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

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Cetuximab + FOLFOXFOLFOX

KRAS wt

24% absolute 65% relative

FOLFOX ± CetuximabRR in KRAS wild-type

Kap

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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

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33

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FOLFOX Cetuximab + FOLFOX

KRAS mt

16% absolute 33% relative

FOLFOX ± CetuximabRR in KRAS mutant

Kap

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Est

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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

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Cetuximab + FOLFOXFOLFOX

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FOLFOX Cetuximab + FOLFOX

KRAS mtKRAS wt

KRAS status and 1st-line FOLFOX ± cetuximab: OPUS

12% absolute 32% relative

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Cetuximab + FOLFOXFOLFOX

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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