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Ian Krop, MD-PhD Dana-Farber Cancer Institute Brigham and Women’s Hospital Harvard Medical School

Ian Krop, MD-PhD Dana-Farber Cancer Institute Brigham and Women’s Hospital Harvard Medical School May 2009. Targeted Therapy: A Giant Step Forward. “Targeted” therapy. Drug which inhibits a protein or molecule that is only expressed in cancer or which only the cancer is dependent

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Ian Krop, MD-PhD Dana-Farber Cancer Institute Brigham and Women’s Hospital Harvard Medical School

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  1. Ian Krop, MD-PhD Dana-Farber Cancer Institute Brigham and Women’s Hospital Harvard Medical School May 2009 Targeted Therapy: A Giant Step Forward

  2. “Targeted” therapy • Drug which inhibits a protein or molecule that is only expressed in cancer or which only the cancer is dependent • Offer the promise of reduced side effects compared to less targeted drugs

  3. Breast cancer is family of different cancers GENES TUMORS Triple Negative HER2+ Estrogen receptor +

  4. Kaplan Meier plots allow comparison of clinical outcome over time 100- Percentage of women WITHOUT recurrence Time

  5. Breast cancer is family of different cancers GENES TUMORS Triple Negative HER2+ Estrogen receptor + Percentage of women WITHOUT recurrence

  6. 20% = 36,000 cases HER 2 + Disease Breast Cancer in the U.S. All Breast Cancer 180,000 + cases

  7. Amplification of the HER2 gene observed in a subset of breast cancers FISH - FISH +

  8. HER2 amplification impacts prognosis % without recurrence Time (months)

  9. HER2 is a cell surface signaling protein

  10. HER2 is a cell surface signaling protein <10,000 HER2 proteins on normal breast cell

  11. HER2 gene amplification results in marked overexpression of HER2 proteins 2,000,000 HER2 proteins on cancer cell

  12. Herceptin (trastuzumab) is a recombinant antibody that specifically binds to the HER2 protein HER2 binding domain

  13. By attaching to HER2, Herceptin prevents HER2 proteins from binding to each other, leading to inhibition of signaling

  14. Herceptin given with chemotherapy improves outcome for patients with HER2+ advanced breast cancer Slamon, et al. NEJM 2001 (data originally presented 1998)

  15. U.S. Adjuvant Herceptin Trials (May, 2005) Chemo+herceptin 85% ACT % Chemoalone 67% Romond, Perez et al, NEJM 2005 B31/N9831 Years From Randomization

  16. Herceptin given with chemotherapy improves outcome for patients with HER2+ advanced breast cancer Slamon, et al. NEJM 2001 (data originally presented 1998)

  17. Her2 Her2 Overcoming Herceptin resistance From Hanahan and Weinberg, 2000

  18. HER2 is a kinase, a protein that adds phosphate to other proteins

  19. Lapatinib is an oral inhibitor of the HER2 kinase

  20. Clinical trial of lapatinib for women with HER2+ metastatic breast cancer that had progressed on Herceptin R A N D O M I Z E Lapatinib + Capecitabine Capecitabine alone

  21. Lapatinib improves outcome in patients with metastatic HER2+ breast cancer Geyer CE et al. N Engl J Med 2006;355:2733-2743

  22. HER2 Kinase inhibitors • Results of first study confirm role for HER2 targeted therapy after progression on Herceptin • Is it better than Herceptin? • Can it add to benefit of Herceptin • Are there particular types of tumors that are better treated with one or the other • Lapatinib being tested in adjuvant setting • Additional inhibitors in development • HKI272 • BIBW227

  23. Clinical trial of Herceptin and xeloda for women with HER2+ metastatic breast cancer that had progressed on Herceptin R A N D O M I Z E Herceptin + Capecitabine Capecitabine alone

  24. Trastuzumab Treatment Beyond Progression in Locally Advanced or MBC Von Minckwitz, G et al, SABCS 2007 and ASCO 2008

  25. The HER Family HER2 can dimerize with itself or other HER family members Courtesy of Kenneth Bloom. Intracellular

  26. Herceptin and pertuzumab bind to distinct epitopes on HER2 extracellular domain Pertuzumab Herceptin Hubbard 2005

  27. HSP90 is a chaperone for proteins like HER2

  28. Trastuzumab-DM1, a novel antibody drug conjugate Drug Drug Herceptin DM1 Her2 • Delivers high concentrations of drug to tumor • Spares normal tissue from toxicity

  29. Trastuzumab-DM1, a novel antibody drug conjugate Drug Drug Herceptin DM1 Her2 • Delivers high concentrations of drug to tumor • Spares normal tissue from toxicity

  30. Trastuzumab-DM1, a novel antibody drug conjugate Drug Drug Herceptin DM1 Her2 • Delivers high concentrations of drug to tumor • Spares normal tissue from toxicity

  31. HER2  A Good ADC Target • Tumor expression >>> Normal-tissue expression • Absolute Expression levels very high • Internalized without down regulation Austin et al. (2004) Mol Biol Cell 15, 5268-82.

  32. Trastuzumab-DM1, a novel antibody drug conjugate • Results of early studies of TDM1 encouraging • Response rate ≈40% in patients whose tumors had progressed on Herceptin • Side effects minimal (validates strategy of antibody–drug conjugate) • Larger trials are underway

  33. PI3-kinase may be an important target in breast cancer

  34. Antibody conjugates Targeting HER2+ Tumors Inhibit Dimerization Moderate receptor expression Inhibit Kinase activity Inhibit downstream effects Burstein, H. J. N Engl J Med 2005;353:1652-1654

  35. Breast cancer is family of different cancers GENES TUMORS Triple Negative HER2+ Estrogen receptor + Percentage of women WITHOUT recurrence

  36. The link between BRCA1 associated breast cancer and basal like cancers • Inherited mutations in the BRCA1 gene account for a small percentage of breast cancers • 80% of BRCA1 associated breast cancers are basal like (triple negative)

  37. The link between BRCA1 associated breast cancer and basal like cancers • BRCA1 associated breast cancers have a fundamental defect in DNA repair • Evolving data suggest that spontaneous TN breast cancers share this defect

  38. Basal-like Tumors Show DNA Damage Sensitivity

  39. NATURE REVIEWS |GENETICS VOLUME 2 | JUNE 2001 | 447

  40. Platinum Damages DNA

  41. 04-183 Preoperative Cis-Platinum in Triple Negative Breast Cancer SURGERY Women with newly diagnosed ER-/PR- /HER2- breast cancer Standard Treatment CisPlatinum x 4 doses Research Biopsy, Blood Tissue for Research

  42. Redundant Mechanisms of DNA Repair X Homologous Recombination Base excision repair

  43. Base excision repair requires PARP Huber et al. DNA Repair 3 (2004) 1103–1108

  44. Redundant Mechanisms of DNA Repair X Homologous Recombination Base excision repair

  45. AZD2281 – PARP inhibitor Hereditary ovarian cancer summary

  46. Next Step SURGERY Women with newly diagnosed ER-/PR-/HER2- breast cancer CisPlatinum/PARP INHIBITOR x 4 doses Standard Treatment Research Biopsy, Blood Tissue for Research

  47. Cancers are dependent on new blood vessel growth (angiogenesis)

  48. Blocking VEGF with Avastin leads to loss of tumor vasculature and tumor regression

  49. Blocking VEGF may also lead to “normalization” of blood vessels

  50. ECOG 2100: Trial Design • Patients enrolled Dec. 2001- March 2004 • First interim analysis with data cut-off Feb. 2005 with 355 events Miller KD ASCO 2005

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