Transcript Document

Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
Eclinicaloptions.com/oncology
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)
 FOLFIRI + cetuximab
9.9
7.6
 FOLFIRI
8.7
8.1
0.68*
1.07†
 FOLFIRI + cetuximab
59.3‡
36.2
 FOLFIRI
43.2
40.2
Median PFS, mos
 HR
ORR, %
*P = .017; †P = .75; ‡P = .0025
1. Van Cutsem E, et al. ASCO 2008. Abstract 2.
Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
Eclinicaloptions.com/oncology
Idelevich, 2011
20060314
FOLFIRI + Panitumumab in 1st-line Treatment of
Metastatic CRC
Metastatic
CRC
(n=150)
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FOLFIRI (Q2W) +
panitumumab 6 mg/kg
(Q2W, on day 1 of each cycle)
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Approx. 56 days
after end of treatment

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;
www.amgentrials.com; protocol ID: 20060314. ClinicalTrials.gov identifier: NCT00508404.
Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
Eclinicaloptions.com/oncology
Idelevich, 2011
20060314
Best Objective Response
Panitumumab + FOLFIRI*
KRAS wt (n=85)
KRAS mt
(n=58)
Objective response, %
Complete response
Partial response
Stable disease
Disease progression
Unevaluable
Not done
CR + PR,%
(95% CI)
Difference, %
(95% CI)
Unadjusted common treatment odds ratio
(95% CI)
2
54
34
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2
56.5
2
36
52
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37.9
(45.3, 67.2)
(25.5, 51.6)
18.54
(0.84, 34.63)
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.
Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
E Idelevich, 2011
clinicaloptions.com/oncology
20060314
Resection Rates – Patients with Liver Only Disease
Overall resections
40
KRAS evaluable
Resection rate (%)
35
20
13
0
KRAS wt
KRAS mt
(n=11/31)
(n=2/16)
Hofheinz R, et al. ASCO 2010, #3545, poster presentation
Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
Eclinicaloptions.com/oncology
Idelevich, 2011
20060314
Progression-free Survival Primary Analysis Set
100
Proportion Event-Free (%)
90
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)
80
HR = 0.46 (95%CI: 0.31–0.70)
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40
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20
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0
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2
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7
8
Months
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.
9
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Insight Into the First-line Treatment of Metastatic Colorectal Cancer
EExpert
Idelevich,
2011
clinicaloptions.com/oncology
20060314
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
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation;
Hofheinz R, et al. J Clin Oncol 2010; 28(15S): #3545, poster presentation.
Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
Eclinicaloptions.com/oncology
Idelevich, 2011
20050181
FOLFIRI ± Panitumumab in 2nd-line Treatment of
Metastatic CRC
FOLFIRI (Q2W) +
panitumumab 6 mg/kg
(Q2W)
Metastatic
CRC
(n=1100)
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1:1
FOLFIRI
(Q2W)
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Disease assessment every 8 weeks
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;28:4706-4713;
ClinicalTrials.gov identifier: NCT00339183; www.amgentrials.com; protocol ID: 20050181.
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Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
Eclinicaloptions.com/oncology
Idelevich, 2011
20050181
Objective Response Rate (%)
Objective Response in Patients with KRAS wt
Tumours (Central Review)
40
30
35
20
10
10
0
Panitumumab
+ FOLFIRI
FOLFIRI
(n=285)
(n=297)

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;28:4706-4713.
Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
Eclinicaloptions.com/oncology
Idelevich, 2011
20050181
Panitumumab Improved Median PFS by 51% in
Patients with KRAS wt Tumours
Events
Progression-Free Probability
1.0
n (%)
Median
(95% CI) months
0.9
Panitumumab +
FOLFIRI (n=303)___
178 (59)
5.9 (5.5–6.7)
0.8
FOLFIRI (n=294)___
203 (69)
3.9 (3.7–5.3)
 2.0
0.7
HR = 0.73 (95%CI: 0.59–0.90)
0.6
p = 0.004
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
Months
Peeters M, et al. J Clin Oncol 2010;28:4706-4713.
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Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
Eclinicaloptions.com/oncology
Idelevich, 2011
20050181
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;28:4706-4713.
Peeters M, et al. ASCO-GI 2010, #282, oral presentation
Metastatic colon cancer patients (100%)
Non - resectable 75%
63%
Non curable
Potentially
Down-sizable
Resectable 25%
12%
Paul Brousse Experience - 1439 Patients
(1988–1999)
Adam R et al Ann Surg. 2004;240:644-658
Treatment of Metastatic CRC
1980
1985
1990
1995
2000
2005
RR %
MS
Months
5Fu
Capecitabine
Irinotecan
Oxaliplatin
EGFR inhibitors
Bevacizumab
20-25
13
40- 50
20-22
~ 60
> 24
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), 2037-2045)
Response rates: recent phase 3 trials
Regimen
Response Rate
Reference
_________________________________________________________________________
FOLFOX
36%
NS;
FOFOX+cetuximab
46%
(OPUS, Bokemeyer)
_____________________________________________________________________________________
FOLFIRI
43%
p=0.004;
FOLFIRI+cetuximab
59%
(CRYSTAL,van Cutsem)
______________________________________________________________________________________
FOLFOX
38%
NS;
FOLFOX+bevacizzumab
38%
(XELOX-1/NO16966 Saltz)
______________________________________________________________________________________
FOLFOX
47%
NS; p=0.06
FOLFOX+panitumumab
55
(PRIME, J-Y Douillard)
______________________________________________________________________________________
FOLFIRI
36%
FOLFOXIRI
60%
p=0.001;
(Falcone)
______________________________________________________________________________________
FOLFOX+bevacizumab
41%
NS;
FOLFOX+bevacizumab+cetuximab
39%
(PACCE; Hecht)
______________________________________________________________________________________
CAPOX+bevacizumab
44%
NS;
CAPOX+becizumab+cetuximab
44%
(CAIRO2; Punt)
______________________________________________________________________________________
Standard Doublets ~ 40% Response Rate (RR)
Response rates: recent phase 3 trials
Regimen
Response Rate
Reference
______________________________________________________________________________________
FOLFOX
36%
NS;
FOFOX+cetuximab
46%
(OPUS, Bokemeyer)
______________________________________________________________________________________
FOLFIRI
43%
p=0.004;
FOLFIRI+cetuximab
59%
(CRYSTAL,van Cutsem)
______________________________________________________________________________________
FOLFOX
38%
NS;
FOLFOX+bevacizzumab
38%
(XELOX-1/NO16966 Saltz)
______________________________________________________________________________________
FOLFOX
47%
NS; p=0.06
FOLFOX+panitumumab
55%
(PRIME, J-Y Douillard)
______________________________________________________________________________________
FOLFIRI
36%
FOLFOXIRI
60%
p=0.001;
(Falcone)
______________________________________________________________________________________
FOLFOX+bevacizumab
41%
NS;
FOLFOX+bevacizumab+cetuximab
39%
(PACCE; Hecht)
______________________________________________________________________________________
CAPOX+bevacizumab
44%
NS;
CAPOX+becizumab+cetuximab
44%
(CAIRO2; Punt)
______________________________________________________________________________________
Adding EGFR inhibitors or using triplet chemotherapy increases RR
Response rates: recent phase 3 trials
Regimen
Response Rate
Reference
_____________________________________________________________________________________
FOLFOX
36%
NS;
FOFOX+cetuximab
46%
(OPUS, Bokemeyer)
_____________________________________________________________________________________
FOLFIRI
43%
p=0.004;
FOLFIRI+cetuximab
59%
(CRYSTAL,van Cutsem)
______________________________________________________________________________________
FOLFOX
38%
NS;
FOLFOX+bevacizzumab
38%
(XELOX-1/NO16966 Saltz)
______________________________________________________________________________________
FOLFOX
47%
NS; p=0.06
FOLFOX+panitumumab
55%
(PRIME, J-Y Douillard)
______________________________________________________________________________________
FOLFIRI
36%
FOLFOXIRI
60%
p=0.001;
(Falcone)
______________________________________________________________________________________
FOLFOX+bevacizumab
41%
NS;
FOLFOX+bevacizumab+cetuximab
39%
(PACCE; Hecht)
______________________________________________________________________________________
CAPOX+bevacizumab
44%
CAPOX+becizumab+cetuximab
44%
NS;
(CAIRO2; Punt)
______________________________________________________________________________________
Bevacizumab does not increase Response Rate (RR)
Kras-dependent RR in First-Line Trials
RR (K-ras w.t.)
RR (K-ras mut)
__________________________________________________________________
OPUS (Bokemeyer)
FOLFOX
37%
49%
FOLFOX+erbitux
61%
33%
__________________________________________________________________
CRYSTAL (van Cutsem)
FOLFIRI
43%
40%
FOLFIRI+erbitux
59%
38%
__________________________________________________________________
PRIME (J-Y Douillard)
FOLFOX
47%
40%
FOLFOX+vectibix
55%
40%
__________________________________________________________________
20060314 (Köhne CH)
FOLFIRI+vectibix
56,5%
37.9%
__________________________________________________________________
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
What is the optimal chemotherapy for the
neoadjuvant treatment of unresectable liver
metastases?
• 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
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
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
Stage IV Colon Cancer
Group I
Curable
disease
!
Group II
Group III
Group IV
Potentially
curable
disease
Symptomatic
non curable
disease
Asymptomatic
non curable
disease
Non curable
Non curable
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
Doublet + bev
WT
Doublet + EGFR inhibitors
Doublet + bevacizumab
MUT
Doublet + bev
Van Cutsem E, et al. WCGIC 2009 Expert Opinion
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
Take-home Messages
Aggressive
Multi-disciplinary
Approach
Thank
you!