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Clinical Trials for Metastatic HER2-positive Breast Cancer

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An overview of Clinical Trials for Metastatic HER2-positive Breast Cancer by Dr. Ian Krop, MD, PhD, Chief and Clinical Research Director, Breast Oncology Center at Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute

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Clinical Trials for Metastatic HER2-positive Breast Cancer

  1. 1. Clinical Trials for Metastatic HER2-positive Breast Cancer Ian Krop MD PhD Director of Clinical Research
  2. 2. Agenda • Clinical trial basics • What makes a HER2+ cancer unique • New HER2-targeted therapies in clinical trials
  3. 3. Clinical Trials: Why Participate? • You have a chance to help others and improve cancer care • You can expand the number of treatment options you have • Many trials involve targeted therapies with the goal of improved effectiveness and decreased side effects • If a new treatment is proven to work and you are receiving it, you may be among the first to benefit 3
  4. 4. Clinical Trials: FAQs • When should I consider a clinical trial?  Clinical trials may be an option for you as early as the first treatment you receive for metastatic breast cancer, but may also be an option further into the course of your disease.  If you are interested in trials, getting connected early to a treatment team who can help identify potential trials for you is key. • Will I have to pay more to be on a trial?  All normal procedures are billed to insurance; anything beyond normal care is paid for by the trial. There should be no “upcharge” for being in a trial • Will I know what medicine I am getting? I don’t want a placebo.  In most trials, both patient and provider know exactly what treatment is being given.  Some larger trials use randomization and placebos, and in some cases neither patient nor provider know identity of study drug.  But in almost every trial with placebo, at minimum a patient receives best standard of care.
  5. 5. Clinical Trials for Metastatic HER+ BC • There are many clinical trials open focusing on HER2+ BC. • Clinical trials are testing the safety and effectiveness of new treatments. • Today we will provide some highlights of a few of the available trials. • These treatments are provided as part of trials because we do not understand whether they are the same, better, or worse, than standard treatments. • Trial treatments may also have different side effects than standard treatments. • Each trial has specific requirements for patients to be included. 5
  6. 6. • There are three main subtypes of breast cancer  ER positive  HER2 positive  Triple negative • Within these, there are other ways to further sub-divide breast cancers • Oncologists use the breast cancer subtype to guide the kinds of treatments to recommend • Clinical trials often will focus on specific subtypes Breast Cancer Subtypes
  7. 7. Amplification of the HER2 gene observed in a subset of breast cancers FISH -
  8. 8. FISH - FISH + Amplification of the HER2 gene observed in a subset of breast cancers
  9. 9. HER2 is a cell surface signaling protein
  10. 10. <10,000 HER2 proteins on normal breast cell HER2 is a cell surface signaling protein
  11. 11. HER2 gene amplification results in marked overexpression of HER2 proteins 2,000,000 HER2 proteins on cancer cell
  12. 12. HER2 binding domain Herceptin (trastuzumab) is a recombinant antibody that specifically binds to the HER2 protein
  13. 13. By attaching to HER2, trastuzumab prevents HER2 proteins from signaling
  14. 14. Trastuzumab (Herceptin) • When added to chemotherapy:  Helps shrink tumor  Delays time to cancer progression  Improves survival
  15. 15. Newer agents targeting HER2 • Pertuzumab • T-DM1 • Lapatinib
  16. 16. Trastuzumab Emtansine (T-DM1) • T-DM1 is an antibody drug- conjugate. • Trastuzumab linked to a potent chemotherapy (DM1). • Average of 3.5 DM1 per antibody.
  17. 17. T-DM1 selectively delivers DM1 to HER2-positive tumor cells Receptor-T-DM1 complex is internalized into HER2-positive cancer cell Potent antimicrotubule agent is released once inside the HER2-positive tumor cell T-DM1 binds to the HER2 protein on cancer cells HER2
  18. 18. 18 Trastuzumab Deruxtecan (DS-8201a): a new antibody drug conjugate • HER2-targeted (like T-DM1) • Different type of chemotherapy than T-DM1 • More chemo molecules on each antibody
  19. 19. 19 Trastuzumab Deruxtecan (DS-8201a): a new antibody drug conjugate • The first trial of Trastuzumab Deruxtecan was in patients with HER2+ metastatic breast cancer, all of whom had T-DM1 • 60% of patients had substantial shrinkage of their tumor • More side effects than T-DM1  Low blood counts, nausea, some hair loss
  20. 20. Trial of Trastuzumab Deruxtecan in Patients Who are Resistant or Refractory to TDM-1 • Large phase 2 trial - total of 220 patients • Patients have to have had cancer that progressed on T-DM1 • Several doses will be tested to determine which is optimal
  21. 21. HER2 is a cell surface signaling protein Kinase Inhibitors
  22. 22. HER2 Kinase Inhibitors • Lapatinib  FDA approved in combination with capecitabine • Neratinib  Awaiting Phase 3 trial results • Tucatanib  Currently in clinical trials
  23. 23. Neratinib • More potent inhibitor than lapatinib • Causes more diarrhea • In approximately 25% of patients whose cancer has progressed on trastuzumab, neratinib causes significant tumor shrinkage • Neratinib is approved for use after trastuzumab in patients with higher risk non-metastatic cancers  Seems to work best in tumors that are estrogen receptor positive
  24. 24. Does hormonal therapy improve the effectiveness of Neratinib in ER+ HER2+ Breast Cancer? Metastatic HER2+/ER+ breast cancer Neratinib + FulvestrantN=152 Neratinib N=76 N=76Randomize Key Eligibility • ER+, HER2+ • Prior Trastuzumab, Pertuzumab, and T- DM1 • No limit on number of prior therapies • Research biopsies required • No prior Neratinib or Fulvestrant
  25. 25. Tucatinib • More specific inhibitor than lapatinib • Causes less diarrhea and rash • In approximately 60% of patients whose cancer has progressed on trastuzumab, tucatinib + capecitabine (Xeloda) + trastuzumab causes significant tumor shrinkage • Tucatinib also has been shown to shrink tumors in the brain in some patients
  26. 26. Phase 2 Study of Tucatinib vs Placebo in Combination With Capecitabine & Trastuzumab in HER2+ Breast Cancer San Antonio Breast Cancer Symposium, December 7, 2017 N=480
  27. 27. Immunotherapy in HER2+ breast cancer • Immunotherapies are designed to activate the immune system to attack cancer cells • Trastuzumab may also have some ability to stimulate the immune system • An immune therapy + trastuzumab caused significant tumor shrinkage in about 15% of patients in a small trial
  28. 28. The immune system consists of many different types of cells with different functions
  29. 29. The AVIATOR trial: Is dual immunotherapy effective in HER2+ MBC • Advanced HER2+ cancer • No prior immunotherapy • PD-L1 unselected Vinorelbine + trastuzumab + avelumab N=40 Vinorelbine + Trastuzumab N=20 Vinorelbine + Trastuzumab + Avelumab + Utomilumab N=40 Discontinue Trastuzumab + avelumab + Utomilumab Discontinue Tumor tissue Fresh or < 2y old Tumor Tissue Vinorelbine 25mg/m2 D1,D8,D15 Trastuzumab D1, D15 Avelumab D1, D15 10mg/kg IV Utomilumab D1 100mg IV 28 day cyclePI: Krop
  30. 30. How Can We Do Better? Participate in Trials! • Clinical trials exist for patients at any step of their breast cancer journey; trials are a part of the continuum of care • There are benefits to being on a trial!  a larger treatment team  possible exposure to cutting edge new medications  helping other patients with breast cancer • None of the advances in breast cancer could have happened without patients volunteering to be in trials!
  31. 31. Promising agents in clinical trials • New antibody drug conjugates  DS8201A • New kinase inhibitors  Neratinib  Tucatinib • Immunotherapies
  32. 32. How do I find a clinical trial? • Talk with your oncologist and let her/him know you may be interested in clinical trials. • Consider a consultation at an academic cancer center. • https://www.cancer.gov/research/nci-role/cancer-centers • We are also happy to see new patients at Dana-Farber – (617) 632-2175. • Consider web resources. • Breastcancertrials.org https://www.breastcancertrials.org/bct_nation/home.seam • Metastatic Breast Cancer Alliance http://www.mbcalliance.org/clinical- trials-in-metastatic-breast-cancer • Best to ask your oncologist what makes sense for you and to know that this can change over time. 32
  33. 33. How Can We Make Progress? Support Clinical Trials!

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