mace l. rothenberg, m.d
DESCRIPTION
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. Stock Ownership. Biomarkers in CRC Management. - PowerPoint PPT PresentationTRANSCRIPT
Mace L. Rothenberg, M.D.
Professor of MedicineIngram Professor of Cancer Research
Biomarkers in Colorectal Cancer Management:
KRAS Mutations and EGFR Inhibitors
Conflict of Interest DisclosureConsultant or Advisory Role
Antigenics OSI
Array BioPharma Pfizer
Bristol Myers-Squibb Roche
Genentech sanofi-aventis
Idera Synta
ImClone Takeda
Johnson & Johnson Zymogenetics
Novacea
Stock OwnershipSynta Targeted Therapeutics
Biomarkers in CRC Management
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.
What is a biomarker?
Prognostic FactorA measurement or characteristic present at the
time of diagnosis that correlates with clinical outcome regardless of treatment
Predictive FactorA measurement or characteristic present at the
time of diagnosis or initiation of treatment that is associated with likelihood of response to therapy
Definitions
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
Biomarkers in CRC Management
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: EVERESTKey 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%)
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
KRAS status and Outcome in CRC Patients Treated with Irinotecan and Standard or Escalating-Doses of
Cetuximab: EVEREST
• Dose escalation did not improve the efficacy in KRAS mutant tumors
Agree
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
KRAS status and Outcome in CRC Patients Treated with Irinotecan and Standard or Escalating-Doses of
Cetuximab: EVEREST
C. Bokemeyer, I. Bondarenko, J. T. Hartmann, F. G. De Braud,
C. Volovat, J. Nippgen, C. Stroh, I. Celik, P. Koralewski
K-Ras status and efficacy of 1st-line treatment of patients with mCRC with FOLFOX ± cetuximab:
OPUS experience
Biomarkers in CRC Management
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
37
61
0
10
20
30
40
50
60
70
Res
po
nse
rat
e (%
)
Cetuximab + FOLFOXFOLFOX
KRAS wt
24% absolute 65% relative
FOLFOX ± CetuximabRR in KRAS wild-type
Kap
lan
-Mei
er
Est
ima
te
0.5
1.0
0.4
0.3
0.2
0.1
0.0
0.6
0.7
0.8
0.9
80 2 4 6 10 12
Progression-free time (months)
FOLFOX ± Cetuximab
FOLFOX
Cetuximab + FOLFOX
PFS in KRAS wild-type
Progression HR = 0.57 for FOLFOX + cetuximab
49
33
0
10
20
30
40
50
60
Res
po
nse
rat
e (%
)
FOLFOX Cetuximab + FOLFOX
KRAS mt
16% absolute 33% relative
FOLFOX ± CetuximabRR in KRAS mutant
Kap
lan
-Mei
er
Est
ima
te
0.5
1.0
0.4
0.3
0.2
0.1
0.0
0.6
0.7
0.8
0.9
80 2 4 6 10 12
Progression-free time (months)
FOLFOX
Cetuximab + FOLFOX
FOLFOX ± CetuximabPFS in KRAS mutant
Progression HR = 1.83 for FOLFOX + cetuximab
37
61
0
10
20
30
40
50
60
70
Res
po
nse
rat
e (%
)
Cetuximab + FOLFOXFOLFOX
49
33
0
10
20
30
40
50
60
Res
po
nse
rat
e (%
)
FOLFOX Cetuximab + FOLFOX
KRAS mtKRAS wt
KRAS status and 1st-line FOLFOX ± cetuximab: OPUS
12% absolute 32% relative
37
61
0
10
20
30
40
50
60
70
Res
po
nse
rat
e (%
)
Cetuximab + FOLFOXFOLFOX
49
33
0
10
20
30
40
50
60
Res
po
nse
rat
e (%
)
FOLFOX Cetuximab + FOLFOX
KRAS mtKRAS wt
KRAS status and 1st-line FOLFOX ± cetuximab: OPUS
28% absolute 46% relative
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