Dr. Olwen Hahn, medical oncologist at the University of Chicago Department of Medicine, discusses recent developments in MBC research and treatment. Joining her is Dionna Koval, a metastatic breast cancer patient advocate.

1. Metastatic Breast Cancer:
Select Updates
Olwen Hahn, MD
Associate Professor of Medicine
The University of Chicago
Dionna Koval
Patient Advocate
June 2020

2. Outline
• Her2- Positive Breast Cancer
• Triple Negative Breast Cancer
• ER+ Breast Cancer
• Surgery in deNovo Mets. BrCa
• Patient – Doctor Communication

3. Normal
Overexpressed HER2
Excessive cellular division
HER2 Signals Cells to Divide
Berger et al. Cancer Res. 1988;48:1238.
Roskoski. Biochem Biophys Res Commun. 2004;319:1.
Rowinsky. Annu Rev Med. 2004;55:433.
Slamon et al. Science. 1987;235:177.
HER2 is overexpressed in
~20-25% of breast cancers

4. HER2-Positive Breast Cancer
Slamon et al. Science. 1987;235:177.
Months
0
12 24 36 48 60 72 84
Disease-freesurvivalprobability
Not amplified (n=52)
Amplified (n=11)
>5 copies
0
P=0.015
0.2
0.4
0.6
0.8
1.0

5. • Targets HER2 receptor
protein, which occurs in 20%
to 25% of patients with
breast cancer
• High affinity (Kd = 5nM) and
specificity
• 95% human, 5% murine
– Decreased potential for
immunogenicity
– Increased potential for
recruiting immune effector
mechanisms
Carter et al, 1992; Park et al, 1993;
Slamon et al, 1987; Genentech, data on file
Trastuzumab: Humanized Anti-HER2 Antibody

6. 7 FDA-Approved HER2-Targeted Agents for MBC
T-DM1, trastuzumab emtansine.
Adapted from Gajria D, et al. Expert Rev Anticancer Ther. 2011;11:263-275.
T-DxD
neratinib
HER2
HER2 HER2
tucatinib

7. Current Approach for Sequencing Therapy:
Advanced HER2+ Breast Cancer
First Line1
• Trastuzumab +
Pertuzumab +
Taxane
Third Line and
Beyond1
• Lapatinib + Capecitabine
• CT + Trastuzumab
– Eribulin, vinorelbine,
gemcitabine,
capecitabine, CMF
• Lapatinib + Trastuzumab
• Hormonal therapy +
Anti-HER2 (for HR+)
• Trastuzumab/Pertuzumab or
T-DM1, if not received prior
• T-DXd (DS-8201)
• Neratinib/Capecitabine
• Tucatinib/Capecitabine/
• Trastuzumab
Second Line1
• T-DM1
• Tucatinib +
Capecitabine +
Trastuzumab**
1. Giordano SH, et al. J Clin Oncol. 2018;36(26):2736-2740; 2. NCCN. Breast Cancer. V2.2020. Feb 5, 2020.

8. Newly Approved Therapies
Fam-trastuzumab deruxtecan-nxki
(DS-8201, T-DXd)
Tucatinib

9. Doi T, et al. J Clin Oncol. 2017;35(suppl):abstract 108..
Fam-trastuzumab Deruxtecan
Structure and Mechanism of Action
Designed with the goal of improving clinical attributes of an ADC

10. DESTINY-BREAST01: Open-Label, Phase II Study of T-DXd
Baseline Characteristics of Note
• 53% HR+
• HER2 IHC 3+ 84%; 1+/2+ (FISH+) 16%
• 92% visceral disease; 13% h/o brain metastases
• Median 6 prior lines of therapy (range, 2–27)
Population
• ≥18 years of age
• Unresectable and/or
metastatic BC
• HER2+ (centrally confirmed
on archival tissue)
• Prior T-DM1
• Excluded patients with
history of significant ILD
• Stable, treated brain
metastases were allowed
T-DM1
resistant/refractory
(n = 249)
R
1:1:1
PK Stage
(n = 65)
PART 1
6.4 mg/kg
(n=22)
7.4 mg/kg
(n=21)
5.4 mg/kg
(n=22)
PART 2
Continuation Stage
(n = 134)
PART 2a
5.4 mg/kg
(n=130)
T-DM1
intolerant
(n = 4)
PART 2b
5.4 mg/kg
(n=4)
Dose-Finding Stage
(n = 54)
R
1:1
5.4 mg/kg
(n=28)
6.4 mg/kg
(n=26)
PART 2a
5.4 mg/kg
(n=130)
PART 2b
5.4 mg/kg
(n=4)
5.4 mg/kg
(n=22)
5.4 mg/kg
(n=28)
184 patients
enrolled at 5.4 mg/kg

11. Modi S, et al. N Engl J Med. 2019;382(7):610-621.
DESTINY-BREAST01: T-DXd Tumor Response
ORR: 60.9%
Complete response rate: 6%
Duration of response: 14.8 mo

12. DESTINY-BREAST01: T-DXd Progression-Free Survival
Median PFS: 16.4 months (95% CI: 12.7, NE)
Median PFS in 24 pts with CNS mets: 18.1 mo (95% CI: 6.7, 18.1)
(Median OS not reached)
Modi S, et al. N Engl J Med. 2019;382(7):610-621.

13. DESTINY-BREAST01 T-DXd: Treatment-Emergent Adverse
Events in >15% of Patientsa
0 20 40 60 80 100
Cough
Headache
Thrombocytopenia
Decreased WBC Count
Diarrhea
Anemia
Decreased Appetite
Neutropenia
Constipation
Vomiting
Alopecia
Fatigue
Nausea
Any TEAE
Grade 1 or 2
Grade ≥3
• Serious TEAEs, 22.8% (drug related, 12.5%)
• TEAEs associated with discontinuation, 15.2% (drug related, 14.7%); majority were due to pneumonitis/ILD (8.7%)
• 9 (4.9%) TEAE-associated deathsb
Patients who received T-DXd 5.4 mg/kg (N = 184)
Preferred
Term, n (%)
Grade
1
Grade
2
Grade
3
Grade
4
Grade
5
Any
Grade/
Total
Interstitial
lung diseasea 5 (2.7) 15 (8.2) 1 (0.5) 0 4 (2.2) 25 (13.6)
Interstitial Lung Disease
Median time from the first infusion of T-DXd to
onset of ILD was 27.6 weeks (range, 6–76 weeks)
Modi S, et al. N Engl J Med. 2019;382(7):610-621.

14. FDA Accelerated Approval 12.20.2019
Fam-trastuzumab deruxtecan-nxki approved for
patients with unresectable or metastatic HER2+
breast cancer who have received 2 or more prior
anti-HER2–based regimens in the metastatic
setting.

15. Breast cancer and Brain Metastases
Presented By Erika Hamilton at TBD

16. Challenges of Systemic Therapy
• Blood-brain barrier
• Limited number of prospective trials
• Many underpowered studies
• Many reports include a variety of tumors
• Most patients with brain metastases have progressed on
several therapies

18. HER2CLIMB Trial design
Presented By Erika Hamilton at TBD

19. HER2CLIMB: Efficacy of Tucatinib
Presented By Erika Hamilton at TBD

20. OS Benefit in Brain Metastases
Presented By Erika Hamilton at TBD

21. FDA Approval 4.17.2020
Tucatinib approved in combination with
trastuzumab and capecitabine, for adult
patients with advanced unresectable or
metastatic HER2+ breast cancer,
including patients with brain
metastases, who have received 1 or more
prior anti-HER2–based regimens in the
metastatic setting.

22. HER2CLIMB Takeaways: Broadening Eligibility Criteria is a Win
Presented By Erika Hamilton at TBD

23. What this means for patients?

24. Triple-negative Breast Cancer (TNBC)
• TNBC lacks estrogen and progesterone hormone receptors (ER
and PR), and does not exhibit overexpression of human
epidermal growth factor receptor 2 (HER2)
• TNBC accounts for ~15% of breast cancers
• More common in
• Young women
• Individuals of African and Hispanic heritage
• BRCA1 germline mutations
• Poorer overall survival vs other forms of breast cancer
• Historically, limited treatment options
Saha P, Nanda R. Ther Adv Med Oncol. 2016; Marra A, et al. BMC Med. 2019;
Schmid P, et al. N Engl J Med. 2018; Jia H, et al. Drug Resist Updat. 2017; Lebert JM, et al. Curr Oncol. 2018.
All Breast
Cancers
ER+
65%–75%
HER2+
15%–20%
Triple
negative
15%

25. The Current Paradigm: Metastatic Treatment
HER2-Negative*
Preferred Regimens
• Anthracyclines
• Doxorubicin
• Liposomal doxorubicin
• Taxanes
• Paclitaxel
• Anti-metabolites
• Capecitabine
• Gemcitabine
• Microtubule inhibitors
• Vinorelbine
• Eribulin
• For germline BRCA1/2 mutations see additional targeted therapy options (BINV-R)
• Platinum (option for patients with triple-negative tumors and germline BRCA1/2
mutation)
• Carboplatin
• Cisplatin
• For PD-L1–positive TNBC see additional targeted therapy options (BINV-R)e
Other Recommended Regimens
• Cyclophosphamide
• Docetaxel
• Albumin-bound paclitaxel
• Epirubicin
• Ixabepilone
Useful in Certain Circumstances
• AC (doxorubicin/cyclophosphamide)
• EC (epirubicin/cyclophosphamide)
• CMF (cyclophosphamide/methotrexate/fluorouracil)
• Docetaxel/capecitabine
• GT (gemcitabine/paclitaxel)
• Gemcitabine/carboplatin
• Paclitaxel/bevacizumab
• Carboplatin + paclitaxel or albumin-bound paclitaxel
NCCN Guidelines. Breast Cancer. v3.2020.*All recommendations are category 2A unless otherwise noted.

26. KEYNOTE 355: Pembrolizumab + chemo for 1L mTNBC
Presented By Erika Hamilton at TBD

27. KEYNOTE 355: Progression-free survival
Presented By Erika Hamilton at TBD

28. Summary of Key IO Trials in TNBC
Presented By Erika Hamilton at TBD

29. Immune mediated AEs with Pembrolizumab
Presented By Erika Hamilton at TBD

30. New Drug Approval

31. Sacituzumab Govitecan: An ADC Targeting Trop2
Bardia A, et al. N Engl J Med. 2019;380(8):741-751.
Other ADCs being investigated in TNBC
-Ladiratuzumab (LIV1A)
-Trastuzumab deruxtecan (HER2 1-2+)

32. Drugs in Development for Advanced TNBC
• Immunotherapy
– With chemo and other targeted therapies
• PARP Inhibitors (approved for BRCA1&2 mutation carriers
alone)
– Alone or with chemo or immunotherapy
• Antibody Drug Conjugates
– Sacituzumab approved, others being investigated
• Androgen Receptor Antagonists

33. What this means for patients?

34. Treatment of ER+ MBC
• First line therapy with cdk 4/6 inhibitor + endocrine backbone
(aromatase inhibitor) is current standard for most patients
• 3 approved cdk 4/6 inhibitors:
– Palbocliclib, Ribocliclib, Abemacliclib
• In 2019: Alpelisib was recently FDA approved (+fulvestrant)
for pts with PIK3C mutations
– SOLAR study – most patients received endocrine therapy alone

35. CDK 4/6i + AI: 1L therapy for HR+/HER2- MBC
Presented By Erika Hamilton at TBD

36. FALCON: Fulvestrant beats AI for 1st line HR+ MBC
Presented By Erika Hamilton at TBD

37. PARSIFAL: Fulvestrant or Letrozole in combination with Palbociclib
Presented By Erika Hamilton at TBD

38. PARSIFAL: PFS ITT Analysis
Presented By Erika Hamilton at TBD

39. Slide 4
Presented By Hope Rugo at TBD

40. BYLieve: A Phase 2, Open-Label, 3-Cohort, Noncomparative Trial (NCT03056755)
Presented By Hope Rugo at TBD

41. <br />Efficacy: Primary Endpoint and PFS Results<br /><br />
Presented By Hope Rugo at TBD

42. What this information means for patients?

43. Role of Surgery to Primary Tumor in
De Novo Metastatic Breast Cancer

44. Background
Presented By Seema Khan at TBD

45. Should Treatment of De novo Metastatic Breast Cancer (MBC) include Local Regional Therapy for the Primary?
Presented By Julia White at TBD

46. Completed randomized trials testing the value of LRT in de novo Stage IV breast cancer have provided conflicting data
Presented By Seema Khan at TBD

47. Design of E2108 <br />Opened in 2011, last patient enrolled in 2015. <br />
Presented By Seema Khan at TBD

48. No Improvement in Survival from Early Local Therapy<br />E2108
Presented By Julia White at TBD

49. Summary: De novo Stage IV Breast Cancer
Presented By Julia White at TBD

50. What this means for patients?

51. Discussing new therapies and data
with your cancer doctor
• Be proactive and ask questions about how the new
information pertains to your situation
• Ask for clarity if you don’t understand
– Don’t be afraid to ask the ‘basic questions’
• Previsit – send your doctor questions electronically
– Allows for preparation
• Bring a list of written questions
• Extra set of ears is important!!

52. Communication Best Practices
• Every patient is unique. Your treatment plan will reflect a
personalized approach to your biology and situation.
• Keys to great doctor-patient relationship:
– Presence, Trust, Collaboration, Open minded
– Willingness to answer questions and address concerns
• There will be challenges
– Changes in therapy; Differences in Opinions
– Conversations about end of life care/planning
• Even in Zoom world; there is role for face to face discussions
– May be Different for Established vs. New Patients

53. How to find a clinical trial
• Ask you doctor
• Academic cancer center have intakes offices
– Nurse navigation and research staff
– Cancer center websites
• Clinicaltrials.gov
• Local and National Advocacy groups:
– ACS, CancerCare, Komen, Living Beyond Breast Cancer
– And many more

54. Thank you!
• Acknowledgements to Dr. Rita Nanda (UChicago) and presenters at ASCO 2020 Virtual Meeting for slides