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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?

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  1. 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

  2. Little New Biomarker Data New Understandings Developing New Paradigms • EGFR Ligands • Angiogenesis/Ethnicity • Stem Cell/Tumor Dormancy • Acquired vs Inherited resistance • Integrated System Biology

  3. 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

  4. EREG mRNA in diferrent Cancers

  5. 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

  6. 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

  7. Stintzing: FIRE 3 Results

  8. 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. Standard Optimal Rx 1: Lo ERRC1, EGFR Res Folflox/Bev Folfox/Bev 2: Lo ERRC1, EGFR Sen Folfox/Bev Folfox/Cetux 3: Hi ERRC1, EGFR Res Folfox/Bev Folfiri/Bev 4: Hi ERRC1, EGFR Sen Folfox/Bev Folfiri/Cetux Estimate PFS for median of groups 2, 3, 4 with selected therapy is 14 months (harzard ratio 1.55)

  9. 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

  10. Most Resistance Manuscripts and Reviews Focus on Redundant Angiogenic Pathways c-Met Ellis ASCO 2012 Ellis, Hicklin, CCR 2008

  11. Cremolini et al. ASCO 2012

  12. 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

  13. Heatmaps in 7 Favorable Polymorphisms in Bevacizumab Validation set Training set Caucasian Hispanic Japanese favorable intermediate poor

  14. AVAGAST Trial, A Simulation Study

  15. Cytokines Increased Prior to Progression On FOLFIRI + Bev Kopetz JCO 2009

  16. 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

  17. 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

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

  19. 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

  20. Systems biology of cancer: Integration of networks (Yarden et al) Metabolism Information/signaling Energy GPCRs ILs & CXCLs Ca++ Signaling Cell Cycle

  21. Stem Cell Markers (LRG5, ALDH, CD44) Gerger et al Clin Cancer Res 2011

  22. 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

  23. Colon Cancer Stem Cell Models Miyabayashi T, et al PNAS 104, 5668, 2007

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

  25. Current “Targetable” Subsets of Colorectal Cancer * Trials utilizing inhibitors specific for pathway derangement

  26. 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.

  27. 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

  28. A murine study in a resistant BRAFmut CRC cell line combining venurafenib and an AKT inhibitor showed promising activity Su et al CR 2012

  29. Tumor effects with available results of tumor genomic alterations. Shimizu T et al. Clin Cancer Res 2012;18:2316-2325

  30. Comparison of Ongoing Approaches

  31. USC Approach: Integrative Sequencing Strategy to Capture Relevant Genes

  32. 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

  33. DHONT Foundation Sharon Carpenter Laboratory

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