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Systemic Management of iCCA: Role of Molecular Therapies

Systemic Management of iCCA: Role of Molecular Therapies. Gregory J. Gores, M.D. Braconi C. et al. Liver International 2019. Evolving molecular stratification of CCA and therapeutic implications. Rizvi et al . Nat Rev Clin Oncol 2017. Fusions. FGFR- fibroblast growth factor receptor

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Systemic Management of iCCA: Role of Molecular Therapies

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  1. Systemic Management of iCCA: Role of Molecular Therapies Gregory J. Gores, M.D.

  2. Braconi C. et al. Liver International 2019

  3. Evolving molecular stratification of CCA and therapeutic implications Rizvi et al. Nat Rev Clin Oncol 2017

  4. Fusions • FGFR- fibroblast growth factor receptor • NRTK (TRK) – neurotrophin receptor tyrosine kinase

  5. Katoh M. Nature Reviews Clinical Oncology 2019

  6. Katoh M. Nature Reviews Clinical Oncology 2019

  7. Katoh M. Nature Reviews Clinical Oncology 2019

  8. BGJ398: Pan-FGFR Kinase Inhibitor • Phase II clinical trial of BGJ398 (n=61; 48 with FGFR2 fusions) • Overall response rate (complete response + partial response) was 14.8% • Median overall progression free survival (PFS) 5.8 months • Disease control rate (DCR) 83.3% • Median duration of disease control 7.5 months Javle et al. J Clin Oncol 2018 Rizvi et al. Hepatology 2018

  9. BGJ398 Javle M. et al. Journal of Clinical Oncology 2018

  10. Javle M. et al. Journal of Clinical Oncology 2018

  11. ARQ 087 Mazzaferro V. et al. British Journal of Cancer 2018

  12. FGFR Targeted Resistance Kinase pocket mutations Katoh M. Nature Reviews Clinical Oncology 2019

  13. FGFR Inhibitors in Clinical Trials Rizvi et al. J Hepatol 2017

  14. NTRK Signaling Cocco E. et al. Nature Reviews Clinical Oncology 2018

  15. TRK Fusions Cocco E. et al. Nature Reviews Clinical Oncology 2018

  16. Cocco E. et al. Nature Reviews Clinical Oncology 2018

  17. Larotrectinib Drilon A. The New England Journal of Medicine 2018

  18. Genetic Alterations • IDH mutations – isocitrate dehydrogenase gain of function mutations • BRAF 600E – gain of function of a serine threonine kinase

  19. Isocitrate Dehydrogenase (IDH) 1/2 Inhibitors • Intrahepatic CCA 28% • Perihilar CCA 7% Kipp et al. Human Pathology 2012 Rizvi et al. Gastroenterology 2017

  20. Ivosidenib in iCCA Lowery MA et al. The Lancet Gastroenterology & Hepatology 2019

  21. Lowery MA et al. The Lancet Gastroenterology and Hepatology 2019

  22. Lowery MA et al. The Lancet Gastroenterology and Hepatology 2019

  23. Waitkus M. et al. Cancer Cell 2018

  24. BRAF V600E – Mutated Biliary Tract Cancer • ROAR trial (GI ASCO 2019) • Basket trial • BRAF and MEK Inhibition • dabrafenib plus trametenib • Overall survival of 11.7 month in 35 patients • Equivalent to Gem/Cis (historical cohort)

  25. Cholangiocarcinoma (CCA) is a Highly Desmoplastic Cancer with a Rich Stroma

  26. Immunotherapy • Checkpoint inhibitors with high tumor mutational burden • Checkpoint inhibitors without high mutational burden • Future directions

  27. Blockade of PD-1 or CTLA-4 Signaling in Tumor Immunotherapy. Ribas A. N Engl J Med 2012;366:2517-2519.

  28. MSH2, MSH6, PMS2, MLH1 mutations Dung TL, et al. Science 2017

  29. basket trial Pembrolizumab Treatment in Mismatch Repair Deficiency Dung TL, et al. Science 2017

  30. Pembrolizumab Treatment in Mismatch Repair Deficiency Dung TL, et al. Science 2017

  31. The Prevalence of Somatic Mutations Across Human Cancer Types TCGA –iCCA median mutation rate of 1.38 per megabase (similar to PDAC) LB Alexandrov et al. Nature 2000, 1-7 (2013) doi:10.1038/nature12477

  32. Immune Checkpoint Blockade (ICB) in CCA • Keynote-158: multi-cohort phase 2 study of the programmed death 1 (PD-1) inhibitor pembrolizumab • 104 patients with previously treated advanced CCA • Objective response rate (ORR) 5.8% • 0 with complete response; 5.8% with partial response • No correlation of ORR with PD-L1 expression Ueno et al. ESMO 2018

  33. Emerging Immunotherapies in CCA

  34. Emerging Immunotherapies in CCA

  35. Evolving molecular stratification of CCA and therapeutic implications Rizvi et al. Nat Rev Clin Oncol 2017

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