Biomarkers in Colorectal Cancer Management:
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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.

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Mace l rothenberg m d

Biomarkers in Colorectal Cancer Management:

KRAS Mutations and EGFR Inhibitors

Mace L. Rothenberg, M.D.

Professor of Medicine

Ingram Professor of Cancer Research


Mace l rothenberg m d

Conflict of Interest Disclosure

Consultant or Advisory Role

Stock Ownership


Biomarkers in crc management

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.


Mace l rothenberg m d

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


Mace l rothenberg m d

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


Mace l rothenberg m d

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%)


Mace l rothenberg m d

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


Mace l rothenberg m d

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


Mace l rothenberg m d

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


Mace l rothenberg m d

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

Key Findings

  • In unselected patients, the addition of cetuximab to FOLFOX improves RR but not PFS


Mace l rothenberg m d

FOLFOX ± Cetuximab

RR in KRAS wild-type

70

24% absolute 

65% relative 

61

60

50

37

40

Response rate (%)

30

20

10

0

FOLFOX

Cetuximab + FOLFOX

KRAS wt


Mace l rothenberg m d

FOLFOX ± Cetuximab

PFS in KRAS wild-type

1.0

Progression HR = 0.57 for FOLFOX + cetuximab

0.9

0.8

0.7

0.6

Kaplan-MeierEstimate

0.5

0.4

0.3

0.2

0.1

0.0

12

4

6

8

10

0

2

Progression-free time (months)

Cetuximab + FOLFOX

FOLFOX


Mace l rothenberg m d

FOLFOX ± Cetuximab

RR in KRAS mutant

60

16% absolute 

33% relative 

49

50

40

33

Response rate (%)

30

20

10

0

FOLFOX

Cetuximab + FOLFOX

KRAS mt


Mace l rothenberg m d

FOLFOX ± Cetuximab

PFS in KRAS mutant

1.0

Progression HR = 1.83 for FOLFOX + cetuximab

0.9

0.8

0.7

0.6

Kaplan-MeierEstimate

0.5

0.4

0.3

0.2

0.1

0.0

12

4

6

8

10

0

2

Progression-free time (months)

Cetuximab + FOLFOX

FOLFOX


Mace l rothenberg m d

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

12% absolute 

32% relative 

60

70

61

49

60

50

50

40

33

37

40

Response rate (%)

Response rate (%)

30

30

20

20

10

10

0

0

FOLFOX

Cetuximab + FOLFOX

FOLFOX

Cetuximab + FOLFOX

KRAS wt

KRAS mt


Mace l rothenberg m d

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

60

70

28% absolute 

46% relative 

61

49

60

50

50

40

33

37

40

Response rate (%)

Response rate (%)

30

30

20

20

10

10

0

0

FOLFOX

Cetuximab + FOLFOX

FOLFOX

Cetuximab + FOLFOX

KRAS wt

KRAS mt


Mace l rothenberg m d

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


Mace l rothenberg m d

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.


Mace l rothenberg m d

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


Mace l rothenberg m d

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


Mace l rothenberg m d

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


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