What is new beyond kras and any markers for anti vegf
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What is New: Beyond Kras and any Markers for Anti VEGF? . Heinz-Josef Lenz Associate Director, Clinical Research Kathryn Balakrishnan Chair for Cancer Research Co-Director, USC Center for Molecular Pathways and Drug Discovery Co-Leader GI Oncology Program

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What is New: Beyond Kras and any Markers for Anti VEGF?

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What is new beyond kras and any markers for anti vegf

What is New:Beyond Kras and any Markers for Anti VEGF?

Heinz-Josef Lenz

Associate Director, Clinical Research

Kathryn Balakrishnan Chair for Cancer Research

Co-Director, USC Center for Molecular Pathways and Drug Discovery

Co-Leader GI Oncology Program

USC/Norris Comprehensive Cancer Center


Little new biomarker data new understandings developing new paradigms

Little New Biomarker Data New Understandings Developing New Paradigms

  • EGFR Ligands

  • Angiogenesis/Ethnicity

  • Stem Cell/Tumor Dormancy

  • Acquired vs Inherited resistance

  • Integrated System Biology


Amphiregulin and epiregulin patient response to cetuximab

Amphiregulin and epiregulin: Patient response to cetuximab

Khambata-Ford S, et al. J Clin Oncol 2007;25:3230–3237;Tabernero J & Macarulla T. J Clin Oncol 2009;27:5487–5491


Ereg mrna in diferrent cancers

EREG mRNA in diferrent Cancers


Predictive analysis

Modelled survival plots by chemo regimen within the KRAS-wt subgroup

1.0

0.8

0.6

Survivor function

0.4

0.2

0

0

6

12

18

24

30

36

42

0

6

12

18

24

30

36

42

Time from randomisation (months)

Time from randomisation (months)

Predictive analysis

KRAS-wt, mFOLFOX

KRAS-wt, Xelox

Interaction

P=0.0042

Interaction

P=0.14

In the mFOLFOX subgroup, high EREG expression is predictive of increased cetuximab efficacy.

Arm A

Arm B

Upper quartile of EREG expression

Median of EREG expression

Lower quartile of EREG expression

Adams et al ASCO 2012


Prognostic ligand expression and kras control arm

Prognostic: Ligand expression and KRASControl arm

EREG, OS

EREG, PFS

1.00

KRAS-mut

low expression

Global log-rank test: P=0.004

Global log-rank test: P=0.014

KRAS-mut

high expression

0.75

KRAS-wt

low expression

Survival

0.50

KRAS-wt

high expression

0.25

0.00

0

6

12

18

24

30

36

42

0

6

12

18

24

30

36

42

Time from randomisation (months)

Time from randomisation (months)

  • The combination of KRAS=wt and high EREG expression selects a good prognostic group.

  • This is in the absence of cetuximab use, suggesting previously reported similar findings in a non randomised series of patients treated with cetuximab (Jacob) may be a prognostic effect not a predictive effect.

Adams et al ASCO 2012


What is new beyond kras and any markers for anti vegf

Stintzing: FIRE 3 Results


Proposed biomarkers for optimal treatment of advanced untreated colorectal cancer

Proposed Biomarkers for Optimal Treatment of Advanced Untreated Colorectal Cancer

  • ERCC1 low optimal for oxaliplatin.

  • Both KRAS WT AND High EGFR Ligands optimal for cetuximab.

StandardOptimal Rx

1: Lo ERRC1,

EGFR ResFolflox/BevFolfox/Bev

2: Lo ERRC1,

EGFR SenFolfox/BevFolfox/Cetux

3: Hi ERRC1,

EGFR ResFolfox/BevFolfiri/Bev

4: Hi ERRC1,

EGFR SenFolfox/BevFolfiri/Cetux

Estimate PFS for median of groups 2, 3, 4 with selected therapy is 14 months (harzard ratio 1.55)


What is new beyond kras and any markers for anti vegf

Emergence of circulating (new) mutant KRAS and Kras amplification as mechanisms of resistance to EGFR inhibitors

S Misale et al. Nature000, 1-5 (2012) doi:10.1038/nature11156

LAD Jr et al. Nature000, 1-4 (2012) doi:10.1038/nature11219


Most resistance manuscripts and reviews focus on redundant angiogenic pathways

Most Resistance Manuscripts and Reviews Focus on Redundant Angiogenic Pathways

c-Met

Ellis ASCO 2012

Ellis, Hicklin, CCR 2008


What is new beyond kras and any markers for anti vegf

Cremolini et al. ASCO 2012


What is new beyond kras and any markers for anti vegf

VEGFR2 associated with PFS

C- (N= 118) mPFS: 9.5 m

TT (N= 306) m PFS: 10.9 m

HR: 1.40 (1.07-1.84)

Log-rank test p=0.015


What is new beyond kras and any markers for anti vegf

Heatmaps in 7 Favorable Polymorphisms in Bevacizumab

Validation set

Training set

Caucasian

Hispanic

Japanese

favorable

intermediate

poor


Avagast trial a simulation study

AVAGAST Trial, A Simulation Study


Cytokines increased prior to progression on folfiri bev

Cytokines Increased Prior to Progression On FOLFIRI + Bev

Kopetz JCO 2009


What is new beyond kras and any markers for anti vegf

Prospective Trials with FGF Levels

Plasma bFGF Levels

HIGH plasma bFGF(n=30):

Irinotecan 180mg/m2

Brivanib 800mg PO qd

FOLFOX + Bevacizumab-Refractory CRC

N=100 screened

Primary endpoint: non-comparative PFS

Low/normal bFGF (n=30):

Irinotecan 180mg/m2

Brivanib 800mg PO qd


Other resistance pathways not discussed

Other Resistance Pathways Not Discussed

Untested in the clinic

Mostly refuted

Under investigation:

Are we targeting ECs or Cancer Stem Cells or Both?

(Notch inhibitors slow in development)

Untested in the clinic

Ellis ASCO 2012


What is new beyond kras and any markers for anti vegf

Vilar E et al. Clin Cancer Res 2011;17:7207-7209


We are still early in molecular classification of colorectal cancer

We are still early in molecular classification of colorectal cancer

Lymphoma

Colorectal Cancer

Breast Cancer

?

Basal

Her2-pos

Luminal A

Luminal B

Sotiriou et al NEJM, 2009; Alizadeh et al, Nature 2000


Systems biology of cancer integration of networks yarden et al

Systems biology of cancer: Integration of networks (Yarden et al)

Metabolism

Information/signaling

Energy

GPCRs

ILs & CXCLs

Ca++ Signaling

Cell Cycle


Stem cell markers lrg5 aldh cd44

Stem Cell Markers (LRG5, ALDH, CD44)

Gerger et al Clin Cancer Res 2011


What is new beyond kras and any markers for anti vegf

Cytoplasm

b-catenin

A Critical Cellular Switch

Nucleus

b-catenin

TCF

Teo et al., PNAS 2005

Differentiation

Non-differentiation

p300

ICG-001

CBP

b-catenin

b-catenin

ICG-001

CBP

p300

cyclin D1

axin 2

Hnkd

Survivin

S100A4

b-catenin

b-catenin

c-jun

fra-1

TCF

TCF


Colon cancer stem cell models

Colon Cancer Stem Cell Models

Miyabayashi T, et al PNAS 104, 5668, 2007


What is new beyond kras and any markers for anti vegf

Relative Survivin expression fold change in CTC in patients treated with PRI724


Current targetable subsets of colorectal cancer

Current “Targetable” Subsets of Colorectal Cancer

* Trials utilizing inhibitors specific for pathway derangement


Braf inhibitor plx4032

100

75

50

100

25

%Change From Baseline

75

(Sum of Lesion Size)

0

50

-25

25

-50

%Change From Baseline

(Sum of Lesion Size)

0

-75

-100

-25

-50

-75

-100

BRAF Inhibitor: PLX4032

Refractory Melanoma

Refractory Colorectal

5% Response Rate

81% Response Rate

Flaherty et al NEJM ‘10

Kopetz et al ASCO ‘10

Hurdle : Oncogene mutation does not imply oncogene dependence

Understand the biological context in which particular mutations occur.


What is new beyond kras and any markers for anti vegf

EGFR and BRAF(V600E) inhibitors synergize to induce apoptosis of CRC cells and to suppress CRC tumour growth in a xenograft model.

A Prahallad et al. Nature 000, 1-5 (2012) doi:10.1038/nature10868


What is new beyond kras and any markers for anti vegf

A murine study in a resistant BRAFmut CRC cell line combining venurafenib and an AKT inhibitor showed promising activity

Su et al CR 2012


What is new beyond kras and any markers for anti vegf

Tumor effects with available results of tumor genomic alterations.

Shimizu T et al. Clin Cancer Res 2012;18:2316-2325


Comparison of ongoing approaches

Comparison of Ongoing Approaches


What is new beyond kras and any markers for anti vegf

USC Approach: Integrative Sequencing Strategy to Capture Relevant Genes


What do we need to do

What do we need to do

  • Molecular Evaluation of Tumor Heterogeneity

  • Molecular Evaluation of refractory Patients

  • Development of Stem Cell targeted drugs

  • Integrated System Biology

  • Increase Biomarker Driven Clinical Trial


What is new beyond kras and any markers for anti vegf

DHONT Foundation

Sharon Carpenter Laboratory


What the germans couldn t do usa italy 1 0 march 2012

What the Germans couldn’t do: USA:Italy 1:0 (March 2012)


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