Learn about the latest treatment options for advanced triple-negative breast cancer. Nancy Lin, MD, a breast oncologist in the Susan F. Smith Center for Women's Cancers at Dana-Farber, discusses new research.
This presentation was originally given as part of the 2015 Metastatic Breast Cancer Forum, held at Dana-Farber Cancer Institute in Boston, Mass. on Oct. 17, 2015.
More information is available at http://www.susanfsmith.org.
Using Data Visualization in Public Health Communications
What's New in Treatment and Clinical Trials for Advanced Triple-Negative Breast Cancer
1. What’s New in Treatment and
Clinical Trials for Advanced Triple-
Negative Breast Cancer
Nancy Lin, MD
Susan F. Smith Center for Women’s Cancers
Dana-Farber Cancer Institute
October 17, 2015
2. Outline
• Definitions: What is TNBC?
• Treatment: How do we treat TNBC?
• New Directions: What are some exciting
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
– But--most patients with triple negative breast cancer do not carry a
hereditary BRCA1 mutation
– Other hereditary mutations: PALB2, RAD51c, BARD1
– National guidelines recommend consideration of genetic testing in women
younger than age 60 with TNBC, regardless of family history
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?
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
– Other health problems
• Blood counts, neuropathy, diabetes, heart problems, liver
function
Choice of Chemotherapy in Metastatic TNBC
9. Drug Route Hair loss Diarrhea Neuropathy PPE Allergic
reactions
Paclitaxel
(Taxol)
IV weekly
2 or 3 wks in a row
Then off 1 wk
Yes No Yes No Possible
Capecitabine
(Xeloda)
Oral twice daily
2 wks in a row
Then off 1 wk
No Yes No Yes No
Eribulin
(Halaven)
IV weekly
2 wks in a row
Then off 1 wk
Sometimes No Yes No No
Choice of Chemotherapy in Metastatic TNBC:
One example
•Was a taxane given previously for early-stage disease? If yes, how long ago?
•What chemotherapies have been given for metastatic cancer previously?
•Able to take and absorb pills?
•How is the liver function?
•On coumadin (warfarin)?
•Problems with blood sugar control?
10. Is all TNBC the same?
ER-negative, PR-negative
HER2-negative
13. 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
14. 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 (everolius, others)
Androgen (testosterone)
signaling
Anti-androgens (bicalutamide, enzalutamide),
Immune CTLA4 blockade (ipilumumab), PD1/PD-L1 blockade
(nivolumab, pembrolizumab, MPDL3280A),
Antibody-drug conjugates IMMU-132, SGN-LIV1A, PF06647263, CDX-011
Cell cycle Dinaciclib
Chk1 GDC0575
Bromodomain TEN-101, GSK525762
Heat shock (stress) Ganetespib, others
Angiogenesis Ramucirumab, cedirinib
16. 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
17. Olaparib in BRCA 1/2 Carriers with
Metastatic Breast Cancer
Tutt et al, 2010
18. Ongoing Olaparib Trial*
Inherited BRCA 1
or
BRCA2 mutation
Up to 2 previous
types
of chemotherapy
for MBC
Olaparib
Choice of standard chemotherapy
-Capecitabine (Xeloda)
-Vinorelbine (Navelbine)
-Eribulin (Halaven)
*Other PARP inhibitors being evaluated in a similar fashion
23. 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.
24. Immunotherapy trials available at DFCI
FIRST LINE TNBC
Protocol # Short Title Eligibility
15-241 Ph3 Abraxane +/- Atezolizumab (PDL1 Ab) Measurable Disease
No prior treatment for metastatic dz
15-307 Ph1/2 Eribulin + Pembrolizumab
SECOND LINE and BEYOND TNBC
15-240 Phase 2 Pembrolizumab Monotherapy 2L+ Measurable disease
Biopsy required
Prior A + T required
15-307 Ph 1/2 Eribulin + Pembrolizumab
11-314 Atezolizumab (PDL1) monotherapy for PDL1+
TNBC
Requires tumor prescreening
Any line of therapy
28. Targeting AR in the Clinic
• Bicalutamide
– TBCRC 011 study
– No objective responses…but 21% had stable disease >
6 months
• Enzalutamide
– Study MDV 3100-11
– 20% of patients had stable disease > 6 months
– “PredictAR” gene signature sorted patients (with 0-1
prior treatments) to those with average disease
control 2 months vs 10 months
30. Antibody Drug Conjugates in TNBC
30
1. Monoclonal antibody specific
for a tumor antigen with
little/no expression on normal
cells
2. Linker that is stable in
circulation but releases the
cytotoxic agent in target cells
3. Potent cytotoxic agent designed
to induce target cell death
when internalized and released
31. IMMU-132
• Target: Trop2 (EGP-1)
– Oncogene associated with increased aggressiveness
and metastasis.
– Prognostic marker in several cancer types
• Linker: pH sensitive linker (CL2A)
• Cytotoxic: SN-38 (Irinotecan active metabolite)
– 7.6 drug molecules/IgG
31
32. Phase I/II Trial of Sacituzumab
Govitecan (IMMU-132), an anti-Trop-
2-SN-38 antibody-drug conjugate, in
refractory/relapsed metastatic triple-
negative breast cancer
Aditya Bardia1, Linda T. Vahdat2, Jennifer R. Diamond3, Alexander N. Starodub4, Rebecca
Moroose5, Steven Isakoff 1, Allyson J. Ocean2, Jordan D. Berlin6, Wells A. Messersmith3, Sajeve
S. Thomas5, Francois Wilhelm7, William A. Wegener8, Pius P. Maliakal7, Robert M. Sharkey7,
David M. Goldenberg7, Ingrid A. Mayer6
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; 2Weill Cornell Medical
College, New York, NY; 3Vanderbilt-Ingram Cancer Center, Nashville, TN; 3University of Colorado Cancer
Center, Aurora, CO;4Indiana University Health Center for Cancer Care, Goshen, IN; 5UF Health Cancer Center,
Orlando, FL; 6Vanderbilt-Ingram Cancer Center, Nashville, TN; 7Immunomedics, Inc., Morris Plains, NJ.
32
34. CDX-011 (glembatumumab vedotin)
• Target: GPNMB
• Cytotoxic- monomethyl-aurostatin E (MMAE)
• EMERGE study – Ph2 CDX-011 vs Investigator Choice
• 122 pts enrolled (TNBC/ER+), median 6 prior
regimens
34
35. Phase 2 EMERGE study
CDX-011 vs Investigator’s choice of rx
35
Common treatment related AE’s: rash, fatigue, nausea, neutropenia, alopecia
*Median number of lines of cytotoxic rx for MBC=4
*
Yardley et al JCO 33:1609, 2015
36. METRIC study
Glembatumumab Vedotin
1.88 mg/kg IV Day 1 of 21-
day cycles
Capecitabine 1250 mg/m2
BID Days 1-14 of 21-day
cycles
2:1 randomization
Primary Endpoint
• Progression free survival by independent review
N=300
Metastatic TNBC
overexpressing gpNMB
0-2 prior chemo for MBC
Prior Taxane and
anthracycline
ClinicalTrials.gov Identifier: NCT01997333
37. Other Antibody Drug Conjugates in
Development for TNBC
• SGN-LIV1A
– Target: LIV-1, transmembrane protein in
65% TNBC
– Ph1 in breast ca ongoing
• PF-06647263
– Target: EFNA4
– Phase 1 in breast cancer ongoing
37
38. How Can We Do Better?
Participate in 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)
39. 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.
41. 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 on-line resources
• Consider receiving care and/or consultation in a center
with a focus on clinical trials
42. 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 entering a trial!
• Future progress depends on.....Making every woman count!