Triple-negative breast cancer is an area of very active research, with many exciting new agents and approaches in the pipeline.

1. What’s New in Biology, Treatment
and Clinical Trials for Metastatic
Triple-Negative Breast Cancer
Nancy Lin, MD
Susan F. Smith Center for Women’s Cancers
Clinical Director, Breast Oncology Center
Geoffrey Shapiro, MD, PhD
Director, Early Drug Development Center
Dana-Farber Cancer Institute

2. Outline
• Definitions: What is TNBC?
• Treatment: How do we treat TNBC?
• New Directions: What are some approaches
being tested in clinical trials?
• Clinical Trials: Which, why, how, when?

3. • There are three main subtypes of
breast cancer
• 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

4. Breast Cancer Subtypes
Breast Cancer Subtypes
ER-positive
HER2-positive
Triple-negative
TALK to your doctor if you are not sure what type of breast cancer you have

5. “Triple Negative” Breast Cancer (TNBC)
• Defined as negative for estrogen, progesterone, and HER2 receptors
• Represents about 15% of all breast cancer
• More likely to present in younger women and in women of African
ancestry
• May be associated with an inherited mutation in BRCA1
– National guidelines recommend consideration of genetic testing in women
younger than age 60 with TNBC, regardless of family history
– But--most patients with triple negative breast cancer do not carry a
hereditary BRCA1 mutation

6. Hormonal
therapy
Hormonal
therapy
Chemotherapy Chemotherapy
Chemotherapy Chemotherapy Chemotherapy
Herceptin +
perjeta +
chemotherapy
TDM1
Lapatinib +
Capecitabine
Herceptin +
chemotherapy
Herceptin +
chemotherapy
Hormone receptor
positive
Triple-negative
HER2-Positive
*Note, these are just examples. Each patient is different and treatment is tailored accordingly.
How Do We Treat
Metastatic Breast Cancer?

7. Chemotherapy for Metastatic TNBC
Many active and tolerable chemotherapy choices

8. • Order of chemotherapy does not appear to influence
survival
• Choose chemotherapy based on:
– Activity level seen in clinical trials
– Amount of active cancer/need for rapid response
– Prior treatments
– Route of administration (pills versus IV)
– Side effect profile
– BRCA 1/2 status
– Other health problems
• Blood counts, neuropathy, diabetes, heart problems, liver function
Choice of Chemotherapy in Metastatic TNBC

9. Drug Route Hair loss Diarrhea Neuropathy Hand
foot
redness
Effect on
blood
counts
Paclitaxel
(Taxol)
IV weekly
2 or 3 wks in a
row Then off 1
wk
Yes No Yes No +
Capecitabine
(Xeloda)
Oral twice daily
2 wks in a row
Then off 1 wk
No Yes No Yes +
Eribulin
(Halaven)
IV weekly
2 wks in a row
Then off 1 wk
Sometimes No Yes No ++
Choice of Chemotherapy in Metastatic TNBC:
One example
•What chemotherapies have been given previously? How long ago?
•Able to take and absorb pills?
•How is the liver function?
•How important is avoidance of hair loss?
•Any baseline neuropathy and how severe?

10. Is all TNBC the same?
ER-negative, PR-negative
HER2-negative

11. Heterogeneity of TNBC
TNBC is not just one disease—
Different subtypes likely have different “Achilles’ heels”
VEGF
EGFR
PTEN
loss
BRCA1-
Basal-like
AR
Immune
infiltrate

12. Many Approaches Under Evaluation for TNBC
in Clinical Trials
Pathway/Drug type Drugs in development
DNA repair PARP inhibitors (olaparib, rucaparib, veliparib), platinum
agents (cisplatin, carboplatin)
PI3K/Akt/mTOR PI3K inhibitors (buparlisib, taselisib, GDC0941,
AZD8186, many others); Akt inhibitors (GDC0068,
others), mTOR inhibitors (everolimus, others)
Androgen (testosterone)
signaling
Anti-androgens (bicalutamide, enzalutamide)
Immune CTLA4 blockade (ipilumumab), PD1/PD-L1 blockade
(nivolumab, pembrolizumab, atezolizumab),
Antibody-drug conjugates IMMU-132, SGN-LIV1A, PF06647263, CDX-011
Cell cycle Dinaciclib, seleciclib
Chk1 GDC0575
Bromodomain TEN-101, GSK525762
Heat shock (stress) Ganetespib, others
Angiogenesis Ramucirumab, cedirinib

13. Targeting DNA repair

14. Environmental Insults Cause DNA Damage
Cross-linking
agents
Cross-links
DNA Damage leads to mutations that can contribute to development of cancer

15. Chemotherapy and radiation used in cancer
treatment also damage DNA
Normal Cells Cancer cells
Six normal DNA
repair
pathways
+ + + + + +
Cancer cells are often deficient in
one or more DNA repair pathway
− + + + + +

16. Cancer cells may become hyper-dependent on a
second DNA repair pathway
Six normal DNA
repair pathways
Normal cells
One defective
pathway leads to
hyper-dependence on
a second pathway
Cancer cells
+ + + + + + −
+
+ + + +

17. The status of the six DNA Repair Pathways can
drive treatment decisions (Precision Medicine)
Cancer Status Clinical Decision
One pathway is defective Use a chemotherapy drug that
requires that pathway for repair
Pathway is restored and the cancer
becomes resistant
Use a chemotherapy drug + an
inhibitor of the restored pathway to
re-sensitize the cancer (combination
treatment)
One pathway is defective and the
cancer is hyper-dependent on a
second pathway
Use an inhibitor of the second
pathway

18. TNBC may be defective in the homologous
recombination (HR) repair pathway
Cancer Status Clinical Decision
HR pathway is defective (inherited
or acquired BRCA mutation)
Sapacitabine or cisplatin damage
DNA in a way that requires HR for
repair; cancer cells defective in HR
are highly sensitive to these agents
HR pathway is restored and the
cancer becomes resistant
Use sapacitabine or cisplatin +
a 2nd drug that disrupts HR (e.g. CDK
inhibitor, HSP90 inhibitor, PI3-Kinase
inhibitor)
Cell defective in the HR pathway
become hyper-dependent on a
second pathway called alt-NHEJ
Alt-NHEJ requires the PARP enzyme.
A PARP inhibitor blocks alt-NHEJ and
is lethal to an HR-defective cancer
cell.

19. Basis of Use of PARP inhibitors in HR-
deficient breast cancer (BRCA-mutated)

20. Concept of Synthetic Lethality
Cancer Status Inhibition of PARP1 Repair Status Cellular Outcome
HR-proficient
(BRCA WT)
– PARP repairs SSBs Cancer and Normal
Cell Survival
HR-proficient + HR (BRCA1/2)
repairs DSBs
Cancer and Normal
Cell Survival
HR-deficient
(BRCA mutated)
– PARP repairs SSBs Cancer and Normal
Cell Survival
HR-deficient
(BRCA mutated)
+ HR is defective
Alt-NHEJ cannot
compensate
No Repair
Normal Cell Survival
Cancer Cell Death
DNA Damage Single-Strand Break Double-Strand Break

21. Concept of Synthetic Lethality has translated to positive
clinical outcomes in patients treated with a PARP inhibitor
(olaparib)

22. Platinum Agents and Breast Cancer
• Include the drugs cisplatin and carboplatin
• DNA cross-linking agents—so there is reason to believe they may
be especially effective in patients with BRCA ½ mutations and/or
with triple negative breast cancer
• These drugs are active in breast cancer in general….but the
questions is:

23. Platinum Agents and Breast Cancer
• Include the drugs cisplatin and carboplatin
• DNA cross-linking agents—so there is reason to believe they may
be especially effective in patients with BRCA ½ mutations and/or
with triple negative breast cancer
• These drugs are active in breast cancer in general….but the
questions is:
How does platinum chemotherapy compare
with other chemotherapy drugs?

24. TNT Trial
Metastatic TNBC
Or
BRCA ½ associated breast cancer
Platinum chemotherapy
Taxane chemotherapy

25. Tutt et al, SABCS 2014

26. PARP Inhibitors
•Tumors of BRCA 1/2+
patients lose 2
important ways to
repair DNA when
treated with a PARP
inhibitor
•Multiple trials testing
PARP vs chemo in
BRCA 1/2 carriers
•Trials combining PARP
with other drugs in
BRCA 1/2 non-carriers

27. Phase 3 Trials Ongoing
Inherited BRCA 1
or
BRCA2 mutation
Up to 2 previous
types
of chemotherapy
for MBC
PARP inhibitor
Choice of standard chemotherapy
-Capecitabine
-Vinorelbine
-Eribulin
-Gemcitabine (allowed in BRAVO and EMBRACA)Olaparib – OLYMPIAD – NCT02000622
Niraparib – BRAVO – NCT01905592
BMN673 – EMBRACA – NCT01945775
Completed accrual, awaiting results
Accruing
Accruing

28. Targeting the Androgen Receptor

29. Androgen Receptor Function: The Basics
Testosterone
Androgen
Receptor

30. Androgen Receptor Function: The Basics
Testosterone
Androgen
Receptor
DNA

31. Targeting AR in the Clinic
• Bicalutamide
– 21% had stable disease > 6 months
• Enzalutamide
– 20% of patients had stable disease > 6 months
– “PredictAR” gene signature sorted patients to those
with average disease control 2 months vs 10 months
– Phase III study (ENDEAR) to be launched will compare
Taxol vs enza vs combination of Taxol + enza for
predictAR+ve patients
Gucalp et al, CCR 2013; Traina et al, ASCO 2015

32. Modulating the immune system

33. The Immunity Cycle

34. APC-T Cell Interaction
T"cell
TCR
CD28
CTLA4
APC
MHC
CD28
B7
T"cell&inhibition
T"cell
TCR
CD28
CTLA4
APC
MHC B7
T"cell&activation
T"cell
TCR
CD28
CTLA4
APC
MHC B7
T"cell&potentiation
Antibody
binds
CTLA"4
X
B7-CTLA-4 interaction is an immune checkpoint.
CTLA-4 antibodies (e.g. ipilimumab) produced the first prolongation in survival
in patients with advanced melanoma

35. The Immunity Cycle

36. T-Cell – Tumor Cell Interaction

37. Adaptive Immune Resistance
• PD-1 – PD-L1 interaction is an immune checkpoint.
• PD-1 or PD-L1 antibodies re-activate the T cells in order to attack the cancer cells
• PD-1 antibodies: Opdivo (nivolumab), Keytruda (pembrolizumab)
• PD-L1 antibody: Tecentriq (atezolizumab)
• Drugs approved for melanoma, lung cancer, renal cell cancer, bladder cancer

38. Durability of Responses is driving the
excitement for this anti-cancer strategy
Data in > 1800 melanoma patients treated with ipilimumab

39. aKaplan-Meier estimate.
Analysis cut-off date: November 10, 2014.
0 8 16 24 32 40 48 56
Time, weeks
Responder
Nonresponder
CR
PR
SD
PD
PD after CR, PR, or SD
Last dose
Treatment ongoing
Best overall response
A Phase Ib Study of Pembrolizumab (MK-3475,anti-PD-1 Ab)
in Patients With Advanced Triple-Negative Breast Cancer.
Nanda et al.
Overall response rate 18.5%
Median time to response 17.9 weeks
Median duration of response not yet reached
Nanda et al, JCO 2016

40. Challenges in Breast Cancer I:
Weak activation of T Cells

41. Strategy: Stimulate anti-tumor immunity
• Chemotherapy
• Radiation
• PARP inhibitors
• Combinations
with other
immunotherapy
agents

42. Atezolizumab (anti-PDL1)
+ nab-Paclitaxel
Adams S, et al. SABCS 2015
Best Overall
Response
1L
(n=9)
2L
(n=8)
3L+
(n=7)
All patients
(n=24)
ORR
(95% CI)
CR
PR
67%
(30, 93)
11%
78%
25%
(3, 65)
0
75%
29%
(4, 71)
0
43%
42%
(22, 63)
4%
67%
SD 11% 25% 29% 21%
PD 0 0 29% 8%

43. Challenges in Breast Cancer II:
Complexity of the Immune Microenvironment
Anti-
Tumor
T Cell
Several other cell types may prevent activation and proliferation of the T cells (CD8 cells)
capable of killing tumor cells.
Strategy: Administer agents capable of disabling T-Regs MDSCs or of reprogramming
macrophages

44. Challenges in Breast Cancer III:
Other Immune Checkpoints Turn off T Cells in
addition to PD-1 – PD-L1
Strategy:
Anti-LAG-3 and
Anti-TIM-3
antibodies

45. Summary of Additional Immune Targets

46. Antibody-Drug Conjugates

47. Antibody Drug Conjugates
1. Antibody that recognizes a
marker on tumor cells that is
not/less present on normal
cells
2. Linker that is stable in
circulation but releases the
drug in target cells
3. Potent drug designed to attack
the cancer cell when
internalized and released

48. Antibody Drug Conjugates
Tumor cell

49. Antibody Drug Conjugates
Tumor cell

50. Antibody Drug Conjugates
Tumor cell

51. Antibody Drug Conjugates
Tumor cell

52. Antibody Drug Conjugates
Tumor cell

53. Antibody Drug Conjugates in
Development for TNBC
• IMMU-132
– Target: Trop2
– Phase 1/2 trial completed, phase III trial planned
• CDX-011
– Target: TPNMB
– Phase 2 completed, phase 3 trial ongoing
• SGN-LIV1A
– Target: LIV-1
– Ph1 in breast ca ongoing
• PF-06647263
– Target: EFNA4
– Phase 1 in breast cancer ongoing
53

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111-006
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254-019
252-001
181-004
255-021
255-027
111-013
254-016
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204-009
-1 0 0
-8 0
-6 0
-4 0
-2 0
0
2 0
4 0
6 0
8 0
1 0 0
BestResponse
(%changeintargetlesionfrombaseline)
Prior chemotherapies = 4 (median; range=1-11)
IMMU-132
54
Objective response = 15/49 = 31%
Disease control = 37/49 = 76%
Clinical benefit ratio [CR+PR+(SD ≥4 mo)] = 63%*
15 May 2015
Bardia et al

55. How Can We Make Progress?
Support Clinical Trials!
• “One reason I chose to participate in a clinical trial
was to help women with triple-negative breast
cancer. It is thanks to women who have enrolled in
clinical trials that we have the treatments that give
us hope.”
– Natalia (LBBC, Guide to Understanding TNBC)

56. 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
• Is being on a trial busy?
– Each trial is different and has a different schedule
• 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.

57. How to learn about trials?
• Know what subtype of breast cancer you have
• Learn about your family history and consider BRCA
testing
• Talk to your doctor and/or nurse
• Consider receiving care and/or consultation in a center
with a focus on clinical trials
• Consider on-line resources

58. Advanced TNBC: Conclusions
• TNBC is unique compared to other types of breast cancer
• Not all TNBC is the same
• Chemotherapy works for TNBC, and there are a number of standard
options
• No single best target has been identified so far; however, TNBC is an area
of very active research; many exciting new agents and approaches in the
pipeline
• Speak to your provider about whether a trial is an option for you
• Future progress depends on.....Making every woman count!