Clinical trials are testing new HER2-targeted therapies for metastatic HER2-positive breast cancer. Some highlights of ongoing trials include a trial of Trastuzumab Deruxtecan for patients resistant to T-DM1, a trial adding hormonal therapy Fulvestrant to Neratinib, and a trial combining immunotherapy with chemotherapy and Trastuzumab. Participating in clinical trials helps advance treatment options and many trials provide access to promising new agents. Talking to your oncologist can help identify potential trials and determine if participation may be an option.

1. Clinical Trials for
Metastatic HER2-positive Breast Cancer
Ian Krop MD PhD
Director of Clinical Research

2. Agenda
• Clinical trial basics
• What makes a HER2+ cancer unique
• New HER2-targeted therapies in clinical trials

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

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

9. HER2 is a cell surface signaling protein

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

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

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

13. By attaching to HER2, trastuzumab prevents
HER2 proteins from signaling

14. Trastuzumab (Herceptin)
• When added to chemotherapy:
 Helps shrink tumor
 Delays time to cancer progression
 Improves survival

15. Newer agents targeting HER2
• Pertuzumab
• T-DM1
• Lapatinib

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. 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
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
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. 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. HER2 is a cell surface signaling protein
Kinase
Inhibitors

22. HER2 Kinase Inhibitors
• Lapatinib
 FDA approved in combination with capecitabine
• Neratinib
 Awaiting Phase 3 trial results
• Tucatanib
 Currently in clinical trials

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. 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. 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. 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. 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. The immune system consists of many different
types of cells with different functions

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. 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. Promising agents in clinical trials
• New antibody drug conjugates
 DS8201A
• New kinase inhibitors
 Neratinib
 Tucatinib
• Immunotherapies

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. How Can We Make Progress?
Support Clinical Trials!