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DISCUSSANT Philip Agop Philip Karmanos Cancer Institute Wayne State University Detroit, MI

Phase I/ II Study of MK-0646 (Dalotuzumab), A Humanized Monoclonal Antibody Against IGF-1R in Combination With Gemcitabine or Gemcitabine + Erlotinib for Advanced Pancreatic Cancer. Javle M , Varadhachary G, Shroff R, Bhosale P, Overman M, Weatherly J, Wolff RA, Abbruzzese J. DISCUSSANT

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DISCUSSANT Philip Agop Philip Karmanos Cancer Institute Wayne State University Detroit, MI

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  1. Phase I/ II Study of MK-0646 (Dalotuzumab), A Humanized Monoclonal Antibody Against IGF-1R in Combination With Gemcitabine or Gemcitabine + Erlotinib for Advanced Pancreatic Cancer Javle M, Varadhachary G, Shroff R, Bhosale P, Overman M, Weatherly J, Wolff RA, Abbruzzese J DISCUSSANT Philip Agop Philip Karmanos Cancer Institute Wayne State University Detroit, MI

  2. Targeted Therapies in Pancreatic Cancer • Several agents tested in combination with gemcitabine with no improvement in clinical outcome, except for a marginal benefit with erlotinib • Multiple genetic and epigenetic abnormalities necessitate multi-targeted approaches and biomarker driven patient selection Ghaneh, P. et al. Gut 2007;56:1134-1152; Jones et al, Science, September, 2008

  3. Insulin-Like Growth Factor-1 Receptor (IGF1-R) Targeting in Pancreatic Cancer • Activation of IGF-1R induces cell proliferation, survival, angiogenesis and invasion in multiple cancers • Targeting IGF-1R in pre-clinical models leads to tumor growth inhibition and may reverse drug resistance • Single anti-IGF-1R agent +/- gemcitabine is unlikely to succeed, especially in an unselected patient population Gualberto and Pollak, Oncogene, 28:3009-3021, 2009; Atzori et al, Targ Oncol, 4:255-266, 2009

  4. Cross Talk and Cooperation between EGFR and IGF-1R Signaling Pathways • EGFR and IGF-1R may function as alternate signaling pathways evading tyrosine kinase inhibition of either receptor • Dual EGFR/IGF-1R blockade in multiple cancer cell lines enhances anti-tumor activity of either drug with more sustained Akt inhibition and apoptosis Morgillo et al, Clin Cancer Res, 13:2795-2803, 2007; Kaulfub et al, 8:821-33, 2009; Huang et al, Cancer Res, 69:161-70, 2009;

  5. Javle et al:Study Design Gemcitabine + MK 0646 Gemcitabine + Erlotinib + MK 0646 G 1000 mg/m2/100 min + MK 5 mg/kg G 1000 mg/m2/100 min + MK 10 mg/kg G 1000 mg/m2/100 min + Erlotinib 100 mg + MK 5 mg/kg G 1000 mg/m2/100 min + Erlotinib 100 mg + MK 10 mg/kg Gemcitabine MK 0646 Erlotinib Gemcitabine MK 0646 R Gemcitabine Erlotinib

  6. Eligibility Criteria • Metastatic disease • PS 0 or 1 • AST/ALT < 2.5 x ULN • No prior therapy

  7. MTD of MK 0646 *1/3 of patients discontinued Erlotinib because of toxicity

  8. Non-Hematological Toxicities to MK 0646 + Gemcitabine +/- Erlotinib(Grade 3 or 4)

  9. Hyperglycemia *Philip et al, Abstract 233, GI Symposium, 2010

  10. Hyperglycemia in Targeting IGF-1R in Pancreatic Cancer • IGF-1R present on normal cells with 84% homology to insulin receptor • Overlap between IGF-1R and insulin receptor when targeting IGF-1R • Up to 40% of patients with pancreatic cancer have diabetes mellitus

  11. Anti-Tumor Activity of MK 0646/Gemcitabine +/- ErlotinibN = 24

  12. SWOG-0727 Study Schema Phase I Phase II R A N D O M I Z E IMC-A12 Erlotinib Gemcitabine IMC-A12 Erlotinib Gemcitabine Phase II Dose Erlotinib Gemcitabine N = 10 Endpoint = PFS N = 45/106 Philip et al, #233, GI Symposium, January 23, 2010

  13. Are we ready to design a Phase III study of an anti-IGF-1R in pancreatic cancer?

  14. Biomarkers (Javle et al) Plasma IGF-1/IGFBP IGF-1 IGFBP EGFR IGF-1R P P Shc IRS Ras PI3K Raf1 Akt MEK PTEN mTOR ERK

  15. Biomarkers (Javle et al) Plasma IGF-1/IGFBP IGF-1 IGFBP EGFR IGF-1R P P Shc IRS Ras PI3K Raf1 Akt MEK PTEN mTOR ERK

  16. Biomarkers (Javle et al) Plasma IGF-1/IGFBP IGF-1 IGFBP EGFR IGF-1R SNPs IRS1 SSTR5 IGF1 IGF2 IGF1R IGF-2R IGFB3 PI3K Akt mTOR P P Shc IRS Ras PI3K Raf1 Akt MEK PTEN mTOR ERK

  17. Biomarkers (Javle et al) Plasma IGF-1/IGFBP IGF-1 IGFBP EGFR IGF-1R SNPs IRS1 SSTR5 IGF1 IGF2 IGF1R IGF-2R IGFB3 PI3K Akt mTOR ? EMT KRas PTEN C-Met src P P Shc IRS Ras PI3K Raf1 Akt MEK PTEN mTOR ERK

  18. Conclusions • Hyperglycemia may not be a dose limiting toxicity to MK 0646 • Too early to determine whether there is a signal for an anti-tumor activity

  19. Developemnt of an Anti-IGF-1R Strategy in Pancreatic Cancer • Further preclinical and clinical validation of an IGF-1R based multi-targeted strategy in pancreatic cancer must be undertaken • Predictive biomarkers must be developed for patient selection and stratification

  20. Are we ready to design a Phase III study of an anti-IGF-1R in pancreas cancer? We need more data! JCO 27(33):5660-5669, 2009

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