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clinicaloptions.com/oncologyExpert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
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
1. Van Cutsem E, et al. ASCO 2008. Abstract 2.
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, %
FOLFIRI + cetuximab 59.3‡ 36.2
FOLFIRI 43.2 40.2
*P = .017; †P = .75; ‡P = .0025
E Idelevich, 2011
clinicaloptions.com/oncologyExpert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
20060314FOLFIRI + Panitumumab in 1st-line Treatment of Metastatic CRC
Approx. 56 daysafter end of treatment
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation;www.amgentrials.com; protocol ID: 20060314. ClinicalTrials.gov identifier: NCT00508404.
Study objectives: To estimate the effect of KRAS mutation status on efficacy and to describe the safety profile
Study endpoints: ORR (1°); PFS, Safety
FOLFIRI (Q2W) +panitumumab 6 mg/kg(Q2W, on day 1 of each cycle)
Metastatic CRC
(n=150)
End
of
treat
ment
Safety follow
up
End
of
study
ScreenIng
Enroll
ment
E Idelevich, 2011
clinicaloptions.com/oncologyExpert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
20060314Best Objective Response
Panitumumab + FOLFIRI*
KRAS wt (n=85) KRAS mt (n=58)
Objective response, % Complete response 2 2 Partial response 54 36 Stable disease 34 52 Disease progression 7 7 Unevaluable 0 2 Not done 2 2
CR + PR,% (95% CI)
56.5(45.3, 67.2)
37.9(25.5, 51.6)
Difference, % (95% CI)
18.54(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.
E Idelevich, 2011
clinicaloptions.com/oncologyExpert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
Resection Rates – Patients with Liver Only Disease
0
20
40
KRAS wt(n=11/31)
KRAS mt(n=2/16)
35
Res
ecti
on r
ate
(%)
13
Overall resections
Hofheinz R, et al. ASCO 2010, #3545, poster presentation
KRAS evaluable
20060314E Idelevich, 2011
clinicaloptions.com/oncologyExpert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
20060314Progression-free Survival Primary Analysis Set
Pro
por
tion
Eve
nt-F
ree
(%)
100
90
70
60
80
50
40
30
20
10
00 1 2 3 4 5 6 7 8 9 1210 11 1613 14 15
Eventsn (%)
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)
HR = 0.46 (95%CI: 0.31–0.70)
Months
Köhne CH, et al. ASCO-GI 2010, #414, poster presentation.
E Idelevich, 2011
clinicaloptions.com/oncologyExpert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
20060314SummaryThis 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.
E Idelevich, 2011
clinicaloptions.com/oncologyExpert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
20050181FOLFIRI ± Panitumumab in 2nd-line Treatment of Metastatic CRC
PRO, patient-reported outcomesPeeters M, et al. J Clin Oncol 2010;28:4706-4713;ClinicalTrials.gov identifier: NCT00339183; www.amgentrials.com; protocol ID: 20050181.
Metastatic CRC
(n=1100)R
1:1
Stratification by:• ECOG score: 0-1 vs. 2• Prior oxaliplatin exposure for mCRC• Prior bevacizumab exposure for mCRC
End
of
treat
ment
Long
term follow
up
Disease assessment every 8 weeksDisease assessment every 8 weeks
Study endpoints: PFS/OS (co-1°); ORR, Safety, PRO
FOLFIRI (Q2W) +panitumumab 6 mg/kg
(Q2W)
FOLFIRI (Q2W)
E Idelevich, 2011
clinicaloptions.com/oncologyExpert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
20050181Objective Response in Patients with KRAS wt Tumours (Central Review)
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.
0
10
20
30
40
Panitumumab+ FOLFIRI
(n=297)
FOLFIRI(n=285)
Ob
ject
ive
Res
po
nse
Rat
e (%
)
35
10
More than 3x as many patients responded to panitumumab
E Idelevich, 2011
clinicaloptions.com/oncologyExpert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
20050181Panitumumab Improved Median PFS by 51% in Patients with KRAS wt Tumours
20181614121086420
Pro
gre
ssio
n-F
ree
Pro
bab
ility
1.0
0.9
0.7
0.6
0.8
0.5
0.4
0.3
0.2
0.1
0.0
Months
Eventsn (%)
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
HR = 0.73 (95%CI: 0.59–0.90)
p = 0.004
Peeters M, et al. J Clin Oncol 2010;28:4706-4713.
E Idelevich, 2011
clinicaloptions.com/oncologyExpert Insight Into the First-line Treatment of Metastatic Colorectal Cancer
20050181Summary 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
E Idelevich, 2011
Metastatic colon cancer patients (100%)
Non curable PotentiallyDown-sizable
12%63%
Non - resectable 75% Resectable 25%
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
5Fu
Capecitabine
20-25 13
Irinotecan
Oxaliplatin
EGFR inhibitors
Bevacizumab
40 -50 20-22
~60 >24
Months
Endpoints for assessment of systemic therapy for potentially resectablepotentially 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 trialsRegimen 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% p=0.001;
FOLFOXIRI 60% (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 trialsRegimen 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% p=0.001;
FOLFOXIRI 60% (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 trialsRegimen 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% p=0.001;
FOLFOXIRI 60% (Falcone)
______________________________________________________________________________________
FOLFOX+bevacizumab 41% NS;
FOLFOX+bevacizumab+cetuximab 39% (PACCE; Hecht)
______________________________________________________________________________________
CAPOX+bevacizumab 44% NS;
CAPOX+becizumab+cetuximab 44% (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)RR (K-ras w.t.) RR (K-ras mut)____________________________________________________________________________________________________________________________________OPUS OPUS (Bokemeyer)
FOLFOX 37% 49%FOLFOX+erbitux 61% 33%__________________________________________________________________CRYSTALCRYSTAL (van Cutsem)FOLFIRI 43% 40%FOLFIRI+erbitux 59% 38% 38%____________________________________________________________________________________________________________________________________
PRIMEPRIME (J-Y Douillard)FOLFOX 47% 40%FOLFOX+vectibix 55% 40%__________________________________________________________________2006031420060314 (Köhne CH)FOLFIRI+vectibix 56,5% 37.9%__________________________________________________________________
Response Rate
• In K-ras In K-ras wild typewild type patients 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 CancerStage IV Colon CancerGroup I Group II Group III Group IVGroup I Group II Group III Group IV
Curable Curable Potentially Symptomatic Asymptomatic Potentially Symptomatic Asymptomatic
disease disease curablecurable non curablenon curable non curablenon curable
disease disease diseasedisease disease disease
!
Non curable Non curable
First line strategy of metastatic CRC
Dose the patient need (or desire) aggressive therapy?
Van Cutsem E, et al. WCGIC 2009 Expert Opinion
Yes ~ 85% No ~ 15%
5FU/Cape +/- bev K-RAS
Unavailable WT MUT
Doublet + bev Doublet + EGFR inhibitors Doublet + bevacizumab
Doublet + bev
+ inh.EGFR(WT))
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
Aggressive Multi-disciplinary
Approach
Take-home Messages
Thank you!