1. KRAS Status in Response to Cetuximab
E Idelevich, 2011
KRAS Status in Response to Cetuximab
Retrospective analysis of CRYSTAL[1]
PFS and ORR benefit of FOLFIRI + cetuximab only observed in mCRC patients with wild-type KRAS
Outcome
Wild-Type KRAS
(n = 348)
Mutated KRAS
(n = 192)
Median PFS, mos
FOLFIRI + cetuximab
9.9
7.6
FOLFIRI
8.7
8.1 HR
0.68*
1.07†
ORR, %
59.3‡
36.2
43.2
40.2
FOLFIRI, 5-fluorouracil/leucovorin/irinotecan; mCRC, metastatic colorectal cancer; ORR, overall response rate; PFS, progression-free survival.
A retrospective analysis of the CRYSTAL study that stratified patients by either wild-type or mutated KRAS status was then conducted. This analysis showed that patients with wild-type KRAS were the only ones who derived clinical benefit from the addition of cetuximab, both in terms of median progression-free survival and median overall response rate. Specifically, the response rate with FOLFIRI chemotherapy alone increased from 43% to 60% with the addition of cetuximab. An increase in response rates correlated with an increased ability to undergo surgical resection.
*P = .017; †P = .75; ‡P = .0025
1. Van Cutsem E, et al. ASCO Abstract 2. 1

2. 20060314 FOLFIRI + Panitumumab in 1st-line Treatment of Metastatic CRC
E Idelevich, 2011
FOLFIRI + Panitumumab in 1st-line Treatment of Metastatic CRC S c r e n I g E n r o l m e t
E n d o f t r e a t m e n t S a f e t
y f
o l l o w u p
E n d o f s t u d y
FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W, on day 1 of each cycle)
Metastatic CRC
(n=150)
Approx. 56 days after end of treatment
This was a first-line, single-arm phase 2 study prospectively evaluating the relationship between KRAS status and response to combination therapy with panitumumab and FOLFIRI.
Eligible patients received panitumumab (6 mg/kg; intravenous infusion [IV]) on day 1 of a 14-day cycle with the initial dose administered over 60 minutes ± 15 minutes prior to chemotherapy. If the first dose was well tolerated subsequent infusions were given over 30 minutes ± 10 minutes prior to chemotherapy. No panitumumab-specific pre-medication was given before administration.
Treatment was to be given until progression or unacceptable toxicity.
Study objectives also included the evaluation of patient reported outcomes, healthcare resource utilisation and any integument and eye toxicity management scheme.
Secondary endpoints also included disease control rate, duration of response, time to response, time to progression, duration of stable disease, and time to treatment failure
All analyses were descriptive
Study objectives: To estimate the effect of KRAS mutation status on efficacy and to describe the safety profile
Study endpoints: ORR (1°); PFS, Safety
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation;
protocol ID: ClinicalTrials.gov identifier: NCT 2

3. 20060314 Best Objective Response
E Idelevich, 2011
Best Objective Response
Panitumumab + FOLFIRI*
KRAS wt (n=85)
KRAS mt (n=58)
Objective response, %
Complete response 2
Partial response 54 36
Stable disease 34 52
Disease progression 7
Unevaluable
Not done
CR + PR,%
(95% CI)
56.5
(45.3, 67.2)
37.9
(25.5, 51.6)
Difference, %
(0.84, 34.63)
Unadjusted common treatment odds ratio (95% CI)
2.12
(1.02, 4.45)
*Two patients did not have measurable disease per RECIST guidelines at baseline and were therefore not included in the analysis of response rate.
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation. 3

4. Resection Rates – Patients with Liver Only Disease
E Idelevich, 2011
Resection Rates – Patients with Liver Only Disease
Overall resections 40
KRAS evaluable 35
In the population of patients with liver-only metastases at baseline (n=52), resections were performed in 29% of patients (n=15) in the full analysis set
In the KRAS WT and MT groups, resection rates in the primary analysis set (KRAS evaluable patients) were 19% (n=6) versus 6% (n=1), respectively, in patients with liver metastases only.
Reference:
Hofheinz R, et al. J Clin Oncol 2010, 28:7s, abstract #3545, poster presentation
Resection rate (%) 20 13
KRAS wt
(n=11/31)
KRAS mt
(n=2/16)
Hofheinz R, et al. ASCO 2010, #3545, poster presentation 4

5. 20060314 Progression-free Survival Primary Analysis Set
E Idelevich, 2011
Progression-free Survival Primary Analysis Set
Events n (%)
Median (95% CI) months
KRAS wt (n=86)______
44 (51)
8.9 (7.6–14.3)
KRAS mt (n=59)______
48 (81)
7.2 (5.6–7.8)
100 90 70 60 80 50 40 30 20 10
HR = 0.46 (95%CI: 0.31–0.70)
Proportion Event-Free (%)
Vectibix + FOLFIRI extends PFS to approximately 9 months 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Months
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.

6. E Idelevich, 2011
Summary
This was the first study to investigate the effect of tumour KRAS status on response to panitumumab plus FOLFIRI in the 1st-line treatment of mCRC
KRAS wt tumours were more likely to respond to treatment with panitumumab plus FOLFIRI (56.5%vs 37.9%)
PFS was longer in patients with KRAS wt tumours
Resection rate was higher in the KRAS wt population
Safety was as expected for an anti-EGFR inhibitor plus irinotecan-based chemotherapy in this setting
PFS was longer in patients with KRAS wt tumours (HR=0.46; 95% CI: )
KRAS wt tumours were more likely to respond to treatment with panitumumab plus FOLFIRI (OR 2.12; 95% CI: 1.02–4.45)
Resection rate was higher in the KRAS wt population (15%) than in the KRAS mt population (7%)
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation;
Hofheinz R, et al. J Clin Oncol 2010; 28(15S): #3545, poster presentation. 6

7. 20050181 FOLFIRI ± Panitumumab in 2nd-line Treatment of Metastatic CRC
E Idelevich, 2011
FOLFIRI ± Panitumumab in 2nd-line Treatment of Metastatic CRC
L o n g t e r m f
o l l o w u p
E n d o f t r e a t m e n t
FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W)
Metastatic CRC
(n=1100) R
1:1
FOLFIRI (Q2W)
Disease assessment every 8 weeks
This was an open-label, randomised, multicentre, phase III trial that compared the efficacy of panitumumab 6.0 mg/kg every 2 weeks (Q2W) plus FOLFIRI versus FOLFIRI alone in patients with previously treated metastatic colorectal cancer. The study was not blinded because of the expected skin toxicity related to panitumumab administration. Study objective: To evaluate the treatment effect of the addition of panitumumab to FOLFIRI on PFS and OS by KRAS status
The study was initially estimated to require 1,100 patients unselected for KRAS tumour status. Based on emerging KRAS data from other panitumumab studies, the protocol was amended after completion of enrollment, and the primary objective was changed to incorporate patient stratification for KRAS status.
Panitumumab was administered by a 60-minute infusion before chemotherapy; if the first panitumumab dose was well tolerated, subsequent infusions could be administered over 30 minutes. All patients received FOLFIRI: 180 mg/m2 irinotecan and 400 mg/m2 racemic leucovorin (or 200 mg/m2 l-leucovorin) by intravenous (IV) infusion on day 1 and FU 400 mg/m2 IV bolus on day 1, followed by 2,400 mg/m2 continuous infusion administered over days 1 and 2.
Patients received study medication until disease progression or intolerability.
Tumour response was assessed by the investigator and by an independent central radiology review blinded to treatment and outcomes using a modification of Response Evaluation Criteria in Solid Tumors (RECIST) every 8 weeks until disease progression; responses (complete response or partial response) were confirmed 28 days after the criteria for response were first met.
Patients were followed-up for safety for at least 30 days after the last study drug administration and for survival every 3 months until approximately 30 months after the last patient was randomised.
Enrollment was from June 2006 to March 2008
Participating countries: Australia, Austria, Belgium, Bulgaria, Czech Republic, Finland, France, Germany, Ireland, Italy, Japan, Lithuania, The Netherlands, Norway, Poland, Portugal, Romania, Russia, Slovakia, Spain, Sweden, Switzerland, Ukraine, United Kingdom, United States
Stratification by:
ECOG score: 0-1 vs. 2
Prior oxaliplatin exposure for mCRC
Prior bevacizumab exposure for mCRC
Study endpoints: PFS/OS (co-1°); ORR, Safety, PRO
PRO, patient-reported outcomes
Peeters M, et al. J Clin Oncol 2010;28: ; ClinicalTrials.gov identifier: NCT ; protocol ID: 7

8. Objective Response Rate (%) Panitumumab + FOLFIRI (n=297)
E Idelevich, 2011
Objective Response in Patients with KRAS wt Tumours (Central Review) 40 30 35
Objective Response Rate (%) 20 10 10
The response rate in the KRAS wt subpopulation who received panitumumab + FOLFIRI in this study is the highest reported in a randomised, phase 3, 2nd-line study. (Response rates for irinotecan-based regimens in 2nd-line therapy are generally between 4% and 16% in KRAS unselected populations1,2)
Similar response rates were observed in the FOLFIRI alone arm (10% and 14% in the KRAS wt and mt subpopulations, respectively), indicating that the patient population in this study was similar to those studied previously.
The high response rate seen with panitumumab-FOLFIRI may be of particular value in patients who experience disease progression during first-line therapy with borderline resectable metastases or symptomatic disease.
References:
Cunningham D, et al. N Engl J Med 2004; 351:337-45;
Sobrero AF, et al. J Clin Oncol 2008; 26:
Response rates by central and investigator review were virtually identical.
Central: 35% pmab +FOLFIRI vs 10% FOLFIRI
Investigator: 35% pmab +FOLFIRI vs 12% FOLFIRI
Unevaluable/not done by central review: 7% pmab vs 10% FOLFIRI
Reasons for “not done” included: no scans performed after screening.
(Scans performed less than 49 days after screening were considered unevaluable)
Panitumumab + FOLFIRI (n=297)
FOLFIRI (n=285)
More than 3x as many patients responded to panitumumab
p < 0.001(descriptive); All responses were confirmed no earlier than 28 days after the response criteria were first met
Peeters M, et al. J Clin Oncol 2010;28: 8

9. Progression-Free Probability
E Idelevich, 2011
Panitumumab Improved Median PFS by 51% in Patients with KRAS wt Tumours
Events n (%)
Median (95% CI) months
Panitumumab + FOLFIRI (n=303)___
178 (59)
5.9 (5.5–6.7)
FOLFIRI (n=294)___
203 (69)
3.9 (3.7–5.3)
 2.0
1.0
0.9
0.8
0.7
HR = 0.73 (95%CI: 0.59–0.90)
p = 0.004
0.6
Progression-Free Probability
0.5
0.4
0.3
0.2
A statistically significant improvement in PFS with panitumumab-FOLFIRI versus FOLFIRI was demonstrated (HR 0.73; 95% CI, 0.59 to 0.90; P.0036, stratified log-rank)
0.1
0.0 20 18 16 14 12 10 8 6 4 2
Months
Peeters M, et al. J Clin Oncol 2010;28: 9 9

10. E Idelevich, 2011
Summary
This is the first randomised study prospectively analysed by KRAS status in 2nd-line mCRC
In patients with KRAS wt tumours, panitumumab significantly improved PFS when added to FOLFIRI
Overall survival was numerically improved (not significant)
The response rate was improved by more than 3x (35% vs 10%)
Safety was as expected for an anti-EGFR antibody in combination with FOLFIRI
Peeters M, et al. J Clin Oncol 2010;28:
Peeters M, et al. ASCO-GI 2010, #282, oral presentation 10 10

11. Metastatic colon cancer patients (100%)
Non - resectable 75%
Resectable 25%
Potentially
Down-sizable
Non curable
12%
63%

12. Paul Brousse Experience - 1439 Patients (1988–1999)
Adam R et al Ann Surg. 2004;240:

13. Treatment of Metastatic CRC
RR % MS
Months
5Fu
20-25 13
Capecitabine
Irinotecan
40- 50
20-22
Oxaliplatin
EGFR inhibitors
~ 60
> 24
Bevacizumab

15. Endpoints for assessment of systemic therapy for potentially resectable disease
Systemic therapy is enabling resection
- Highest RR maximizes resection rate (Folprecht et al)
Endpoints
- PFS is primary efficacy endpoint (ECNTG, 2007)
- Secondary endpoints
* Response Rate
* Liver related toxicity
* Achievement of R0 resection of all disease
Are biological essential?
- if acceptable toxicity, higher RR, improved resection rates and ultimately improved PFS are demonstrated (European Journal of Cancer, 43 (2007), )

16. Response rates: recent phase 3 trials
Regimen Response Rate Reference
_________________________________________________________________________
FOLFOX % NS;
FOFOX+cetuximab % (OPUS, Bokemeyer)
_____________________________________________________________________________________
FOLFIRI % p=0.004;
FOLFIRI+cetuximab % (CRYSTAL,van Cutsem)
______________________________________________________________________________________
FOLFOX % NS;
FOLFOX+bevacizzumab % (XELOX-1/NO16966 Saltz)
FOLFOX % NS; p=0.06
FOLFOX+panitumumab (PRIME, J-Y Douillard)
FOLFIRI % p=0.001;
FOLFOXIRI % (Falcone)
FOLFOX+bevacizumab % NS;
FOLFOX+bevacizumab+cetuximab 39% (PACCE; Hecht)
CAPOX+bevacizumab % NS;
CAPOX+becizumab+cetuximab % (CAIRO2; Punt)
Standard Doublets ~ 40% Response Rate (RR)

17. Response rates: recent phase 3 trials
Regimen Response Rate Reference
______________________________________________________________________________________
FOLFOX % NS;
FOFOX+cetuximab % (OPUS, Bokemeyer)
FOLFIRI % p=0.004;
FOLFIRI+cetuximab % (CRYSTAL,van Cutsem)
FOLFOX % NS;
FOLFOX+bevacizzumab % (XELOX-1/NO16966 Saltz)
FOLFOX % NS; p=0.06
FOLFOX+panitumumab % (PRIME, J-Y Douillard)
FOLFIRI % p=0.001;
FOLFOXIRI % (Falcone)
FOLFOX+bevacizumab % NS;
FOLFOX+bevacizumab+cetuximab % (PACCE; Hecht)
CAPOX+bevacizumab % NS;
CAPOX+becizumab+cetuximab % (CAIRO2; Punt)
Adding EGFR inhibitors or using triplet chemotherapy increases RR

18. Response rates: recent phase 3 trials
Regimen Response Rate Reference
_____________________________________________________________________________________
FOLFOX % NS;
FOFOX+cetuximab % (OPUS, Bokemeyer)
FOLFIRI % p=0.004;
FOLFIRI+cetuximab % (CRYSTAL,van Cutsem)
______________________________________________________________________________________
FOLFOX % NS;
FOLFOX+bevacizzumab % (XELOX-1/NO16966 Saltz)
FOLFOX % NS; p=0.06
FOLFOX+panitumumab % (PRIME, J-Y Douillard)
FOLFIRI % p=0.001;
FOLFOXIRI % (Falcone)
FOLFOX+bevacizumab % NS;
FOLFOX+bevacizumab+cetuximab 39% (PACCE; Hecht)
CAPOX+bevacizumab % NS;
CAPOX+becizumab+cetuximab % (CAIRO2; Punt)
Bevacizumab does not increase Response Rate (RR)

19. Kras-dependent RR in First-Line Trials
RR (K-ras w.t.) RR (K-ras mut)
__________________________________________________________________
OPUS (Bokemeyer)
FOLFOX % %
FOLFOX+erbitux % %
CRYSTAL (van Cutsem)
FOLFIRI % %
FOLFIRI+erbitux % %
PRIME (J-Y Douillard)
FOLFOX % %
FOLFOX+vectibix % %
(Köhne CH)
FOLFIRI+vectibix ,5% %

20. In K-ras wild type patients
Response Rate
In K-ras wild type patients
- FOLFOX or FOLFIRI+EGFR inhibitors has shown
55%- 60% response rate
FOLFOXIRI
- 60% response rate in small phase 3 trial

21. What is the optimal chemotherapy for the neoadjuvant treatment of unresectable liver metastases?

22. In patients with K-ras unknown or mutant
- FOLFOX remains a standard treatment
- FOLFOXIRI is an option (resectability, RR + PFS), but
unknown toxicity profile in larger series
- FOLFOX + bevacizumab is safe, but neither improves
response rates nor resection rates
In patients with wildtype K-ras
- FOLFOX or FOLFIRI + EGFR inhibitors improve resection rates
- FOLFIRI + cetuximab improves resection rate compared
FOLFIRI

23. Treatment of unresectable mCRC
Patients needing or desiring an aggressive approach:
- patients with potentially resectable metastases
- patients with clearly symptomatic disease in whom tumor regression is needed
KRAS wild type patients:
- CT + panitumumab, CT+cetuximab
-evidence for response is greater for cetuximab in neoadjuvant
approach
KRAS mutant patients:
- CT + bevacizumab
- FOLFOXIRI may be an option if contraindications for bevacizumab and downsizing is desired
Van Cutsem E, et al. WCGIC 2009 Expert Opinion

24. Treatment of unresectable mCRC Specific issues
Treat with biologicals until progression or toxicity, or until metastases become resectable
Continue treatment until progression with biologicals, even if one of the cytotoxic partners (oxaliplatin, irinotecan) is stopped
No clear evidence to administer biologicals beyond progression
Correlation of rash and activity after anti-EGFR antibodies has no immediate practical implications in clinical practice
Van Cutsem E, et al. WCGIC 2009 Expert Opinion

25. Stage IV Colon Cancer Group I Group II Group III Group IV
Curable Potentially Symptomatic Asymptomatic
disease curable non curable non curable
disease disease disease !
Non curable
Non curable

26. First line strategy of metastatic CRC
Dose the patient need (or desire) aggressive therapy?
Yes ~ 85%
No ~ 15%
K-RAS
5FU/Cape +/- bev
+ inh.EGFR(WT)
Unavailable WT
MUT
Doublet + bev
Doublet + bev
Doublet + EGFR inhibitors
Doublet + bevacizumab
Van Cutsem E, et al. WCGIC 2009 Expert Opinion

27. Optimal Chemotherapy for the neoadjuvant treatment of non- resectable liver metastases – Do we have to include biologics in this setting?
Conversion Therapy Considerations: Practical Management
Role of FOLFOX better established than FOLFIRI
- Better toxicity profile, more clinical data
FOLFOXIRI attractive …
Limit duration of pre-operative therapy to 3-4 months
- Don’t treat to best response, but to resectability
- Decrease hepatotoxicity
Role of biologics is evolving
- Bevacizumab is not mandatory!
- If Bevacizumab is used, d/c 6 wks before planned surgery
EGFR inhibitors could emerge as best option in K-ras wild type CRC

28. Multi-disciplinary Approach
Take-home Messages
Aggressive
Multi-disciplinary Approach

30. Thank
you!