Download FOLFOX ± Cetuximab

Biomarkers in Colorectal Cancer
Management:
KRAS Mutations and EGFR Inhibitors
Mace L. Rothenberg, M.D.
Professor of Medicine
Ingram Professor of Cancer Research
Conflict of Interest Disclosure
Consultant or Advisory Role
Antigenics
OSI
Array BioPharma
Pfizer
Bristol Myers-Squibb
Roche
Genentech
sanofi-aventis
Idera
Synta
ImClone
Takeda
Johnson & Johnson
Zymogenetics
Novacea
Stock Ownership
Synta
Targeted Therapeutics
Biomarkers in CRC Management
What is a biomarker?
A specific, measurable, physical trait that
can be used as a surrogate for a process
of interest
The trait can be a physical finding, a drug
level, activation status of a molecule, or
imaging characteristic
The process that it reflects should be
clinically meaningful: tumor presence or
absence, response to therapy,
development of toxicity, etc.
Biomarkers in CRC Management
Definitions
Prognostic Factor
A measurement or characteristic present at the
time of diagnosis that correlates with clinical
outcome regardless of treatment
Predictive Factor
A measurement or characteristic present at the
time of diagnosis or initiation of treatment that
is associated with likelihood of response to
therapy
Biomarkers in CRC Management
Relationship of efficacy with KRAS status in
patients with irinotecan-refractory mCRC treated
with irinotecan and escalating doses of
cetuximab – the EVEREST experience
S Tejpar, M Peeters, Y Humblet, JB Vermorken, G De Hertogh,
W. De Roock, J. Nippgen, A. von Heydebreck, C. Stroh, E. Van
Cutsem
KRAS status and Outcome in CRC Patients Treated
with Irinotecan and Standard or Escalating-Doses of
Cetuximab: EVEREST
Key Findings
• Escalating cetuximab dose until Grade 2+ skin toxicity occurs results
in higher RR (30% vs 16%) – but not PFS (median 4.8 vs 3.9 months) or
OS (median 8.6 vs 10.0 months) than with standard doses
S Tejpar et al: ASCO 2007, Abst. 4037
• Association of skin rash with PFS was present in KRAS wt and
mutant subsets (but stronger in KRAS wt)
• There was a non-significant trend towards higher RR in the
cetuximab dose escalation arm only in KRAS wt patients (42% vs 30%).
• No responses were seen in KRAS mutant patients, regardless of
cetuximab dose. In fact, the rate of SD patients in the dose escalation
arm was lower than the standard arm (33% vs 45%)
KRAS status and Outcome in CRC Patients Treated
with Irinotecan and Standard or Escalating-Doses of
Cetuximab: EVEREST
Conclusions
• Patients with KRAS wt tumors benefited from irinotecan +
cetuximab treatment
Agree
• In the dose escalation arm, a trend towards increased
responses was observed in patients with KRAS wild-type
tumors
Yes, but the 39% relative improvement in RR was
not matched by the 14% improvement in PFS
• Dose escalation did not improve the efficacy in KRAS
mutant tumors
Agree
KRAS status and Outcome in CRC Patients Treated
with Irinotecan and Standard or Escalating-Doses of
Cetuximab: EVEREST
Conclusions
• Skin toxicity and KRAS status are independent predictors
of outcome
Yes, but KRAS was the much stronger of the two
• Predictive markers that act independently of KRAS were
identified
But these will only help us if we understand their
biological significance
Biomarkers in CRC Management
K-Ras status and efficacy of 1st-line treatment of
patients with mCRC with FOLFOX ± cetuximab:
OPUS experience
C. Bokemeyer, I. Bondarenko, J. T. Hartmann, F. G. De Braud,
C. Volovat, J. Nippgen, C. Stroh, I. Celik, P. Koralewski
Abstract #4000
KRAS status and 1st-line FOLFOX ± cetuximab:
OPUS
Key Findings
• In unselected patients, the addition of cetuximab
to FOLFOX improves RR but not PFS
FOLFOX ± Cetuximab
RR in KRAS wild-type
70
61
Response rate (%)
60
24% absolute 
65% relative 
50
40
37
30
20
10
0
FOLFOX
Cetuximab + FOLFOX
KRAS wt
FOLFOX ± Cetuximab
PFS in KRAS wild-type
1.0
Progression HR = 0.57 for
FOLFOX + cetuximab
0.9
Kaplan-Meier Estimate
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
Progression-free time (months)
Cetuximab + FOLFOX
FOLFOX
FOLFOX ± Cetuximab
RR in KRAS mutant
60
Response rate (%)
50
49
40
16% absolute 
33% relative 
33
30
20
10
0
FOLFOX
Cetuximab + FOLFOX
KRAS mt
FOLFOX ± Cetuximab
PFS in KRAS mutant
1.0
Progression HR = 1.83 for
FOLFOX + cetuximab
0.9
Kaplan-Meier Estimate
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
Progression-free time (months)
Cetuximab + FOLFOX
FOLFOX
KRAS status and 1st-line FOLFOX ± cetuximab:
OPUS
60
70
61
50
Response rate (%)
Response rate (%)
60
50
40
12% absolute 
32% relative 
37
30
20
40
20
10
0
0
Cetuximab + FOLFOX
KRAS wt
33
30
10
FOLFOX
49
FOLFOX
Cetuximab + FOLFOX
KRAS mt
KRAS status and 1st-line FOLFOX ± cetuximab:
OPUS
60
70
61
50
Response rate (%)
Response rate (%)
60
50
40
37
30
20
40
33
20
10
0
0
Cetuximab + FOLFOX
KRAS wt
28% absolute 
46% relative 
30
10
FOLFOX
49
FOLFOX
Cetuximab + FOLFOX
KRAS mt
KRAS status and 1st-line FOLFOX ± cetuximab:
OPUS
Toxicity and Tolerability
• Patients treated with FOLFOX + cetuximab received
roughly the same chemotherapy doses and dose intensity as
those treated with FOLFOX alone
But …
• There was a difference in patterns of toxicity based on
KRAS status:
• Patients with KRAS wt tumors treated with FOLFOX +
cetuximab tended to have a higher rate of Grade 3/4
hematological and GI toxicities than those treated with
FOLFOX alone
• Patients with KRAS mutant tumors treated with
FOLFOX + cetuximab had lower rates of these toxicities
KRAS status and 1st-line FOLFOX ± cetuximab:
OPUS
Conclusions
• Addition of cetuximab to 1st-line FOLFOX  RR and PFS in
patients with KRAS wt tumors
Agree
• Patients with KRAS mutant tumors do not profit from the
addition of cetuximab
Agree but …
• Is it possible that patients with KRAS mutant tumors
are harmed by the addition of cetuximab to FOLFOX?
• Trend towards lower RR and shorter PFS when
compared to those treated with FOLFOX alone is of
concern.
KRAS status and 1st-line FOLFOX ± cetuximab:
OPUS
Questions and Concerns - 1
• Is this effect limited to FOLFOX or is it seen
with other regimens like FOLFIRI
• See Van Cutsem - CRYSTAL presentation (Abst #2)
– Sunday, June 1 and Cervantes poster (Abst #4129),
Monday, June 2
• Is this effect limited to cetuximab or is it also
observed with panitumumb?
• See Cohn PRECEPT poster (Abst #4127) – Monday,
June 2
KRAS status and 1st-line FOLFOX ± cetuximab:
OPUS
Questions and Concerns - 2
• Is this effect limited to 1st-line therapies or is it
seen in all lines of therapy?
• See Di Fiore poster discussion (Abst #4035) –
Sunday, June 1
• Is this effect seen with EGFR mAbs when
used as a single agent?
• Apparently not (Amado – J Clin Oncol – 2008)
These findings will determine whether KRAS status
should be established prior to the use of EGFR mAbs
in patients with mCRC
Possible Mechanisms for Resistance of
KRAS Mutated Tumors to EGFR Inhibitors
• Ras-induced up-regulation of VEGF
Zachary & Gliki: Cardiovasc Res 49:568-581, 2001
• Activation of Ras   terminal differentiation and 
tumor stem cell population
KM Haigis et al: Nature Genetics 40:600-608, 2008
• K-Ras mutation   DNA methylation   expression
of tumor suppressor and apoptotic genes
SK Patra: Exp Cell Res 314:1193-1201, 2008
• KRAS mutation   expression or activity of DNA
repair genes
Pure speculation