KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience

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KRAS status and efficacy in the first-line
treatment of patients with metastatic colorectal
cancer (mCRC) treated with FOLFIRI with or
without cetuximab The CRYSTAL experience

• Authors E. Van Cutsem, I. Lang, G. D'haens, V.
  Moiseyenko, J. Zaluski, G. Folprecht, S. Tejpar,
  O. Kisker, C. Stroh, P. Rougier

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CRYSTAL Trial
10 Endpoint PFS
RANDOMI ZE
FOLFIRI Cetuximab N608
N1217 EGFR expression via IHC
FOLFIRI N609
Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2
IV weekly
11
Van Custem E Proc ASCO 2007
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ResultsEfficacy
Grade 3/4 toxicity FOLFIRI N 650 () FOLFIRI Cetuximab N 648 ()
Response Rate 39 47
Median PFS 8.0 8.9
1 yr PFS 23 34
Median OS NR NR
p0.0038
HR 0.85 (0.73-0.99) p0.048
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ResultsPatient Characteristics
ITT
Centrally assessed for KRAS mutation by QT-PCR
exon 12/13
n 540
n 1198
Wild-type KRAS (n348) Mutant KRAS (n192)
Male, 57.8 57.8
Age lt 65, 65.8 59.9
Prior adjuvant Rx, 21.6 12.5
Treatment, n () FOLFIRI FOLFIRI Cetuximab 176 (51) 172 (49) 87 (45) 105 (55)
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ResultsEfficacy
Wild-type KRAS Wild-type KRAS Mutant KRAS Mutant KRAS Mutant KRAS
FOLFIRI FOLFIRI Cetux FOLFIRI FOLFIRI FOLFIRI Cetux
Median PFS, mos 8.7 9.9 9.9 8.1 7.6
1yr PFS rate, 25 43 43 NR NR
ORR CR PR 43.2 0 43.2 59.3 1.2 58.1 59.3 1.2 58.1 40.2 0 40.2 36.2 0 36.2
SD 43.8 30.8 30.8 46.0 46.7
HR 0.68 p 0.017
HR 1.07 p 0.75
p 0.025
p 0.46
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KRAS status and efficacy in the first-line
treatment of patients with mCRC treated with
FOLFOX with or without cetuximab The OPUS
experience

• Authors C Bokemeyer, I Bondarenko, J Hartmann, F
  De Braud, C Volovat, C Stroh,J Nippgen, I Celik,
  P Koralewski

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OPUS Phase II
RANDOMI ZE
FOLFOX Cetuximab N170
N338 EGFR Metasatic CRC
FOLFOX N168
Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2
IV weekly
11
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ResultsEfficacy
FOLFOX Cetuximab FOLFOX
Response Rate 45.6 35.7
Median PFS, months 7.2 7.2
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ResultsPatient Characteristics
ITT
Centrally assessed for KRAS mutation by QT-PCR
exon 12/13
n 233
n 337
Wild-type KRAS (n134) Mutant KRAS (n99)
Male, 55.2 49.5
Age lt 65, 63.4 62.6
Prior adjuvant Rx, 18.7 17.2
Treatment, n () FOLFOX FOLFOX Cetuximab 73 (54) 61 (46) 47 (47) 52 (53)
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ResultsEfficacy
Wild-type KRAS Wild-type KRAS Mutant KRAS Mutant KRAS Mutant KRAS
FOLFOX FOLFOX Cetux FOLFOX FOLFOX FOLFOX Cetux
Median PFS, mos 7.2 7.7 7.7 8.6 5.5
1yr PFS rate, NR NR NR NR NR
ORR CR PR 37.0 1.4 35.6 60.7 3.3 57.4 60.7 3.3 57.4 48.9 4.3 44.7 32.7 0 32.7
SD 16.4 4.9 4.9 36.2 51.9
HR 0.57 p 0.016
HR 1.83 p 0.019
p 0.011
p 0.11
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ResultsToxicity

• No difference in skin rash or other toxicity by
  KRAS status in CRYSTAL or OPUS

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STUDY COMMENTARY

• Together with Panitumumab monotherapy in 3rd line
  setting (Van Custem JCO 2007) these two trials
  demonstrate that monoclonal antibody blockade
  against EGFR only benefit patients with wild-type
  KRAS
• Similar findings with EGFR TKIs in NSCLC and
  pancreatic adenoCA
• No overall survival data reported for either
  CRYSTAL or OPUS

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Bottom Line for Canadian Medical Oncologists

• Addition of Cetuximab to first line FOLFOX or
  FOLFIRI only benefits patients with wild type
  KRAS
• Biologically plausible ? mAb to receptor will not
  shut off signaling if a downstream kinase (KRAS)
  is constitutively active
• Addition of Cetuximab to first line FOLFOX in
  KRAS mutant patients appears to be detrimental
• ? Biology of this phenomenon
• Optimal sequence of biological therapy in KRAS
  wild-type patients remains to be determined
• Should obtain KRAS mutational status on all
  patients where Cetuximab is considered
• NCIC CO.17 is the only trial to demonstrate OS
  benefit with EGFR mAb
• Retrospective survival analysis by KRAS status is
  eagerly awaited