KRAS Status in Response to Cetuximab

1
KRAS Status in Response to Cetuximab
E Idelevich, 2011

• Retrospective analysis of CRYSTAL1
• 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,
FOLFIRI cetuximab 59.3 36.2
FOLFIRI 43.2 40.2
P .017 P .75 P .0025
1. Van Cutsem E, et al. ASCO 2008. Abstract 2.
2
20060314FOLFIRI Panitumumab in 1st-line
Treatment of Metastatic CRC
E Idelevich, 2011
Endoftreatment
S a f e t y f ollowup
Endofs t u d y
S c r e e n I n g
E n r o l l m e n t
FOLFIRI (Q2W) panitumumab 6 mg/kg(Q2W, on day
1 of each cycle)
Metastatic CRC (n150)
Approx. 56 daysafter 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.
3
20060314Best Objective Response
E Idelevich, 2011
Panitumumab FOLFIRI Panitumumab FOLFIRI
KRAS wt (n85) KRAS mt (n58)
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) 18.54(0.84, 34.63)
Unadjusted common treatment odds ratio(95 CI) 2.12 (1.02, 4.45) 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. Two patients did not have measurable disease per RECIST guidelines at baseline and were therefore not included in the analysis of response rate. 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.
4
Resection Rates Patients with Liver Only Disease
E Idelevich, 2011
20060314
Overall resections
40
KRAS evaluable
35
Resection rate ()
20
13
0
KRAS wt (n11/31)
KRAS mt (n2/16)
Hofheinz R, et al. ASCO 2010, 3545, poster
presentation
5
20060314Progression-free Survival Primary
Analysis Set
E Idelevich, 2011
Eventsn () Median (95 CI) months
KRAS wt (n86)______ 44 (51) 8.9 (7.614.3)
KRAS mt (n59)______ 48 (81) 7.2 (5.67.8)
HR 0.46 (95CI 0.310.70)
Proportion Event-Free ()
0
1
2
3
4
5
6
7
8
9
12
10
11
16
13
14
15
Months
Köhne CH, et al. ASCO-GI 2010, 414, poster
presentation.
6
20060314Summary
E Idelevich, 2011

• 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 (56.5vs
  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.
7
20050181FOLFIRI Panitumumab in 2nd-line
Treatment of Metastatic CRC
E Idelevich, 2011
Longterm f ollowup
Endoftreatment
FOLFIRI (Q2W) panitumumab 6 mg/kg(Q2W)
Metastatic CRC (n1100)
R
FOLFIRI (Q2W)
11
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 2010284706-4713ClinicalTrials.gov
identifier NCT00339183 www.amgentrials.com
protocol ID 20050181.
8
20050181Objective Response in Patients with KRAS
wt Tumours (Central Review)
E Idelevich, 2011
40
30
35
Objective Response Rate ()
20
10
10
0
Panitumumab FOLFIRI(n297)
FOLFIRI(n285)

• More than 3x as many patients responded to
  panitumumab

p lt 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 2010284706-4713.
9
20050181Panitumumab Improved Median PFS by 51
in Patients with KRAS wt Tumours
E Idelevich, 2011
Eventsn () Median (95 CI) months
Panitumumab FOLFIRI (n303)___ 178 (59) 5.9 (5.56.7)
FOLFIRI (n294)___ 203 (69) 3.9 (3.75.3)
? 2.0
1.0
0.9
0.8
0.7
HR 0.73 (95CI 0.590.90) p 0.004
0.6
Progression-Free Probability
0.5
0.4
0.3
0.2
0.1
0.0
Months
Peeters M, et al. J Clin Oncol 2010284706-4713.
10
20050181Summary
E Idelevich, 2011

• 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 2010284706-4713.
Peeters M, et al. ASCO-GI 2010, 282, oral
presentation
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Metastatic colon cancer patients (100)
12
Paul Brousse Experience - 1439 Patients
(19881999)
Adam R et al Ann Surg. 2004240644-658
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Treatment of Metastatic CRC

• 1980 1985 1990 1995 2000 2005
  RR MS

Months
5Fu
20-25
13
Capecitabine
Irinotecan
40- 50
20-22
Oxaliplatin
EGFR inhibitors
60
gt 24
Bevacizumab
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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)

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Response rates recent phase 3 trials

• Regimen Response
  Rate Reference
• __________________________________________________
  _______________________
• FOLFOX
  36 NS
• FOFOXcetuximab 46
  (OPUS,
  Bokemeyer)
• __________________________________________________
  ___________________________________
• FOLFIRI
  43
  p0.004
• FOLFIRIcetuximab
  59
  (CRYSTAL,van Cutsem)
• __________________________________________________
  ____________________________________
• FOLFOX
  38 NS
• FOLFOXbevacizzumab 38
  (XELOX-1/NO16966
  Saltz)
• __________________________________________________
  ____________________________________
• FOLFOX
  47 NS
  p0.06
• FOLFOXpanitumumab 55
  (PRIME, J-Y
  Douillard)
• __________________________________________________
  ____________________________________
• FOLFIRI
  36
  p0.001
• FOLFOXIRI
  60
  (Falcone)
• __________________________________________________
  ____________________________________
• FOLFOXbevacizumab 41
  NS
• FOLFOXbevacizumabcetuximab 39
  (PACCE Hecht)

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Response rates recent phase 3 trials

• Regimen Response
  Rate Reference
• __________________________________________________
  ____________________________________
• FOLFOX
  36 NS
• FOFOXcetuximab 46
  (OPUS,
  Bokemeyer)
• __________________________________________________
  ____________________________________
• FOLFIRI
  43
  p0.004
• FOLFIRIcetuximab
  59
  (CRYSTAL,van Cutsem)
• __________________________________________________
  ____________________________________
• FOLFOX
  38 NS
• FOLFOXbevacizzumab 38
  (XELOX-1/NO16966
  Saltz)
• __________________________________________________
  ____________________________________
• FOLFOX
  47 NS
  p0.06
• FOLFOXpanitumumab 55
  (PRIME, J-Y
  Douillard)
• __________________________________________________
  ____________________________________
• FOLFIRI
  36
  p0.001
• FOLFOXIRI
  60
  (Falcone)
• __________________________________________________
  ____________________________________
• FOLFOXbevacizumab 41
  NS
• FOLFOXbevacizumabcetuximab 39
  (PACCE Hecht)

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Response rates recent phase 3 trials

• Regimen Response
  Rate Reference
• __________________________________________________
  ___________________________________
• FOLFOX
  36 NS
• FOFOXcetuximab 46
  (OPUS,
  Bokemeyer)
• __________________________________________________
  ___________________________________
• FOLFIRI
  43
  p0.004
• FOLFIRIcetuximab
  59
  (CRYSTAL,van Cutsem)
• __________________________________________________
  ____________________________________
• FOLFOX
  38 NS
• FOLFOXbevacizzumab 38
  (XELOX-1/NO16966
  Saltz)
• __________________________________________________
  ____________________________________
• FOLFOX
  47 NS
  p0.06
• FOLFOXpanitumumab 55
  (PRIME, J-Y
  Douillard)
• __________________________________________________
  ____________________________________
• FOLFIRI
  36
  p0.001
• FOLFOXIRI
  60
  (Falcone)
• __________________________________________________
  ____________________________________
• FOLFOXbevacizumab 41
  NS
• FOLFOXbevacizumabcetuximab 39
  (PACCE Hecht)

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Kras-dependent RR in First-Line Trials

• RR (K-ras
  w.t.) RR (K-ras mut)
• __________________________________________________
  ________________
• OPUS (Bokemeyer)
• FOLFOX 37
  49
• FOLFOXerbitux 61
  33
• __________________________________________________
  ________________
• CRYSTAL (van Cutsem)
• FOLFIRI 43
  40
• FOLFIRIerbitux 59
  38
• __________________________________________________
  ________________
• PRIME (J-Y Douillard)
• FOLFOX 47
  40
• FOLFOXvectibix 55
  40
• __________________________________________________
  ________________
• 20060314 (Köhne CH)
• FOLFIRIvectibix 56,5
  37.9
• __________________________________________________
  ________________

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Response Rate

• In K-ras wild type patients
• - FOLFOX or FOLFIRIEGFR inhibitors has shown
• 55- 60 response rate
• FOLFOXIRI
• - 60 response rate in small phase 3 trial

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

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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, CTcetuximab
• -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
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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
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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

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First line strategy of metastatic CRC

• Dose the patient need (or desire) aggressive
  therapy?

No 15
Yes 85
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
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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
• - Dont 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

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Take-home Messages

• Aggressive
• Multi-disciplinary Approach

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