutsem Eur J Cancer 2007; Kemeny et al. NEJM 1999

90. What Do We Expect from Ideal
Conversion Chemotherapy?
• High (anatomical) response rate
– RR = aim of therapy in stage IV CRC only for
• Conversion therapy
• Patients with significant tumor-related symptoms
• Good toxicity profile
– No hepatotoxicity
– No interference with surgery
– No interference with liver regeneration

91. Survival after Liver Resection of CRC Mts
Paul Brousse Hospital (Apr. 88 - Jul. 99)
91%
100
Survival (%)
80
Resectable : 335
Initially non resectable : 138
66%
P= 0.01
60
48%
30%
52%
40
33%
20
23%
No Surgery
0
1
2
3
4
5
6
Years
7
8
9
10
Adam R et al. Ann Surg 2004

92. Adam R, J Clin Oncol 27. 2009

93. Conversion therapy: prospective phase II
studies in non-resectable liver mts*
Schedule
Author
Selected
Patients
N°. of
Patients
RR (%)
Resezioni
R0 (%)
FOLFOX4
Alberts
Yes
42
52
30
FFL4-10 crono
Giacchetti
Yes
151
59
32
FOLFOX4 +
Cetuximab
GOIM2402
No
53
60
21
FOLFOX4 +
Cetuximab
André
No
43
72
23
FOLFIRI
Barone
Yes
40
48
33
Folprecht
No
19
68
21
FOLFOXIRI
Masi
No
74
71
26
FOLFOXIRI
de la Camara
Yes
212
64
43
FOLFOXIRI
Quenet
Yes
26
73
35
POCHER
Garufi
Yes
26
83
60
AIO+CPT-11 +
Cetuximab
* No extrahepatic metastases

94. Phase III studies in non-selected pts with PCT
Treatment
N.
RR
(%)
Mts resection (%)
Author
IFL
FOLFOX
IROX
264
267
265
31
45
35
1
4
4
Goldberg, 2004
5FU/AF (AIO)
5FU/AF (AIO) +
IRI
216
214
34
64
1
3
Köhne, 2005
FOLFIRI
FOLFOX
109
111
56
54
9
15
Tournigand,
2004
FOLFIRI
FOLFOX
178
182
34
36
5,1
4,4
Colucci, 2005
XELOX
FUOX
171
171
37
46
10
12,9
Diaz-Rubio,
2007
FOLFIRI
FOLFOXIRI
147
138
34
43
4
10
Souglakos, 2006
FOLFIRI
FOLFOXIRI
122
122
41
66
6 (12 liver only)
15 (36 liver only)
Falcone, 2007

95. Conversion therapy
Studies
N
RR
Resection (R0)
20–40
50–70%
29–43%
20–40
40–70%
~20%
200–500 30–60%
8–24%
Phase II
Selected
Phase II
Non-selected
Phase III
Non-selected
Folprecht et al Ann Oncol 2005

96. Conversion Therapy: Resectability Correlates
With Response Rate
Studies including
selected patients
(liver metastases only,
no extrahepatic disease)
(r=0.96; p=0.002)
0.6
Resection rate
0.5
0.4
Studies including
nonselected patients
with mCRC (solid
line)
(r=0.74; p<0.001)
0.3
0.2
0.1
0
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Response rate
Folprecht G, et al. Ann Oncol 2005;16:1311–1319
Phase III studies including
nonselected patients
with mCRC (dashed line)
(r=0.67; p=0.024)

97. Cetuximab increases pts candidates to
hepatic resection
60
* KRAS WT
** ITT
LLD=liver limited disease

98. CRYSTAL e OPUS: Cetuximab
increases patients with ETS
CRYSTAL
Cetuximab + FOLFIRI
38%
62%
≥20%* (n=184)
<20%* (n=115)
n=299
OPUS
Cetuximab + FOLFOX4
31%
69%
≥20%* (n=54)
<20%* (n=24)
n=78
*Radiologic evaluation reported by the
investigator and reviewed by an IRC
FOLFIRI
51%
49%
≥20%* (n=163)
<20%* (n=169)
n=332
FOLFOX4
54%
46%
≥20%* (n=41)
<20%* (n=49)
n=90
Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)

99. Response rate with CT doublet plus cet,
pan or bev
RR(%)
FOLFIRI/ Cet
FOLFOX/ Cet
OxMdG/ XELOX/ Cet
FOLFOX/ Pan
IFL/ Beva
FOLFOX/ XELOX/ Beva
XELOX/ Beva>XELOX/ Beva
XELO/ Beva>Beva
Cape/ Beva
Cape/ MitoC/ Beva
0
10
20
30
40
50
60
70
Van Cutsem et al, NEJM 2009, JCO 2011; Bokemeyer et al, JCO 2009; Maughan et al, ASCO 2010;
Douillard et al, ECCO-ESMO 2009, JCO 2010, ASCO 2011; Hurwitz et al, NEJM 2004; Saltz et al,
JCO2008; Tabernero et al, 2010; Tebbutt et al, JCO 2010

100. Phase III studies in non-selected pts with
PCT+biologics
Pts
RR
Res
R0
FOLFIRI (KRASwt)
FOLFIRI+Cet (KRASwt)
599
599
43
59
2.5
6.0
1.5 (4.5*)
4.8 (9.8*)
XELOX/FOLFOX
XELOX/FOLFOX+Bev
701
699
38
38
11.6
12.3
-
FOLFOX (KRAS wt)
331
FOLFOX+Pan (KRAS wt) 325
48
57
18
28
-
* Liver limited disease
Falcone, JCO 2007; Van Cutsem, JCO 2009, Saltz, JCO 2008; Douillard, ASCO 2011

101. Summary of randomized trials with
EGFR mAbs plus CT in KRAS wt CRC
Grothey A et al, JCO 2012

102. RR allows to standardize resectability
The CELIM phase II study
Folprecht G et al, Lancet Oncol 2009

103. The CELIM study
Standardizing resectability
FOLFOX + Cet
N = 53
FOLFIRI + Cet
N = 53
K-RAS WT
N = 67
RESPONSE
RR
68%
(n = 36)
57%
(n = 30)
70%
(n = 47)
95% CI
54-80%
42-70%
58-81%
RESECTION RATE
All resections
49%
(n = 26)
43%
(n = 23)
46%
(n = 31)
R0 resections
38%
(n = 20)
30%
(n = 16)
34%
(n = 23)
Folprecht G et al, Lancet Oncol 2009

104. Resectability after CT + cetuximab
(Studio CELIM)
5/7
Non resecabile
Resecabile
Voto dei revisori (%)
Basale (A)
Voto dei revisori
(%)
Resecabile
Non resecabile
Dopo trattamento (B)
Non resecabile
Scelta chemioterapia
Bordeline per resecabilità all'esplorazione
Resecabile
Pazienti
Folprecht et al, Lancet Oncol 2010
104

105. CT+ Cet
Surgery
20 pts
70 pts
R
Median No. of CT cycle: 6
68 pts
CT
Ye LC, JCO 2013
Surgery
9 pts

106. Results
Arm A
Arm B
P
Response rate (%)
25.7
7.4
<.01
R0 resection rate (%)
57.1
29.4
<.01
41
18
.013
Median survival (m)
30.9
21.0
.013
Median survival in resected
46.4
25.7
<.01
3-yrs survival (%)

107. cCR vs pCR of liver mts following CT
Author
Pts
N. liver mts
with cCR
Liver mts with
confirmed pCR
Benoist et al
J Clin Oncol 2006
38
66
17%
Tanaka et al
Ann Surg 2009
23
72
69%
Auer et al
Cancer 2010
39
118
66%
van Vledder et al
J Gastrointest Surg
2010
40
112
45%
Ferrero et al
J Gastrointest Surg
2012
33
67
39 %

108. pCR is associated with better long-term outcome
767 undergone CT and hepatectomy
(1985-2006)
Factors predicting a pCR
p
RR
Age ≤60 yrs
0,03
4,1
Diameter ≤3 cm
0,05
3,1
CEA ≤30 ng/ml
0,03
5,6
cRC/RP after
CHT
0,04
3,9

109. Clinical and biological risk factors in
pts with liver mts
– pTN
• Timing
•
•
Synchronous Mts
Metachronous Mts
– Characteristics of Mts
•
•
Number/diameter
Site/anatomic relationships
– CEA
•
Basal/Absolute value
– Free Interval
– Resection
•
•
•
– Extra-hepatic disease
From T resection
From M resection
From end of adj CT
•
R0, R1, R2

110. R0 vs R1 in liver resection +/- pre-operative CT
R0
R1
No pre-operative CT (N. 172)
DFS (m)
17
8
p<0,001
OS (m)
53
30
p<0,001
Pre-operative CT (n. 92)
DFS (m)
Ayez et al, Ann Surg Oncol 2011
18
9
p=0,303
OS (m)
65
nr
p=0,645

111. Unfavourable prognostic factors for OS
Author
Timing
CEA
Mts
Ø mts
Margin
Fong, 1999
<12 m
>60
>1
≥5 cm
Pos
Iwatsuki, ’99
≤30 m
>2
>8 cm
Scheele, ’01
pT
G3
Nagashima, ’04
pN
N+
Syn
≥5 cm
N+
Rees, 2008
>3
N2
G3
Yes
>1
Pawlik, 2005
Minagawa, ’07
≥50
N+
>60
>1
≥5 cm
>1
Vigano, ’08
Syn
Konopke, ’09
Syn
Reissfelder, ‘09
N+
Settmacher, ‘11
N2
Extra-liv
LFN
≥5 cm
Pos
Yes
>3
>200
≥4
>200
≥2
Yes

112. Predictors of Recurrence after Liver
Resection
N+ in the primary
DFI < 12 months
> 1 extrahepatic mts
∅ > 5 cm
CEA > 200 ng/ml
The Fong’s Clinical Score
80%
70%
60%
5 yrs Survival





50%
40%
30%
20%
10%
0%
0
1
2
Score
Fong Y, Ann Surg 1999
3
4
5

113. Survival in liver mts is related to prognostic factors
1.613 consecutive pts with CRC liver mts
(2000-2010)
Negative prognostic factors
• Undiffer. primary tumour
• Metastases ≥4
• Size ≥5 cm
• No liver surgery
5 yrs OS
Low risk
47%
<0,001
High risk
Dexiang et al, Ann Surg Oncol 2012
p
7%

114. No dangerous halo
Focal dangerous halo
a
Diffuse spiculated dangerous halo
CT
st
Po
ol
h
at
p
ict
ed
pr
al
viv
ur
ss
b
y
gDiffuse polylobated dangerous halo
o
Rubbia-Brandt et al 2007; Mentha et al 2009; Maru et al 2010
c
d

115. Patterns di danno epatico da chemioterapia
Pattern
Farmaco
Impatto clinico
Evidenza
Steatosi
5Fluorouracile
Aumento morbilità
(complicanze
infettive)
Analisi multivariata in
studio caso-controllo
Sindrome da
ostruzione
sinusoidale
Oxaliplatino
Aumento morbilità ed
emotrafusioni
Studio caso-controllo
e analisi retrospettiva
Steatoepatite
Irinotecan
Aumento morbilità e
mortalità a 90 giorni
Analisi multivariata in
studio caso-controllo
Sclerosi biliare
extra-epatica
Floxouridina
i.a.
Danno biliare a lungo
termine (permanente)
Studio caso-controllo e
analisi retrospettiva
Vauthey et al, J Clin Oncol 2006; Khan et al, J Hepatobiliary Pancreat Surg 2009

116. Timing of Conversion Therapy
• Evaluation for conversion therapy
• CT firstly (2-4 months): less exposure-less tox
(importance of ETS)
– Except symptomatic patients
• Surgery of primary tumour firstly
• Surgery
– Metastases and primary tumour
• In two stage hepatectomy resection of primary tumour better
during first intervention
• Post-operative CT
– Overall 12 cycles (6 months) on CT, including preand post-surgery

117. Strategies in potentially resectable liver
metastases

118. Synchronous resectable CRC liver
metastases
•
•
•
UK hospitals: retrospective analysis
112 consecutive patients (200-2012)
36 simultaneous resections and 76 sequential resections
Slesser AAP et al, Eur J Surg Oncol 2013
3 yrs OS: 75% vs 64% p = 0.379
3 yrs DFS: 33% vs 32% p = 0.837
Simultaneous resection results in similar short-term and
long-term outcome as pts receiving sequential resection
with comparable metastatic disease

119. Combined first-stage hepatectomy and CRC
resection in a two stage hepatectomy strategy
• 33 pts from two institutions (2000-2008)
Karoui M et al., Brit J Surg 2010
Survival for
completing procedure
3 yrs 5 yrs
OS
80% 48%
DFS 44% 22%
In pts with bilobar synchronous CRC liver mts candidate for
two-stage hepatectomy, combined resection of the primary
and first-stage hepatectomy optimizes procedures and CT

120. First-liver approach for synchronous liver mts
A systematic review of four cohort studies
121 patients:
90 pts (74%) completed the planned treatment
23 pts (19%) progressed during treatment protocol
Preferred algorithm: CT → liver res → CT/CT-RT → Primary res → CT?

121. First-liver approach for synchronous liver mts
A systematic review of four cohort studies
Brouquet’s study (156 pts)
Combined Classic Reverse
Pts
43
72
27
N. mts
1
3
4
3yr OS
65
58
79
5yr OS
55
48
39
Combined = primary+liver resection
Classic = primary resection first
Reverse = liver resection first
Conclusion: a) Similar outcomes
b) Reverse for asympt primary
Jegatheeswaran S et al, JAMA Surg 2013
De RosaA et al, Hepatobil Pancr Sci 2013
Comparison among studies
5 yrs OS: 31-41%

122. Patients based analysis comparing liver-first
and combined approach
Survival
No differences regarding the approach
(p =0.94)
5 yrs Overall Survival
Mayo SC et al, J Am Coll Surg 2012

123. Some arguments to be considered in MDT
Combined Surgery
• Preferred with limited
disease
• Removes all macroscopic
cancer, but might leave
occult metastases
• Prevents delay of
adjuvant tehrapy
• May avoid post-operative
immunodeficiency
Staged Surgery
• Preferred in high risk
patients
• Majority of metastatic
disease is not suitable for
resection
• Allows more aggressive
surgery and optimizes
chances of R0 and CT
• Early control of systemic
disease
• First stage: easy side of
liver

124. Trattamento di I linea (induzione)
Fattori correlati al
paziente
Presentazione clinica
Finalità
del
trattamento
Fattori correlati al
tipo di trattamento
Manifestazioni cliniche
della biologia neoplastica
Fattori correlati ai
farmaci

125. Aspetti clinici
Paziente
- Localizzazione
- Dinamica di crescita
- Sintomi
- Impossibilità di
trattamento in caso
di fallimento
- Biomarcatori progn.
-Età biologica
- Comorbidità
- Performance Status
-Capacità di tollerare
trattamenti intensi
- Capacità psicologica/
volontà di affrontare
trattamenti intensi
Attività/tossicità
- Potenzialità di indurre
una riduzione max delle
mts
- Potenzialità di prolungare
PFS o OS
- Profilo di tossicità
- Farmacosensibilità
Fattori che
influenzano la
scelta
Farmaci
- Disponibilità
- Rimborsabilità
- Sostenibilità

126. Opzioni terapeutiche
• Categorie di farmaci
– Citotossici, Biologici
• Numero di farmaci
– Monoterapia, Doppiette, Triplette
– …..
• Strategie
–
–
–
–
–
–
Trattamento sino a progressione
Sequenze di linee
“Stop and go”
Mantenimento/Depotenziamento
“Watchful waiting”
“Rechallenge”

127. Possibili Scenari
 Malattia metastatica resecabile
 Malattia metastatica potenzialmente resecabile
Malattia non resecabile
 Malattia asintomatica non voluminosa
 Malattia “bulky” ma asintomatica
 Paziente “unfit”
 Sintomi cancro-correlati
Sopravvivenza
Continuum
Sintomi
of care
QoL
P

128. Continuum terapeutico e Obiettivo sopravvivenza
I Fase - Induzione
Scelta dominante
Bilancio
P
RP/SD
Scelta
II Fase – Rescue
non cross-resistente
Interruzione
Mantenimento
Prosecuzione
Recidiva
II Fase
P
Rechallenge

129. 1a linea: IFL + bevacizumab vs IFL
Median progression-free survival
6.2 vs 10.6 months
HR=0.54 p<0.0001
0.8
0.8
IFL + bevacizumab
IFL + placebo
0.6
0.4
0.2
IFL + bevacizumab
IFL + placebo
0.6
0.4
0.2
6.2m
0
Median survival
15.6 vs 20.3 months
HR=0.66 p<0.001
1.0
Probability of survival
Probability of being progression free
1.0
0
15.6m
10.6m
10
Time (months)
20
30
0
0
10
20.3m
20
30
40
Time (months)
Hurwitz et al. NEJM 2004

130. PFS in NO16966:
General and On-Treatment Populations
1.0
FOLFOX or XELOX + placebo
PFS estimate
FOLFOX or XELOX + bevacizumab
0.8
HR=0,83 (IC 97,5%): 0,72 - 0,95)
p=0,0023
0.6
HR=0,63 (IC 97,5%): 0,52 - 0,75)
p<0,0001
0.4
0.2
0
8.0
0
5
9.4
10
10.4
15
20 Months
Bev-containing arm: Separation after ≈6 months occurs between the PFS for
General vs. On-treatment populations
Saltz LB, ASCO 2007

131. Rassegna dei principali studi di fase III
con Bevacizumab associato a politerapia
AVF 21072
NO169661
XELOX or
FOLFOX ± Bev
XELOX ± Bev
IFL ± Bev
E32003
FOLFOX4 ± Bev
FOLFOX ± Bev
Bev
Control
(n = 286) (n = 291)
Bev
(n=699)
OR (%)
Median PFS
(mos) (95% CI)
Control
(n=701)
Bev
(n=350)
Control
(n=350)
Bev
(n=349)
Control
(n=351)
Bev
(n=402)
Control
(n=411)
38
38
NA
NA
NA
NA
45
35
22.7
8.6
9.4
8.0
9.3
7.4
9.4
8.6
10.6
6.2
7.3
4.7
∆ Median PFS
1.4
1.9
Hazard Ratio
0.83
0.77
(mos)
(95% CI)
Median OS
(mos) (95% CI)
∆ Median OS
(mos)
Hazard Ratio
(95% CI)
#
(0.72, 0.95) p = 0.0023
#
21.3
19.9
1.4
0.89
(0.76, 1.03) p = 0.077
0.8
(0.63, 0.94)
21.4
2.2
(0.68, 1.04)
(0.73, 1.08)
21.2
#
20.3
0.9
0.94
(0.75, 1.16)
2.6
0.54
0.89
#
19.2
0.84
4.4
0.61
p < 0.001
20.3
15.6
4.7
0.66
p < 0.001
97.5% CI
Saltz LB, et al. J Clin Oncol 2008; 26:2013-9; 2Hurwitz H, et al. N Engl J Med 2004; 350:2335-42; 3Giantonio 2007.
1
p < 0.0001
12.9
10.8
2.1
0.75
p = 0.0011

132. CRYSTAL study: OS in unselected
patients
All mCRC patients
CRYSTAL
Erbitux + FOLFIRI (n=599)
FOLFIRI (n=599)
1.0
OS estimate
0.8
0.6
19.9
HR=0.878
p=0.0419
18.6
0.4
0.2
0.0
0
6
12
18
24
30
36
42
48
Time (months)
Van Cutsem E, et al. J Clin Oncol 2011;29:2011–2019
54

133. Analysis by KRAS optimizes clinical
outcome
KRAS analyzed
population
CRYSTAL
Erbitux + FOLFIRI (n=316)
FOLFIRI (n=350)
1.0
OS estimate
0.8
0.6
23.5
HR=0.796
p=0.0093
20.0
0.4
0.2
0.0
0
6
12
18
24
30
36
42
48
Time (months)
Van Cutsem E, et al. J Clin Oncol 2011;29:2011–2019
54

134. CRYSTAL KRAS WT mCRC (n=666): PFS
Advantage statistically and clinically meaningful
1.0
FOLFIRI (n=350)
Cetuximab + FOLFIRI (n=316)
PFS estimate
0.8
HR=0.70; p=0.0012
0.6
1-year PFS rate
25% vs 43%
0.4
0.2
0
8.4
0
4
9.9
8
12
Time (months)
16
20
Van Cutsem, et al. ASCO 2010; Van Cutsem, et al. JCO 2011

135. CRYSTAL: efficacy according to KRAS
FOLFIRI
FOLFIRI +
cetuximab
n
350
316
RR (%)
39.7
57.3
< 0.0001
mPFS (mos)
8.4
9.9
0.0012
mOS (mos)
20
23.5
0.0094
FOLFIRI
FOLFIRI +
cetuximab
P value
n
183
214
RR (%)
36.1
31.3
0.34
mPFS (mos)
7.7
7.4
0.26
mOS (mos)
16.7
16.2
0.75
KRAS wild-type
KRAS mutated
Δ 1.5
Δ 3.5
P value
Interaction test: PFS p = 0.03; OS p = 0.046; ORR p = 0.0005
Van Cutsem et al, ASCO GI 2010

136. PRIME: OS and PFS in KRAS wt
patients
Panitumumab + FOLFOX4: ~2 Years Median
OS in Patients with KRAS WT Tumours
Douillard JY, et al. J Clin Oncol 2010; 28:4697-705.
Panitumumab + FOLFOX 4: Median PFS of 9.6
Months in Patients with KRAS WT Tumours

137. KRAS Status in Response to Cetuximab
 CRYSTAL and OPUS meta-analysis[1]
– Pooled efficacy analysis of two randomized phase III trials
– CRYSTAL: FOLFIRI + cetuximab vs FOLFIRI alone[2]
– OPUS: FOLFOX + cetuximab vs FOLFOX alone[3]
– After 90% of samples were subjected to KRAS genotype
testing, HRs for benefit of addition of cetuximab shown to be
highly statistically significant in patients with wild-type KRAS
– PFS—HR: 0.66 (P < .0001)
– OS—HR: 0.81 (P = .0062)
1. Bokemeyer C, et al. ASCO 2010. Abstract 3506. 2. Van Cutsem E, et al. N Engl J Med.
2009;360:1408-1417. 3. Bokemeyer C, et al. J Clin Oncol. 2009;27:663-671.

138. Combinazione a 3 farmaci
Studio GONO
FOLFIRI
N=122
FOLFOXIRI
N=122
P-value
RR* (%)
34
60
<0.0001
CR+PR+SD* (%)
68
81
R0 resection
(%) (all patients)
6
15
0.033
R0 resection (%)
(liver limited)
12
36
0.017
PFS (mos)
6.9
9.8
0.0006
OS (mos)
16.7†
22.6
0.032
* externally reviewed; †67% 2nd line FOLFOX
Falcone et al, JCO 138
2007

139. Stato dell’arte al 2011
• Gli anti-EGFR hanno un ruolo definito nei paz
KRAS wt in prima linea
• L’efficacia del Bev in prima linea è limitata al PFS,
quando combinato con uno schema
comprendente una FP infusionale
• Il FOLFOXIRI è una alternativa valida in prima
linea
• Il Bev è efficace in seconda linea in combinazione
con FOLFOX
• Gli anti-EGFR (Pan) in seconda linea in
combinazione con FOLFIRI migliorano la PFS, ma
non la OS
• La monoterapia può essere una opzione nei
pazienti fragili o nella malattia torpida

140. MACRO: Bev di Mantenimento vs Bev
+ XELOX continuativo
Patients with
previously
untreated mCRC
(N = 480)
Induction
Therapy
XELOX +
Bevacizumab
6 cycles
XELOX + Bevacizumab
(n = 239)
Bevacizumab
(n = 241)
Disease
progression,
severe
toxicity, or
consent
withdrawal
Maintenance cycles administered q3w:
Oxaliplatin 130 mg/m2 IV on Day 1
Capecitabine 1000 mg/m2 BID PO on Days 1-14
Bevacizumab 7.5 mg/kg IV on Day 1
Tabernero et al, ASCO 2010

141. MACRO: Durata paragonabile della
PFS

No significant difference between treatment arms in any efficacy outcome

Noninferiority of bevacizumab vs XELOX + bevacizumab cannot be
confirmed
– The median PFS HR 95% CI (0.89-1.37) beyond the planned noninferiority limit of
1.32
Bevacizumab
(n = 241)
XELOX/
Bevacizumab
(n = 239)
HR
(95% CI)
OR
(95% CI)
Median PFS,* mos
9.7
10.4
1.11
(0.89-1.37)
--
Median OS,* mos
21.7
23.4
1.04
(0.81-1.32)
--
49
46
--
0.89
(0.62-1.27)
Outcome
Confirmed objective
response, %
*Median follow-up: 20.4-21.1 mos.
Tabernero et al, ASCO 2010

142. Studio ML18147 (fase III)
BEV + standard
first-line CT (either
oxaliplatin or
irinotecan-based)
(n=820)
Standard second-line CT
(oxaliplatin or irinotecanbased) until PD
PD
Randomise 1:1
CT switch:
Oxaliplatin → Irinotecan
Irinotecan → Oxaliplatin
Primary endpoint
Secondary endpoints
included
Stratification factors
BEV (2.5 mg/kg/wk) +
standard second-line CT
(oxaliplatin or irinotecanbased) until PD
• Overall survival (OS) from randomisation
•Progression-free survival (PFS)
•Best overall response rate
•Safety
• First-line CT (oxaliplatin-based, irinotecan-based)
• First-line PFS (≤9 months, >9 months)
• Time from last BEV dose (≤42 days, >42 days)
• ECOG PS at baseline (0/1, 2)
Study conducted in 220 centres in Europe and Saudi Arabia

143. OS: popolazione ITT
CT (n=410)
BEV + CT (n=409)
1.0
OS estimate
0.8
0.6
Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)
p=0.0062 (log-rank test)
0.4
Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)
p=0.0211 (log-rank test)
0.2
9.8 mo
0
0
6
11.2 mo
12
18
24
30
36
42
48
Time (months)
No. at risk
CT
410
293
162
51
24
7
3
2
0
BEV + CT 409
328
188
64
29
13
4
1
0
Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)
a
Primary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose
of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)

144. PFS: popolazione ITT
CT (n=410)
BEV + CT (n=409)
1.0
PFS estimate
0.8
0.6
Unstratifieda HR: 0.68 (95% CI: (0.59–0.78)
p<0.0001 (log-rank test)
0.4
Stratifiedb HR: 0.67 (95% CI: 0.58–0.78)
p<0.0001 (log-rank test)
0.2
0
4.1 mo
0
No. at risk
CT
410
BEV+CT 409
5.7 mo
6
12
18
24
30
36
42
Time (months)
119
189
20
45
6
12
4
5
0
2
0
2
0
0
a
Primary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose
of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)

145. Velour: studio di fase III
600 pts
Aflibercept 4 mg/kg IV
+ FOLFIRI q 2 weeks
Patients with metastatic
colorectal cancer after
failure of an oxaliplatinbased regimen
R
DISEASE
PROGRESSION
1:1
DEATH
600 pts
STRATIFICATION FACTORS:
Prior bevacizumab (Y/N)
ECOG PS (0 vs 1 vs 2)
FIRST PATIENT IN: November 2007
ENROLLMENT COMPLETED:
1226 randomized, 1216 treated
Final analysis at 863 OS events
Placebo + FOLFIRI
q 2 weeks
PRIMARY ENDPOINT: OS
SECONDARY ENDPOINTS:
ORR, PFS, safety, PK
Clinicaltrials.gov. NCT00561470. Van Cutsem, et al. Ann Oncol. 2011;22(suppl 5). Abstract O-0024 and
presentation at: ESMO 13th WCGIC. June 22-25, 2011; Barcelona, Spain.
145

146. Velour: overall survival ITT population
Censor
Placebo/FOLFIRI: median = 12.06 months
Aflibercept/FOLFIRI: median = 13.50 months
1.0
0.9
0.8
Stratified HR = 0.817 [95.34% CI, 0.713–0.937]
Log-rank P = 0.0032
KAPLAN-MEIER
ESTIMATE
0.7
0.6
0.5
0.4
0.3
0.2
Cut-off date: February 7, 2011
Median follow-up: 22.28 months
TIME
(months)
0.1
0.0
NUMBER
AT RISK
SURVIVAL
PROBABILITY
0
3
614
612
573
566
6
9
485 401
498 416
79.1%
81.9%
12
15
286 193
311 216
50.3%
56.1%
18
21
131 87
148 104
30.9%
38.5%
24
27
51
31
75
49
18.7%
28.0%
30
14
33
12.0%
22.3%
33
36
39

147. Velour: PFS ITT population
Censor
Placebo/FOLFIRI: median = 4.67 months
Aflibercept/FOLFIRI: median = 6.9 months
1.0
0.9
0.8
Stratified HR = 0.758 [99.99% CI, 0.578–0.995]
Log-rank P = 0.00007
KAPLAN-MEIER
ESTIMATE
0.7
0.6
0.5
0.4
0.3
0.2
TIME
(months)
0.1
NUMBER
AT RISK
Cut-off date: May 6, 2011
0.0
0
3
6
9
12
15
18
614
612
355
420
171
247
94
99
46
43
24
17
9
7
21
24
27
30

148. CORRECT study
2:1
Evaluation with CT scan of abdomen and chest every 8 weeks
• Multicenter, randomized, double-blind, placebo-controlled, phase III
– Stratification: prior anti-VEGF therapy, time from diagnosis of metastatic disease, geographical
region
• Global trial: 16 countries, 114 centers
• Recruitment: May 2010 to March 2011

149. Sopravvivenza globale
Primary endpoint met prespecified stopping criteria at interim analysis
(1-sided p<0.009279 at approximately 74% of events required for final analysis)

150. Sopravvivenza libera da malattia
Regorafenib significantly improves PFS compared to placebo

151. Modellizzazione del Tumor Shrinkage
utilizzando la misurazione del diametro maggiore
LDi(t)
• La somma delle misurazioni dei diametri maggiori
delle lesioni “target” che quantifica le dimensioni del
tumore viene elaborata informaticamente per il
tempo di valutazione t e il paziente i:1
1. Mansmann U, et al. ASCO GI 2012 (Abstract No. 580);
2. Eisenhauer EA, et al. Eur J Cancer 2009;45:228–247

152. Ruolo della risposta nella 1° linea
Analisi dello studio Crystal
CRYSTAL (KRAS wt)
• Quantitativa
Response rate (%)
60
50
p<0.001
57
40
30
40
20
10
0
• Qualitativa
Change in lesion (%)
n=72 n=68
100
80
60
40
20
0
-20
-40
-60
-80
-100
ERBITUX + FOLFIRI (n=316)
FOLFIRI (n=350)
FOLFIRI (n=276)
• Early tumor shrinkage
55%
<20%
≥20%
45%
ERBITUX + FOLFIRI (n=251)
36%
64%
<20%
≥20%
Köhne C-H, et al. ASCO 2011 (Abstract No. 3576); Van Cutsem E, et al. ASCO 2010 (Abstract No. 3570); Piessevaux H, et al. ESMO 2010 (Abstract No. 596P)

153. CRYSTAL e OPUS: Cetuximab
increases patients with ETS
CRYSTAL
Cetuximab + FOLFIRI
38%
62%
≥20%* (n=184)
<20%* (n=115)
n=299
OPUS
Cetuximab + FOLFOX4
31%
69%
≥20%* (n=54)
<20%* (n=24)
n=78
*Radiologic evaluation reported by the
investigator and reviewed by an IRC
FOLFIRI
51%
49%
≥20%* (n=163)
<20%* (n=169)
n=332
FOLFOX4
54%
46%
≥20%* (n=41)
<20%* (n=49)
n=90
Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)

154. ETS is related to better PFS in
Cetuximab-treated patients
Cetuximab + FOLFIRI
FOLFIRI
1.0
0.8
mPFS 14.1 mo
0.6
HR 0.32
p<0.001
0.2
mPFS 7.3 mo
0
5
10
15
20
mPFS 9.7 mo
0.6
0.0
mPFS 7.4 mo
0
5
10
15
20
25 (mesi)
FOLFOX4
≥20%* (n=54)
<20%* (n=24)
1.0
HR 0.58
p<0.001
0.2
25 (mesi)
Cetuximab + FOLFOX4
≥20%* (n=41)
<20%* (n=49)
1.0
0.8
mPFS 11.9 mo
0.4
0.6
OPUS
0.8
0.6
mPFS 7.2 mo
0.4
HR 0.22
p<0.001
0.2
0.0
0.8
0.4
0.4
0.0
≥20%* (n=163)
<20%* (n=169)
mPFS 5.7 mo
0
5
CRYSTAL
≥20%* (n=184)
<20%* (n=115)
1.0
10
15
20 (mesi)
*Radiologic evaluation reported by the investigator and reviewed by an IRC
HR 0.89
p=NS
0.2
0.0
mPFS 7.2 mo
0
5
10
15
20 (mesi)
Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)

155. Ruolo della risposta nella 1° linea
Analisi dello studio Crystal
CRYSTAL (KRAS wt)
• Quantitativa
Response rate (%)
60
50
p<0.001
57
40
30
40
20
10
0
• Qualitativa
Change in lesion (%)
n=72 n=68
100
80
60
40
20
0
-20
-40
-60
-80
-100
ERBITUX + FOLFIRI (n=316)
FOLFIRI (n=350)
FOLFIRI (n=276)
• Early tumor shrinkage
55%
<20%
≥20%
45%
ERBITUX + FOLFIRI (n=251)
36%
64%
<20%
≥20%
Köhne C-H, et al. ASCO 2011 (Abstract No. 3576); Van Cutsem E, et al. ASCO 2010 (Abstract No. 3570); Piessevaux H, et al. ESMO 2010 (Abstract No. 596P)

156. CRYSTAL e OPUS: Cetuximab
increases patients with ETS
CRYSTAL
Cetuximab + FOLFIRI
38%
62%
≥20%* (n=184)
<20%* (n=115)
n=299
OPUS
Cetuximab + FOLFOX4
31%
69%
≥20%* (n=54)
<20%* (n=24)
n=78
*Radiologic evaluation reported by the
investigator and reviewed by an IRC
FOLFIRI
51%
49%
≥20%* (n=163)
<20%* (n=169)
n=332
FOLFOX4
54%
46%
≥20%* (n=41)
<20%* (n=49)
n=90
Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)

157. ETS is related to better PFS in
Cetuximab-treated patients
Cetuximab + FOLFIRI
FOLFIRI
1.0
0.8
mPFS 14.1 mo
0.6
HR 0.32
p<0.001
0.2
mPFS 7.3 mo
0
5
10
15
20
mPFS 9.7 mo
0.6
0.0
mPFS 7.4 mo
0
5
10
15
20
25 (mesi)
FOLFOX4
≥20%* (n=54)
<20%* (n=24)
1.0
HR 0.58
p<0.001
0.2
25 (mesi)
Cetuximab + FOLFOX4
≥20%* (n=41)
<20%* (n=49)
1.0
0.8
mPFS 11.9 mo
0.4
0.6
OPUS
0.8
0.6
mPFS 7.2 mo
0.4
HR 0.22
p<0.001
0.2
0.0
0.8
0.4
0.4
0.0
≥20%* (n=163)
<20%* (n=169)
mPFS 5.7 mo
0
5
CRYSTAL
≥20%* (n=184)
<20%* (n=115)
1.0
10
15
20 (mesi)
*Radiologic evaluation reported by the investigator and reviewed by an IRC
HR 0.89
p=NS
0.2
0.0
mPFS 7.2 mo
0
5
10
15
20 (mesi)
Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)

158. ETS is related to prolonged OS in
Cetuximab-treated patients
Cetuximab + FOLFIRI
FOLFIRI
≥20%* (n=163)
<20%* (n=169)
1.0
0.8
0.8
mOS 30.0 mo
0.6
mOS 24.1 mo
0.6
HR 0.71
p=0.006
0.4
0.4
0.2
HR 0.53
p<0.001
mOS 18.6 mo
0.0
0
10
20
30
40
50
60 (mesi)
Cetuximab + FOLFOX4
≥20%* (n=54)
<20%* (n=24)
1.0
0.4
HR 0.43
p=0.006
mOS 15.7 mo
0.0
0
10
FOLFOX4
20
30
40
50
0.8
mOS 21.6 mo
0.6
0.4
0.2
0.0
HR 0.89
p=NS
mOS 17.8 mo
0.2
0.0
60 (mesi)
≥20%* (n=41)
<20%* (n=49)
1.0
mOS 26.0 mo
0.6
mOS 18.6 mo
OPUS
0.8
0.2
CRYSTAL
≥20%* (n=184)
<20%* (n=115)
1.0
0
10
20
30
40 (mesi)
*Radiologic evaluation reported by the investigator and reviewed by an IRC
0
10
20
30
40 (mesi)
Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)

159. TRIBE Study Design
FOLFIRI+bev
508 mCRC pts
1st line
unresectable
stratified by
 center
 PS 0/1-2
 adjuvant CT
(up to 12 cycles)
5-FU/LV
+Bev
R
PD
FOLFOXIRI+bev
(up to 12 cycles)
INDUCTION
5-FU/LV
+Bev
MAINTENANCE

160. Primary endpoint: PFS (updated) – ITT population
FOLFIRI + bev
Progression-free survival probability
FOLFOXIRI + bev
Median follow up: 32.3 mos
FOLFIRI + bev: N = 256 / Progressed = 226
FOLFOXIRI + bev: N = 252 / Progressed = 213
FOLFIRI + bev, median PFS : 9.7 mos
FOLFOXIRI + bev, median PFS : 12.1 mos
Unstratified HR: 0.77 [0.64-0.93]
p=0.006
Stratified HR: 0.75 [0.62-0.90]
p=0.003
F-up time (months)
FOLFIRI/bev
256
203
94
46
26
14
7
3
0
0
FOLFOXIRI/bev
252
208
125
74
35
21
11
5
2
1

161. Secondary endpoint: Response rate
(updated) - ITT population
FOLFIRI + bev
N = 256
FOLFOXIRI + bev
N = 252
Complete Response
3%
5%
Partial Response
50%
60%
Response Rate
53%
65%
Stable Disease
32%
25%
Progressive Disease
11%
6%
Not Assessed
4%
4%
p
Best Response, %
0.006

162. Secondary endpoint: OS (preliminary) – ITT population
FOLFIRI + bev
FOLFOXIRI + bev
Median follow up: 32.3 mos
Overall survival probability
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 [0.66-1.05]
p=0.125
Stratified HR: 0.79 [0.63-1.00]
p=0.054
F-up time (months)
FOLFIRI/bev
256
233
216
172
109
69
36
15
5
0
FOLFOXIRI/bev
252
234
205
175
119
70
35
15
4
0

169. PRIME study RAS analysis
PFS (primary analysis)
WT KRAS exon 21
WT RAS2
100
100
HR = 0.80 (95% CI, 0.66–0.97)
P = 0.02
80
70
60
50
40
30
20
90
Proportion event-free (%)
Proportion event-free (%)
90
HR = 0.72 (95% CI, 0.58–0.90)
P = 0.004
80
70
60
50
40
30
20
10
10
0
0
0
2
4
6
8
10 12 14 16 18 20 22 24
Months
Events
n (%)
199 (61)
9.6 (9.2–11.1)
FOLFOX4 (n = 331)
215 (65)
8.0 (7.5–9.3)
2
4
6
8
10 12 14 16 18 20 22 24
Months
Events
n (%)
Median (95% CI)
months
Panitumumab +
FOLFOX4 (n = 259)
156 (60)
10.1 (9.3–12.0)
FOLFOX4 (n = 253)
170 (67)
7.9 (7.2–9.3)
Median (95% CI)
months
Panitumumab +
FOLFOX4 (n = 325)
0
1. Douillard JY, et al. J Clin Oncol 2010;28:4697-705;
2. Douillard JY, et al. N Engl J Med 2013; 369:1023-34.
WT RAS, WT KRAS & NRAS exons 2/3/4
(includes 7 patients harbouring KRAS/NRAS codon 59 mutations)

170. PRIME study RAS analysis
OS (primary analysis)
WT RAS2
WT KRAS exon 21
100
100
HR = 0.83 (95% CI, 0.67–1.02)
P = 0.072
80
70
60
50
40
30
20
90
Proportion alive (%)
Proportion alive (%)
90
HR = 0.78 (95% CI, 0.62–0.99)
P = 0.043
80
70
60
50
40
30
20
10
10
0
0
0
4
8
12
16 20
Months
24
28
32
36
Events
n (%)
165 (51)
23.9 (20.3–28.3)
FOLFOX4 (n = 331)
190 (57)
19.7 (17.6–22.6)
4
8
12
1. Douillard JY, et al. J Clin Oncol 2010;28:4697-705;
2. Douillard JY, et al. N Engl J Med 2013; 369:1023-34.
16 20
Months
24
28
32
36
Events
n (%)
Median (95% CI)
months
Panitumumab +
FOLFOX4 (n = 259)
128 (49)
26.0 (21.7–30.4)
FOLFOX4 (n = 253)
148 (58)
20.2 (17.7–23.1)
Median (95% CI)
months
Panitumumab +
FOLFOX4 (n = 325)
0
WT RAS, WT KRAS & NRAS exons 2/3/4
(includes 7 patients harbouring KRAS/NRAS codon 59 mutations)

171. PEAK study WT KRAS exon 2 mCRC
Metastatic
CRC
WT KRAS exon 2
(n = 285)
o
f
(Q2W)
t
r
e
a
t
m
e
n
t
R
1:1
S
a
f
e
E
n
d
mFOLFOX6 (Q2W) +
panitumumab 6 mg/kg
mFOLFOX6 (Q2W) +
bevacizumab 5 mg/kg
(Q2W)
Tumour Assessment Q8W (±7 days);
Treatment administered until
disease progression, death,
or withdrawal from study
t
y
30 days
(+ 3 days)
f
o
l
l
o
w
u
p
P
o
s
t
t
r
e
a
t
m
e
n
t
f
o
l
l
o
w
E
n
d
o
f
s
t
u
d
y
u
p
Every 3 months (±28 days)
until end of study
• Study endpoints: PFS (1°); OS, ORR, resection rate, safety, exploratory biomarker analysis
• No formal hypothesis testing was planned
Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster);
Protocol ID: 20070509; ClinicalTrials.gov identifier: NCT00819780.
ORR, objective response rate; mFOLFOX6, modified FOLFOX6

172. Analisi RAS dello studio PEAK
PFS
WT RAS
WT KRAS esone 2
100
100
HR* = 0.84 (95% CI, 0.64–1.11)
P = 0.22
80
70
60
50
40
30
20
90
Proportion event-free (%)
Proportion event-free (%)
90
HR* = 0.66 (95% CI, 0.46–0.95)
P = 0.03
80
70
60
50
40
30
20
10
10
0
0
0
4
8
12
16
20 24
Months
Events
n (%)
28
32
36
40
0
4
8
12
16
20 24
Months
28
32
36
40
Events
n (%)
Median (95% CI)
months
Median (95% CI)
months
Panitumumab +
100 (70)
mFOLFOX6 (n = 142)
10.9 (9.7–12.8)
Panitumumab +
mFOLFOX6 (n = 88)
57 (65)
13.0 (10.9–15.1)
Bevacizumab +
108 (76)
mFOLFOX6 (n = 143)
10.1 (9.0–12.0)
Bevacizumab +
mFOLFOX6 (n = 82)
66 (80)
10.1 (9.0–12.7)
Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster).
*Stratified Cox proportional hazards model; No formal hypothesis testing
was planned; WT RAS, WT KRAS & NRAS exons 2/3/4

173. Analisi RAS dello studio PEAK
OS
WT KRAS esone 2
WT RAS
90
80
80
Proportion alive (%)
100
90
Proportion alive (%)
100
70
60
50
40
30
20
HR* = 0.62 (95% CI, 0.44–0.89)
P = 0.009
10
0
70
60
50
40
30
20
HR* = 0.63 (95% CI, 0.39–1.02)
P = 0.058
10
0
0
4
8
12 16 20 24 28 32 36 40 44
Months
Events
n (%)
52 (37)
34.2 (26.6–NR)
Bevacizumab +
mFOLFOX6 (n = 143)
78 (55)
24.3 (21.0–29.2)
4
8
12 16 20 24 28 32 36 40 44
Months
Events
n (%)
Median (95% CI)
months
Panitumumab +
mFOLFOX6 (n = 88)
30 (34)
41.3 (28.8–41.3)
Bevacizumab +
mFOLFOX6 (n = 82)
40 (49)
28.9 (23.9–31.3)
Median (95% CI)
months
Panitumumab +
mFOLFOX6 (n = 142)
0
*Stratified Cox proportional hazards model; No formal hypothesis testing
was planned; WT RAS, WT KRAS & NRAS exons 2/3/4;
Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster).
NR, not reached

174. Obiettivo sopravvivenza – Anti-angio
Terapia
Studio
PFS
OS
IFL+B
AVF2107
10.6
20.3
Fp+Ox+B*
N016966
10.4
-
XELOX+B
N016966
9.3
21.4
FOLFOX+B
N016966
9.4
21.2
FOLFOXIRI+B TRIBE
12.1
31
CT+B
ML18147
5.7
11.2
1.6
1.4
FOLFIRI+A
VELOUR
6.9
13.5
1.2
1.5
Regorafenib
CORRECT
1.9
6.4
0.2
1.4
FOLFOX+B
Di Giantonio
7.3
12.9
2.6
2.1
FOLFIRI+B
FIRE III
10.3
25.0
* On-treatment
Δ PFS Δ OS
Δ rispetto al braccio di controllo

175. Obiettivo sopravvivenza
Terapia personalizzata: Cet I linea
Terapia
Studio
PFS
OS
FOLFIRI+C
CRYSTAL
8.9
19.9
FOLFIRI+C KRAS wt
CRYSTAL
9.9
23.5
FOLFOX+P KRAS wt PRIME
9.6
23.9
FOLFIRI+C ETS
CRYSTAL
14.1
30.0
FOLFIRI+C
FIRE III
10.0
28.7
FOLFIRI+C panRAS
FIRE III
10.4
33.1
FOLFIRI+C panRAS
CAPRI
11.3
-
FOLFOX+P panRAS
PRIME
10.1
26.0
FOLFOX+P panRAS
PEAK
13
41.3

176. Obiettivo sopravvivenza
Sequenza vs Terapia personalizzata
XELOX+B
OS: 21.4 m
ML18147
ΔOS: 1.4 m
VELOUR
ΔOS: 1.5 m
Regorafenib
ΔOS: 1.4 m
22.8 m
24.3 m
25.6 m
FOLFIRI+B
FIRE III
OS 25.0 m
FOLFOXI+B
Di Giantonio
ΔOS: 2.1 m
27.1 m
FIREIII
FOLFIRI+C panRAS
OS: 33.1

177. Classification of CRC based on
correlation of clinical, morphological
and molecular features
Feature
Group 1
(12%)
Group 2
(8%)
Group 3
(20%)
Group 4
(57%)
Group 5
(3%)
MSI status
H
S/L
S/L
S
H
CIMP
H
H
L
Negative
Negative
+++
+++
++
+/-
+/-
KRAS
-
+
+++
++
++
BRAF
+++
++
-
-
-
TP53
-
+
++
+++
+
Location
R>L
R>L
L>R
L>R
R>L
Serration
+++
+++
+
+/-
+/-
Mucinous
+++
+++
+
+
++
Poor diff
+++
+++
+
+
++
Methylation
Jass JR, Hystopathology 2007

179. Colon cancer: genetic vs stage progression
METASTASIS
Lung
Liver
Skin
Bone
Ovary
Peritoneum
STAGING
NORMAL TISSUE
ADENOMA
EARLY CARCINOMA (StageS I & II)
Mucosa
Submucosa
Circular
Muscle
Longitudinal
Muscle
Pericolic Lymph Nodes
Artery and
Capillaries
GENETIC PROGRESSION
20 - 40 years
Mutation
or loss
Mutation
Loss
Mutation
and loss
Axin
β-catenin
APC
B-RAF
KRAS
TGFβ−RII
SMAD2/4
TP53
LATE CARCINOMA (Stages III & IV)

180. Multi-step colon-cancer progression
NORMAL COLON EPITHELIA
E-cadh β
RAS
Src
ADENOMA
PI3K
K3
GS
JNK
β
β
Proteasome
Ax
in
1. Wnt/β-catenin
Oncogenic Activation
APC
AKT
2. K-Ras
Oncogenic
Activation
(other alterations)
CARCINOMA
Gro
Lef
Tcf/Lef genes
OFF
ON
PROLIFERACION
FOXO
FOXO genes
OFF
ON
QUIESCENCE
PROLIFERATION
QUIESCENCE, INVASION?
PROLIFERATION
DIFFERENTIATION
3. JNK activation?
Stress or ligands
METASTASIS
Stage III & IV

181. Wnt/b-catenin & PI3k/Akt signalling
crosstalk drives cancer cell fate
NICHE
WNT
INHIBITORS
OXIDATIVE
ESTRESS
GROWTH
FACTORS
RTK
XAV939
β
EGFR/PI3K/AKT
INHIBITORS
CETUXIMAB
Proteasome
Axin
JNK
APC
RAS
β
β
FOXO3a
β
PI3K
API2
AKT GDC-0068
β
Lef
β
ON
PROLIFERATION
ON
FOXO3a
APOPTOSIS
CYCLE ARREST
& METASTASIS
CELL FATE

182. Small molecules to Inhibit
Wnt/β-catenin Oncogenic Signal
Small molecules
Blocking antibodies
Dr. Paul Polakis. Genentech
Wnt
LRP
Fz
TNK
in
Ax
Dsh
β
C
AP
β
β
β
K3
GS
β
β
Lef
ON
Tcf/Lef genes
Vitamin D
Palmer HG et al
Small molecules

183. Back-up