Pathology and Oncology Expert Perspectives in the
Management of Triple-Negative Breast Cancer:
Case Explorations and Answers to FAQs
Ira J. Bleiweiss, MD
Professor of Pathology and
Laboratory Medicine
Perelman School of Medicine
Chief of Breast Pathology
Hospital of the University of Pennsylvania
Sara M. Tolaney, MD, MPH
Chief, Division of Breast Oncology
Associate Director
Susan F. Smith Center for Women's Cancers
Dana-Farber Cancer Institute
Associate Professor of Medicine
Harvard Medical School

Disclosures
Ira J. Bleiweiss, MD
No relevant financial relationships to disclose
Sara M. Tolaney, MD, MPH
Advisory board/panel: 4D Pharma, ARC Therapeutics, Artios, AstraZeneca, Bayer,
BeyondSpring, Bristol Myers Squibb, Eisai, Genentech/Roche, Gilead, Incyte, Lilly,
Menarini/Stemline, Merck, Myovant, Novartis, Pfizer, Reveal Genomics, Sanofi, Seagen,
Umoja Biopharma, Zentalis, and Zymeworks
Consultant: Aadi Bio, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, CytomX,
Daiichi Sankyo, Eisai, Genentech/Roche, Gilead, Lilly, Menarini/Stemline, Merck,
Novartis, OncXerna, Pfizer, Seagen, and Zetagen
Grants/research support: AstraZeneca, Bristol Myers Squibb, Cyclacel, Eisai, Exelixis,
Genentech/Roche, Gilead, Lilly, Merck, Nanostring, Novartis, OncoPep, Pfizer, Sanofi,
and Seagen
i3 Health has mitigated all relevant financial relationships

Learning Objectives
TNBC = triple-negative breast cancer.
Evaluate receptor and expression status for prognostication and treatment
selection in TNBC
Differentiate the pathological characteristics of the various types of TNBC
Select optimal therapy for TNBC based on shared goals, biomarker testing,
and clinical data on novel therapies
Discuss strategies for timely recognition and mitigation of adverse events
associated with novel TNBC therapies

Overview of TNBC:
Epidemiology and Clinical Burden

Features of Triple-Negative Breast Cancer
10%-15% of all breast cancers
Defined by immunohistochemistry
Lacks expression of ER and PR, and low or no expression of HER2
Affected patients more often younger (<40 years old), Black
May be associated with BRCA1 mutations and/or BRCA pathway
dysfunction
ER = estrogen receptor; PR = progesterone receptor; HER2 = human epidermal growth factor receptor 2.
ACS, 2023.

TNBC Has Poorer Prognosis Than Other BC Subtypes
BC = breast cancer.
Foulkes et al, 2010; Dent et al, 2007; Gaedcke et al, 2007; Nofech-Mozes et al, 2009.
High initial sensitivity to chemotherapy
However, there are high relapse rates and
higher likelihood of distant disease progression
More aggressive visceral disease (liver, lung)
Higher frequency of brain metastases
TNBC recurrence peaks within the first 3 years
after treatment
The likelihood of distant recurrences
postsurgery declines after 5 years
The mean time to distant recurrence is
approximately 2.4 years for TNBC compared
with 4.4 years for ER+ patients
Most deaths occur in the first 3-5 years

Testing Guidelines and Methods
for Hormone
(Estrogen/Progesterone)
Receptors and HER2:
a Pathologist’s View

What Is My Approach to Biomarker Testing?
bx = biopsy.
NCCN, 2023.
Major pro: allows direct visual assessment of tumor by pathologist
Currently: estrogen receptor/progesterone receptor (ER/PR) and HER2
assessed on every new invasive carcinoma (almost always core bx)
Test multiple primaries? No, unless they have different histologies
Test core bxs of lymph nodes? Yes, generally, but no guidelines
I assess likelihood of positive staining based on tumor type, grade, patient
age
My goal: maximize chance of a positive stain, overcome heterogeneity –
more likely for PR, less for ER, even less for HER2
Routine by Immunohistochemistry (IHC)

What Is My Approach to Biomarker Testing? (cont.)
FISH = fluorescence in situ hybridization; chemorx = chemotherapy.
NCCN, 2023; Allison et al, 2020; Wolff et al, 2023.
Retest negative stains (ER, HER2) on surgical specimens
Repeat testing on residual invasive tumor after neoadjuvant chemorx
Current testing definition of triple-negative:
Negative ER: <1% invasive tumor cells staining
Negative PR: <1% invasive tumor cells staining
Negative HER2: 0 or 1+ (weak staining), or 2+ with negative in situ
hybridization (ISH) – note that a 2+ IHC result reflexively results in ISH
testing, usually FISH
Routine by IHC

But Things Are Rarely That Simple
ASCO/CAP = American Society of Clinical Oncology/College of American Pathologists; RT-PCR = reverse transcriptase polymerase chain reaction.
Hammond et al, 2010; Allison et al, 2020.
After numerous prior changes in guidelines:
2010 ASCO/CAP guidelines: ER/PR+ if >1% tumor cells any staining.
Meant to maximize antihormonal therapy, not missing patients
However: this created a subclass of borderline ER cases,
qualified for 21-gene testing, but 21-gene testing results often
ER– by RT-PCR, meaning ? Most of these patients behaved like
triple-negative
Currently, 2019 ASCO/CAP guidelines created a new category,
ER/PR low positive, if any intensity staining in 1%-10% of
invasive tumor
A Bit of ER/PR Guidelines History

Biomarker Testing: PD-L1
PD-L1 = programmed cell death ligand 1; met = metastasis.
NCCN, 2023; Marletta et al, 2022.
Non-bone distant metastatic triple-negative breast carcinoma:
IHC testing for PD-L1, using antibody 22C3
Complicated interpretive guidelines, difficult to interpret, subjective:
Staining of both tumor and inflammatory cells
Often extreme intratumoral heterogeneity – overcome by staining one
block from each available specimen: primary, lymph node met, distal
met. Note: not validated on bone mets or on cytology
Reflex Testing by IHC

What Are Caveats of Biomarker Testing?
Taqi et al, 2018; Allison et al, 2020.
Many factors can influence staining accuracy, including preanalytic:
Time until formalin fixation
Duration of formalin fixation
Thickness and quality of tissue
Decalcification method
Staining platform used
Interpretative:
Invasive tumor only – sometimes difficult
Semi quantitative % vs machine-read precise %
Experience of interpreting pathologist
Internal positive controls to assure valid test
IHC

What Should the Pathology Report Include?
Slide courtesy of Ira J Bleiweiss, MD.
For ER/PR, should clearly state:
Positive, low positive, or negative
% cells staining and average stain intensity (0-3+)
For HER2, should clearly state:
Positive, equivocal, or negative with stain intensity (0-3+)
Any ISH results: ratio of HER2 to normal control, average HER2 copy
#/cell
Presence or absence of adequate internal controls
All above followed by required explanatory paragraph
Biomarker Testing: Reporting

Clinicopathological
Characteristics and Prognosis

Pathology of TNBC
Bleiweiss, personal communication, 2023; Amin et al, 2017; Handa et al, 2015.
Important facts to be aware of:
1. ER status correlates strongly with nuclear grade of breast cancer, ie, little
to no nuclear variation (lack of pleomorphism) = ER+
2. Variability in nuclear size and shape tends to be ER–
3. Above depends also on age. Severe nuclear pleomorphism in older,
postmenopausal patients may be ER+, while same in younger patients
tends to be ER–
4. Since nuclear pleomorphism is a large determinant of grade, most triple-
negative breast cancer is poorly differentiated duct (with exceptions to
follow)
Not Just 1 Type of Cancer

Pathology of TNBC (cont.)
NOS = not otherwise specified.
Images courtesy of Ira J. Bleiweiss, MD.
Usual Type: Poorly Differentiated Duct, NOS
ER–, PR–, HER2–

NOS = not otherwise specified.
Usual Type: Poorly Differentiated Duct, NOS
Patch of ER positivity today
would be called low positive

WT1 = Wilms' tumor gene 1.
Subtype: BRCA1 Mutation–Associated Patient With Breast and Ovarian
Chronic inflammatory infiltrate, “medullary” features
Breast
Breast
ER–, PR–, HER2–, WT1–

Subtype: BRCA1 Mutation – Breast and Ovarian
Ovarian primary, not metastatic breast, even higher grade
Omentum Omentum-WT1 Omentum-ER

What are some unusual variants of
TNBC to be aware of?

diff = differentiated.
Metaplastic Carcinoma: Duct + Squamous ± Sarcoma
Chondrosarcoma
Osteosarcoma
Relatively chemo-resistant

Rare Adenoid Cystic Carcinoma: GOOD Prognosis, Solid, Basaloid
Variant-Worse

LGASC = low-grade adenosquamous.
Low-grade
adenosquamous
Rare Metaplastic GOOD Prognosis: Fibromatosis-Like, LGASC

Special Rare Types: Secretory, Apocrine (Can Be HER2+)

What Are Caveats in the Pathology Report?
Dx = diagnosis.
Min et al, 2013; Kim et al, 2011.
Be very wary if pathology report reads:
infiltrating well-differentiated duct carcinoma,
ER–/PR–/HER2–
Something is wrong – grade, staining, mixup,
or diagnosis
This core bx was called tubular carcinoma,
triple-negative that does not exist
Dx: microglandular adenosis
Rare but benign

What Are Caveats in the Pathology Report? (cont.)
Marrazzo et al, 2020; Pareja et al, 2019; Kaur et al, 2022.
Be very wary if pathology report reads:
mucinous carcinoma, ER–/PR–/HER2–
Something is wrong – grade, staining, mixup,
or diagnosis
Possible dx: invasive micropapillary and
mucinous carcinoma or (rare) mucinous
cystadenocarcinoma
Remember: triple-negative breast cancer
should be poorly diff with pleomorphic nuclei

What are the guideline-
recommended treatment
selection and sequencing
strategies for TNBC?

How Do BC Subtypes Compare for Survival?
Howlader et al, 2018; Bauer et al, 2007.
TNBC is associated with shorter overall survival compared with other
subtypes despite anthracycline + taxane therapy

Can we improve outcomes by
adding immunotherapy?

Combining Checkpoint Inhibition With Chemotherapy
Slide courtesy of Sara Tolaney, MD.
Rationale for Combining Pembrolizumab With C
Chemotherapy results in: Pembrolizumab
chemotherapy
pCR=pathologic complete response as defined as ypT0/Tis ypN0; TNBC=triple-negative breast cancer; PAC=paclitaxel, doxorubicin, cy
Tumor lysis
and antigen
sheddinga
PD-L1 expressiond
KN173
(N=60
0
20
40
60
80
100
Before chemo After chemo
PD-L1+
PD-L1+
0
10
20
30
40
50
60
70
Pembro + T/AC ±
pCR
rate,
%

KEYNOTE-355: Study Design
Pembrolizumab + Chemotherapy for Advanced, Metastatic TNBC
Patient Eligibility Criteria:
• Age ≥18 years
• Central determination of TNBC
and PD-L1 expression
• Previously untreated locally
recurrent inoperable or metastatic
TNBC
• Completion of treatment with
curative intent ≥6 months prior
to first disease recurrence
• ECOG performance status 0 or 1
• Life expectancy ≥12 weeks from
randomization
• Adequate organ function
• No systemic steroids
• No active CNS metastases
• No active autoimmune disease
R
2:1
Progressive
disease/cessation of
study therapy
Stratification Factors:
• Chemotherapy on study (taxane vs
gemcitabine/carboplatin)
• PD-L1 tumor expression (CPS ≥1 vs CPS <1)
• Prior treatment with same class chemotherapy in the
neoadjuvant or adjuvant setting (yes vs no)
ECOG = Eastern Cooperative Oncology Group; CPS = combined positive score.
Cortes et al, 2020.
Pembrolizumab + Chemotherapy
Placebo + Chemotherapy

KEYNOTE-355: PFS Analysis
PFS = progression-free survival; ITT = intention to treat.
Rugo, Cortez et al, 2021.
PD-L1 CPS ≥1
PD-L1 CPS ≥10 ITT
Pembro

KEYNOTE-355: Overall Survival at PD-L1 CPS ≥10
Rugo, Cortez et al, 2021.
n/N Events
HR
(95% CI)
P-value
(one-sided)
Pembro + Chemo 155/220 70.5% 0.73
(0.55-0.95)
0.0093*
Placebo + Chemo 84/103 81.6%
58.3%
44.7%
23.0
months
16.1
months
48.2%
34.0%
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
0
10
20
30
40
50
60
70
80
90
100
Time, months
Percentage
of
Patients
No. at risk
220 214 193 171 154 139 105
127 116
103 98 91 77 66 55 35
46 39
91 84 78 73
30 25 22 22
59 17
43 31
17 6
12 8
2 0
2 0

Pembrolizumab for TNBC
AEs = adverse events; Pbo = placebo.
Schmid et al, 2021.
Immune-Mediated AEs and Infusion Reactions in Combined Phases

What about strategies that
target DNA repair?

Efficacy of PARP Inhibitors
PARPi = poly ADP ribose polymerase inhibitor; gBRCA = germline BRCA; TPC = treatment of physician’s choice; mo = months;
ORR = objective response rate; HR = hazard ratio; CI = confidence interval; BICR = blinded independent central review; carbo = carboplatin.
Robson et al, 2017; Litton et al, 2018; Díeras et al, 2020.
OlympiAD
Olaparib vs TPC
EMBRACA
Talazoparib vs TPC
BROCADE3
Veliparib/carbo/paclitaxel
placebo/carbo/paclitaxel
PFS
7.0 mo vs 4.2 mo
HR=0.58
95% CI (0.43-0.80)
8.6 mo vs 5.6 mo
HR=0.54
95% CI (0.41-0.71)
14.5 mo vs 12.6 mo
HR=0.705
95% CI (0.56-0.88)
ORR
59.9% vs 28.8%
(n=100) (n=19)
BICR assessment
62.6% vs 27.2%
(n=137) (n=31)
Investigator assessment
75.8% vs. 74.1%
(n=216) (n=106)
Investigator assessment
Patients With gBRCA Mutations and Metastatic Breast Cancer
Critical to obtain germline testing on all metastatic breast cancer patients to
see if they could be a candidate for PARPi

Safety of PARP Inhibitors
Robson et al, 2017; Litton et al, 2018; Díeras et al, 2020.
OlympiAD
Olaparib vs TPC
EMBRACA
Talazoparib vs TPC
BROCADE3
Velaparib/carbo/paclitaxel vs
placebo/carbo/paclitaxel
Grade ≥3
adverse
events
36.6% vs 50.5%
Hematologic: 55% vs 38%
Nonhematologic: 32% vs 38%
Serious: 25.5% vs 25.4%
97% vs 96%
Most
common
with PARPi
Olaparib
Anemia:
16.1% vs 4.4
Neutropenia:
9.3% vs 26.4%
Fatigue:
2.9% vs 1.1%
Transaminitis:
1.5%-2.4% vs
1.0%-0
Headache:
1.0% vs 2.2%
Talazoparib
Anemia: 39.2% vs 4.8%
Neutropenia: 20.9% vs 34.9%
Thrombocytopenia:
14.7% vs 1.6%
Vomiting: 2.4% vs 1.6%
Back pain: 2.4% vs 1.6%
Dyspnea: 2.4% vs 2.4%
Headache: 1.7% vs 0.8%
Fatigue: 1.7% vs 3.2%
Veliparib + carbo/paclitaxel
Neutropenia: 81% vs 29%
Thrombocytopenia:
40% vs 28%
Anemia: 42% vs 40%
Nausea: 6% vs 4%
Fatigue: 7% vs 4%
Peripheral neuropathy:
4% vs 5%
Diarrhea: 5% vs 3%
Leukopenia: 30% vs 28%
Headache: 1% vs 2%
Vomiting: 4% vs 2%

TBCRC 048: Olaparib for MBC Expanded
MBC = metastatic breast cancer; PALB2 = partner and localizer of BRCA2; gPALM2 = germline PALB2; sBRCA = somatic BRCA;
ATM = ataxia-telangiectasia mutated; CHEK2 = checkpoint serine-threonine kinase 2; PR = partial response; SD = stable disease.
Tung et al, 2020a; Tung et al, 2020b.
Benefit in gPALB2 + sBRCA
PALB2
N=13
sBRCA1/2
N=17
ATM & CHEK2
N=17
Germline: 9/11 PR (82%)
10/11 had tumor regression;
1 SD > 1 year
Somatic: 0/2 – both SD
(limited assessments)
8/16 PR (50%) 0/13 germline
0/4 somatic
New cohorts are beginning for gPALB2 and sBRCA1/2 breast cancer

What about strategies that
use antibody-drug conjugates?

NCCN Guidelines Recommendation
SG = sacituzumab govitecan; T-DXd = trastuzumab deruxtecan; MSI-H = microsatellite instability high; TMB-H = tumor mutational burden–high.
NCCN, 2023.
SG and T-DXd As the Preferred Choice for Second-Line TNBC
NCCN Breast Cancer Guidelines Version 4.2023: HR– and HER2– TNBC
Setting Subtype/Biomarker Regimen
First line
PD-L1 CPS ≥10 regardless of germline BRCA
mutation status
Pembrolizumab + chemotherapy (albumin-bound paclitaxel,
paclitaxel, paclitaxel, or gemcitabine and carboplatin (Category
(Category 1, preferred)
PD-L1 CPS <10 and no germline BRCA1/2
mutation
Systemic chemotherapy
PD-L1 CPS <10 and germline BRCA1/2 mutation
mutation
• PARPi: olaparib, talazoparib (Category 1, preferred)
• Platinum: cisplatin or carboplatin (Category 1, preferred)
preferred)
Second line
Germline BRCA1/2 mutation • PARPi: olaparib, talazoparib (Category 1, preferred)
Any
• Sacituzumab govitecan (Category 1, preferred)
• Systemic chemotherapy
No germline BRCA1/2 mutation and HER2 IHC
1+ or 2+/ISH-negative
Fam-trastuzumab deruxtecan-nxki (Category 1, preferred)
Third line and
beyond
Biomarker-positive
(ie, MSI-H, NTRK, RET, TMB-H)
Targeted agents
Any Systemic chemotherapy

Sacituzumab Govitecan (SG)
Trop-2 = human trophoblast cell-surface antigen 2.
Vidula et al, 2017; Ambrogi et al, 2014; Goldenburg & Sharkey, 2020; Nagayama et al, 2020; Cardillo et al, 2015; Goldenburg et al, 2015; FDA, 2021.
Trop-2 is expressed in all subtypes of
breast cancer and is linked to poor
prognosis
SG is distinct from other ADCs
Antibody highly specific for Trop-2
High drug-to-antibody ratio (7.6:1)
Internalization and enzymatic cleavage by
tumor cell not required for the liberation of
SN-38 from the antibody
Hydrolysis of the linker also releases the
SN-38 cytotoxic extracellularly in the tumor
microenvironment, providing a bystander
effect
Granted FDA approval for metastatic
TNBC
A First-in-Class Trop-2‒Directed Antibody Drug Conjugate (ADC)
Humanized
anti‒Trop-2
antibody
• Directed toward
Trop-2, an
epithelial
antigen
expressed on
many solid
cancers
SN-38 payload
• SN-38 more
potent than
parent
compound,
irinotecan
Linker for SN-38
• Hydrolyzable linker for
payload release
• High drug-to-antibody
ratio (7.6:1)

1) Binding
2) Internalization
3) Intracellular trafficking
4) Lysosomal degradation
5) Cell cytotoxicity
6) Bystander effect
• Rapid internalization and efficient release of the
the SN-38 payload intracellularly in Trop-2–
expressing cancer cells and extracellularly into the
into the surrounding tumor microenvironment
microenvironment
• Before internalization of the ADC, the
linker can be cleaved at the pH of the
tumor microenvironment, releasing SN-38
payload outside the targeted tumor cell
• DNA damage to the targeted cell and
a bystander effect on adjacent tumor
cells that may not express Trop-2 Endosome Lysosome
Bystander effect
1
2
4
3
5
6
6
SG
Tumor cell
Tumor cell
Cell death due to DNA damage
SN-38
Topo 1
SG Is a First-in-Class Trop-2–Directed ADC
Topo 1 = topoisomerase I.
Rugo et al, 2020; Kopp et al, 2023.
Concentrates SN-38 Payload Intracellularly and in the Surrounding
Tumor Microenvironment

ASCENT: Phase 3 Confirmatory Study
mTNBC = metastatic triple-negative breast cancer; IV = intravenous; OS = overall survival; DOR = duration of response; TTR = time to response;
QOL = quality of life.
Bardia et al, 2021; Bardia et al, 2020; Clinicaltrials.gov, 2022.
Sacituzumab Govitecan in Second-Line and Later mTNBC
Primary End Point
• PFS for patients without brain
metastases (BMNeg)
Secondary End Points
• PFS for the ITT population, OS,
ORR, DOR, TTR, QOL, and
safety
Stratification factors
• Number of prior chemotherapies (2 or 3 vs >3)
• Geographic region (North America vs Europe)
• Presence/absence of known brain metastases (yes/no)
R
1:1
Metastatic TNBC
• ≥2 chemotherapies, 1 of
which could be in
neo/adjuvant setting
provided progression
occurred within a 12-
month period
• Patients with stable brain
metastasis were allowed
(N=529)
Sacituzumab govitecan
10 mg/kg IV
Days 1 and 8, every 21 days
(n=267)
Treatment of
physician’s choice
(n=262)
Continue treatment
until progression or
unacceptable toxicity

ASCENT: PFS and OS for BMNeg Patients
Bardia et al, 2022.
The ASCENT trial demonstrated statistically significant and clinically meaningful improvement
in PFS and OS over single-agent chemotherapy in the primary study population
BICR Analysis SG (n=235) TPC (n=233)
No. of events 167 150
Median PFS, mo (95% CI) 5.6 (4.3–6.3) 1.7 (1.5–2.6)
HR (95% CI), P value 0.39 (0.31–0.49), P<.0001
Analysis based on final database lock confirmed the improvement in clinical outcomes over TPC:
• Median PFS of 5.6 vs 1.7 months (HR 0.39, P<0.0001)
• Median OS of 12.1 vs 6.7 months (HR 0.48, P<0.0001)
• OS rate at 24 months of 22.4% (95% CI: 16.8-28.5) vs 5.2% (95% CI: 2.5-9.4)
Progression-free survival
(BICR analysis)
Overall survival
SG (n=235) TPC (n=233)
No. of events 173 199
Median OS, mo
(95% CI)
12.1 (10.7–14.0) 6.7 (5.8–7.7)
HR (95% CI), P value 0.48 (0.39–0.59), P<.0001

ASCENT: Response Rates (BMNeg and ITT Population)
Bardia et al, 2022.
Analysis based on final database lock confirmed the improvement in clinical outcomes over TPC:
Objective response rate of 35% vs 5%, P<0.0001
Clinical benefit rate of 45% vs 9%, P<0.0001
Median duration of response of 6.3 (95% CI:5.5-79) vs 3.6 months (95% CI, 2.8-not evaluable)
The clinical benefit of SG over TPC observed in the ITT population was consistent with that of the BMNeg
population:
Objective response rate of 31% vs 4%, P<0.0001
Clinical benefit rate of 40% vs 8%, P<0.0001
Median duration of response of 6.3 (95% CI:5.5-7.9) vs 3.6 months (95% CI:2.8-NE)
SG
(n=235)
TPC
(n=233)
ORR, n (%) 82 (35%) 11 (5%)
P value P<0.0001
Best overall response, n (%)
Complete response 10 (4%) 2 (1%)
Partial response 72 (31%) 9 (4%)
Clinical benefit rate, n (%) 105 (45%) 20 (9%)
P value P<0.0001
Median DOR, mo (95% CI) 6.3 (5.5-7.9) 3.6 (2.8-NE)
Median TTR, mo (range) 1.5 (0.7-10.6) 1.45 (1.3-4.2)

Approved for patients with ≥2
systemic therapies, at least 1 of
them for metastatic disease
No. of events 21 23
Median PFS, mo (95%) CI 5.7 (2.6–8.1) 1.5 (1.4–2.6)
HR (95% CI) 0.41 (0.22–0.76)
No. of events 22 24
Median OS—mo (95% CI) 10.9 (6.9–19.5) 4.9 (3.1–7.1)
HR (95% CI) 0.51 (0.28–0.91)
100
PFS
probability
(%)
80
60
40
20
0
0 3 6 9 12 15
Time (months)
SG
TPC
Censored
33 19 8 2 1 0
32 23 16 12 6 5 2 1 0
1
SG
TCP 32 3 2 1 1 0
28 8 2 2 2 2 1 1 1
1
No. of patients still at risk
Overall survival
OS
probability
(%)
0
0
Time (months)
100
80
60
40
20
3 6 9 12 15 18 21 24 27
SG
TPC
Censored
SG
TCP
No. of patients still at risk
33 29 26 19 13 9 7 1 0
3231 2826 2119 1715 1311 7
7 2
4 0
0 0
32 22 12 6 5 3 1 1 1
2927 1714 10 8 5 5 5 5 2
2 1
1 1
1 0
In patients with 2L mTNBC, PFS and OS improvement was consistent with the overall study population
ASCENT: Sacituzumab Govitecan PFS and OS
Carey et al, 2022.

Clinical Benefit With SG vs TPC
H-score = histochemical score.
Hurvitz et al, 2021.
Irrespective of Level of Trop-2 Expression in Previously Treated mTNBC
Trop-2 High; H-score: 200–300 Trop-2 Medium; H-score: 100–200 Trop-2 Low; H-score: <100
SG (n=85) TPC (n=72) SG (n=39) TPC (n=35) SG (n=27) TPC (n=32)
Median PFS, mo (95% CI) 6.9 (5.8–7.4) 2.5 (1.5–2.9) 5.6 (2.9–8.2) 2.2 (1.4–4.3) 2.7 (1.4–5.8) 1.6 (1.4–2.7)
Median OS, mo (95% CI) 14.2 (11.3–17.5) 6.9 (5.3–8.9) 14.9 (6.9–NE) 6.9 (4.6–10.1) 9.3 (7.5–17.8) 7.6 (5.0–9.6)
Overall survival
0
PFS
probability
(%)
100
80
60
40
20
Time (months)
0 5 10 15 20 25
OS
probability
(%)
100
80
60
40
20
Time (months)
0 5 10 15 20 25
Events/censored
SG: Trop-2 High 60/25
SG: Trop-2 Medium 26/13
SG: Trop-2 Low 19/8
TPC: Trop-2 High 47/25
TPC: Trop-2 Medium 24/11
TPC: Trop-2 Low 24/8
Events/censored
SG: Trop-2 High 53/32
SG: Trop-2 Medium 22/17
SG: Trop-2 Low 20/7
TPC: Trop-2 High 64/8
TPC: Trop-2 Medium 23/12
TPC: Trop-2 Low 25/7

ASCENT-03: Study Design (NCT05382299)
PD-1 = programmed cell death protein 1; gem = gemcitabine; AUC = area under curve.
Clinicaltrials.gov, 2023h.
Sacituzumab Govitecan vs TPC for First-line PD-L1– mTNBC
Crossover to SG allowed
after BICR-verified
disease progression
Stratification Factors:
• De novo vs recurrent disease within 6-12 months of treatment in the curative setting vs recurrent
disease >12 months after treatment in the curative setting
• Geographic region
N=540
(≤25% de novo)
Key Eligibility Criteria
• Previously untreated, inoperable, locally
advanced, or metastatic TNBC
• PD-L1– tumors (CPS <10, IHC 22C3
assay) OR PD-L1+ tumors (CPS ≥10,
IHC 22C3 assay) if treated with anti–
PD-(L)1 agent in the curative setting
• ≥6 months since treatment in curative
setting
• Prior anti–PD-(L)1 agent allowed in the
curative setting
• PD-L1 and TNBC status
centrally confirmed
Treated until BICR-
confirmed progression or
Long-term
follow-up
Sacituzumab Govitecan
10 mg/kg IV on
Days 1 and 8 of 21-day cycles
TPC Chemotherapy
Gem + carbo: gem 1,000 mg/m2 with
carbo AUC 2 IV on Days 1 and 8 of 21-day
cycles
Paclitaxel: 90 mg/m2 IV on Days 1, 8, and
15 of 28-day cycles
Nab-paclitaxel: 100 mg/m2 IV on Days 1,
8, and 15 of 28-day cycles
R
1:1

ASCENT-04: Study Design (NCT05382286)
Clinicaltrials.gov, 2023g.
SG + Pembro vs TPC + Pembro First-Line PD-L1+ mTNBC
• Previously untreated,
inoperable, locally
advanced, OR metastatic
TNBC
• PD-L1+ (CPS ≥10, IHC
22C3 assay)
• PD-L1 and TNBC status
centrally confirmed
• ≥6 months since treatment
in curative setting
SG + Pembrolizumab (Pembro)
SG: 10 mg/kg IV
on Days 1 and 8 of 21-day cycles
Pembro: 200 mg IV
on Day 1 of 21-day cycles
TPC Chemotherapy + Pembro
Pembro dosed as above
TPC: gem 1,000 mg/m2 with carbo AUC 2 IV
on Days 1 and 8 of 21-day cycles
OR paclitaxel 90 mg/m2 IV
on Days 1, 8, and 15 of 28-day cycles
OR nab-paclitaxel: 100 mg/m2 IV
on Days 1, 8, and 15 of 28-day cycles
Long-term
follow-up
Treated until BICR-
confirmed progression or
Crossover to SG allowed after
BICR-confirmed progression
Stratification factors:
• De novo vs recurrent disease within 6–12 months of treatment in the curative setting vs recurrent disease >12
months after treatment in the curative setting
• Geographic region (US/Canada vs rest of world)
• Prior exposure to anti-PD-(L)1 therapy
N=440
R
1:1

HER2 IHC examples
HER2+
HER2-low
HER2–
34% to 63% of breast cancer patients considered
HER2– under current guidelines express low levels
of HER2
Prevalence of HER2-Low by HR Status
Schettini et al, 2020.
IHC 0 IHC +1 IHC +2
HR+ Disease
N=2,485
TNBC
N=620
IHC 0
37%
IHC +1
46%
IHC +2
17%
IHC 0
66%
IHC +1
26%
IHC +2
8%
HER2–

Trastuzumab Deruxtecan (T-DXd)
Modi et al, 2022a.
Structure and Mechanism of Action
Internalization of T-DXd leads to release of the DXd payload and
subsequent cell death in the target tumor cell and neighboring tumor
cells through the bystander effect

DESTINY-Breast04: First Randomized Phase 3 Study
Q3W = every 3 weeks.
Modi et al, 2022b.
Trastuzumab Deruxtecan for HER2-Low MBC
• Centrally assessed HER2 status (IHC 1+ vs IHC 2+/ISH–)
• 1 versus 2 prior lines of chemotherapy
• HR+ (with vs without prior treatment with CDK4/6 inhibitor) versus HR–
HR+ ≈ 480
HR– ≈ 60
R
2:1
Primary end point
• PFS by BICR (HR+)
Key secondary end points
• PFS by BICR (all patients)
• OS (HR-positive and all
patients)
• HER2-low (IHC 1+ vs IHC 2+/ISH-–
), unresectable, and/or MBC
treated with 1-2 prior lines of
chemotherapy in the metastatic
setting
• HR+ disease considered endocrine
refractory
T-DXd
5.4 mg/kg Q3W
(n=373)
TPC
Capecitabine, eribulin,
gemcitabine, paclitaxel,
nab-paclitaxel
(n=184)

DESTINY-Breast04: PFS in HR+ and All Patients
Modi et al, 2022a; Modi et al, 2022b.
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
0
20
40
60
80
100
Progression-Free
Survival
Probability
(%)
Months
No. at Risk
373 365 325 295 290 272 238 217 201 183 156 142 118 100 88 81 71 53 42 35 32 21 18 15 8 4 4 1 1 0
184 166 119 93 90 73 60 51 45 34 32 29 26 22 15 13 9 5 4 3 1 1 1 1 1 1 0
T-DXd (n = 373):
TPC (n = 184):
HR+
No. at Risk
331
T-DXd (n = 331): 324 290 265 262 248 218 198 182 165 142 128 107 89 78 73 64 48 37 31 28 17 14 12 7 4 4 1 1 0
163
TPC (n = 163): 146 105 85 84 69 57 48 43 32 30 27 24 20 14 12 8 4 3 2 1 1 1 1 1 1 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
Months
0
20
40
60
80
100
Progression-Free
Survival
Probability
(%)
T-DXd
mPFS:
10.1 mo
TPC
mPFS:
5.4 mo
Hazard ratio:
0.51
95% CI: 0.40-0.64
P< 0.0001
Δ 4.7
mo
Hazard ratio:
0.50
95% CI: 0.40-0.63
P<0.0001
Δ 4.8
mo
TPC
mPFS:
5.1 mo
T-DXd
mPFS: 9.9 mo
All Patients

DESTINY-Breast04: OS in HR+ and All Patients
mOS = median overall survival.
No. at Risk
331
T-DXd (n = 331): 325 323319 314 309 303 293 285 280 268 260 250 228 199 190 168 144 116 95 81 70 51 40 26 14 9 8 6 6
163
TPC (n = 163): 151 145143 139 135 130 124 115 109 104 98 96 89 80 71 56 45 37 29 25 23 16 14 7 5 3 1 0
2 1 1 1 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
Months
0
20
40
60
80
100
Overall
Survival
Probability
(%)
T-DXd
mOS: 23.9 mo
TPC
mOS: 17.5
mo
Hazard ratio:
0.64
95% CI: 0.48-0.86
P=0.0028
Δ 6.4 mo
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
Months
0
20
40
60
80
100
Overall
Survival
Probability
(%)
No. at Risk
373
T-DXd (n = 373): 366 363357 351 344 338 326 315 309 296 287 276 254 223 214 188 158 129 104 90 78 59 48 32 20 14 12 10 8
184
TPC (n =
184):
171 165161 157 153 146 138 128 120 114 108 105 97 88 77 61 50 42 32 28 25 18 16 7 5 3 1 0
3 1 1 1 0
T-DXd
mOS: 23.4 mo
TPC
mOS: 16.8
mo
Hazard ratio:
0.64
95% CI: 0.49-0.84
P=0.0010
Δ 6.6 mo
HR+ All Patients

DESTINY-Breast04: Exploratory End Points
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Months
0
20
40
60
80
100
Progression-Free
Survival
Probability
(%)
No. at Risk
40
T-DXd (n = 40): 39 33 29 28 25 21 20 19 18 13 13 11 11 10 8 7 5 5 4 4 4 4 3 1 0
18
TPC (n = 18): 17 11 7 6 4 3 3 2 2 2 2 2 2 1 1 1 1 1 1 0
T-DXd
mPFS: 8.5 mo
TPC
mPFS: 2.9 mo
Hazard ratio:
0.46
95% CI: 0.24-0.89
Δ 5.6
mo
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Months
0
20
40
60
80
100
Overall
Survival
Probability
(%)
No. at Risk
40
T-DXd (n = 40): 39 38 37 36 34 34 32 31 30 28 27 26 26 23 23 19 14 13 9 9 8 7 7 6 6 5 4 4
18
TPC (n = 18): 17 16 14 14 14 3 11 10 8 8 8 7 6 6 5 5 5 5 3 3 2 2 2 0
T-DXd
mOS: 18.2 mo
TPC
mOS: 8.3 mo
Hazard ratio:
0.48
95% CI: 0.24-0.95
Δ 9.9
mo
PFS OS
PFS and OS in HR– Patients

0
10
20
30
40
50
60
Percentage
3.6
Progressive disease, %
Not evaluable, %
Clinical benefit rate, %
Duration of response, months
7.8% 21.1% 12.5% 33.3%
4.2% 12.7% 7.5% 5.6%
71.2% 34.3% 62.5% 27.8%
10.7% 6.8% 8.6% 4.9%
DESTINY-Breast04: Confirmed ORR
Complete Response
Partial Response
HR+ HR–
T-DXd (n=333) T-DXd (n=40)
TPC (n=166) TPC (n=18)
Confirmed Objective Response Rate
52.6%
50.0%
16.3% 16.7%
49.2
47.5
2.5
0.6
15.7
5.6
11.1

Determining HER2-Low Status
Miglietta et al, 2021; Modi et al, 2022b;
Prat et al, 2022.
HER2-low status changes over
time
Which timepoint and what type
of biopsy should be used to
define a tumor as HER2-low?
DESTINY-Breast04 required
“adequate archived or recent
tumor-biopsy specimens”
Excluded: fine-needle aspirates,
other cytologic specimens,
decalcified bone metastases
In DESTINY-Breast04, T-DXd had
consistent efficacy regardless of
tumor sample characteristics
Biopsy Considerations DESTINY-Breast04: Median PFS by Tumor Sample Characteristics
Practical Definition of HER2-Low
A HER2-nonamplified tumor showing HER2-low
expression on any prior specimen in course of disease
Hazard Ratio
(T-DXd vs TPC)
Subgroup T-DXd TPC
Hazard Ratio
(95% CI)
0.47 (0.32-0.70)
0.50 (0.38-0.66)
0.46 (0.35-0.59)
0.57 (0.33-1.0)
0.48 (0.37-0.61)
0.57 (0.30-1.1)
0.78 (0.24-2.54)
0.44 (0.28-0.70)
0.49 (0.37-0.66)
0.54 (0.20-1.4)
4.2
5.4
5.3
3.0
5.3
4.8
6.8
4.3
5.1
2.8
9.6
10.9
10.9
7.5
10.3
9.7
7.0
11.4
9.8
6.6
Tumor Location
Primary (n=196)
Metastases (n=359)
Specimen Type
Biopsy (n=448)
Excision/resection (n=108)
Archival tissue (n=482)
Newly obtained tissue (n=75)
Specimen Collection Date
2013 and earlier (n=29)
2014-2018 (n=175)
2019 or later (n=310)
Missing (n=43)
mPFS, Mo
3
2
1
0

Decreasing ORR by degree of HER2 expression
IHC 3+ IHC 1+ or 2+ IHC 0
DAISY Trial: Benefit Even in HER2 0
Diéras et al, 2022.
Phase 2 Study T-DXd for Advanced Breast Cancer
Total
Cohort 1
(HER2-overexpressing)
Cohort 2
(HER2–low expressing
Cohort 3
(HER2-nondetected)
Best overall response
confirmed, n/N
[95% CI]
86 / 177 (48.6%)
[41.0-56.2]
48 / 68 (70.6%)
[58.3-81.0]
27 / 72 (37.5%)
[26.4-49.7]
11 /37 (29.7%)
[15.9-47.0]
Median DOR, months
[95% CI]
8.5 [6.5-9.8] 9.7 [6.8-13] 7.6 [4.2-9.2] 6.8 [2.8-not reached]
Median PFS, months
[95% CI]
7.0 [6.0-8.7] 11.1 [8.5-14.4] 6.7 [4.4-8.3] 4.2 [2.0-5.7]

How do you choose between
sacituzumab govitecan or T-DXd?

Both SG and T-DXd (HR– Patients) Can Improve PFS
Bardia et al, 2021; Modi et al, 2022a; Hurvitz et al, 2022; Modi et al, 2022b.
SG (n=235) TPC (n=233)
Median PFS, months
(95% CI)
5.6
(4.3−6.3)
1.7
(1.5-2.5)
HR (95% CI), P value 0.41 (0.32−0.52)，P<0.0001
T-DXd
mPFS：8.5 mo
5.6 mo
月
TPC
mPFS：2.9个
T-DXd
(n=40):
TPC (n=18):
HR: 0.46
95% CI, 0.24-0.89
In the main study population of ASCENT and HER2–low expression mTNBC of DB-04, both SG and T-DXd can significantly improve PFS compared
with TPC, but only a small part of mTNBC population in DB-04 is used for exploratory analysis of survival end points. Therefore, it is used to
generate hypotheses, and the results need to be interpreted carefully
DESTINY-Breast04: PFS (HR– Patients)
ASCENT: PFS (Primary Study
Population)
Primary end point Exploratory
end point
HR almost consistent in
ASCENT and DB-04, even
lower in ASCENT

SG (n=235) TPC (n=233)
Median OS, months
(95% CI)
12.1
(10.7–14.0)
6.7
(5.8-7.7)
HR (95% CI), P value 0.48 (0.38–0.59), P<0.0001
OS(%)
SG
TPC
Censored
T-DXd
mOS: 18.2 mo
月
9.9 mo
TPC
mOS：8.3 mo
HR：0.48
95% CI: 0.24-0.95
In the main study population of ASCENT and HER2–low expression mTNBC of DB-04, both SG and T-DXd can significantly improve OS compared with TPC, but only a
small part of mTNBC population in DB-04 is used for exploratory analysis of survival end points. Therefore, it is used to generate hypotheses, and the results need to
be interpreted carefully
DESTINY-Breast04: OS (HR– Patients)
ASCENT: OS (Primary Study Population)
Both SG and T-DXd (HR– Patients) Can Improve OS
Bardia et al, 2021; Modi et al, 2022a; Hurvitz et al, 2022; Modi et al, 2022b.
HR in ASCENT and DB-04 is
almost consistent

SG (n=235) TPC (n=233)
Treatment-emergent adverse event
a
Any
grade
e %
Grade
3, %
Grade
4, %
Any
grade,
%
Grade
3, %
Grade
4, %
Hematologic
Neutropeniab 63 34 17 43 20 13
Anemia 35 8 0 24 5 0
WBC count
decreased
13 7 1 10 4 1
Febrile
neutropenia
6 5 1 2 2 <1
Gastrointestinal
Diarrhea 59 11 0 12 <1 0
Nausea 57 2 <1 26 <1 0
Vomiting 29 1 <1 10 <1 0
Other
Fatigue 45 3 0 30 5 0
Alopecia 46 0 0 16 0 0
ASCENT DESTINY-Breast04
• The most common grade 3-4 TEAEsa in the SG arm were neutropenia and diarrhea, which were manageable and did not interrupt treatment due to treatment-
related neutropenia and diarrhea. Neutropeniaa was the most common serious TEAEs reported with T-DXd in DB-04
• Alopecia occurred in 46% of SG-treated patients and 38% of T-DXd-treated patients reported alopecia in DB-04
ASCENT vs DESTINY-Breast04
aTreatment-emergent adverse event is defined as an adverse event with the start date on or after the date of the first dose of study treatment and up to 30 days after the date of the last
dose of the study treatment. bNeutropenia is combined “neutropenia” and “neutrophil count decreased.”
Bardia et al, 2022; Rugo, Tolaney, et al, 2021; Modi et al, 2022a.
Treatment-Emergent Adverse Events (TEAEs)

DESTINY-Breast04: Trastuzumab Deruxtecan
aThe median time to ILD/pneumonia onset for T-DXd patients was 129.0 days (range, 26-710).
bA total of 17 patients (4.6%) in the T-DXd group reported. Left ventricular dysfunction; 1 patient initially presented with decreased ejection fraction
and subsequently developed heart failure.
cBoth heart failure patients recovered. dProvided information refers to full DESTINY-Breast04 study population.
ILD = interstitial lung disease.
Modi et al, 2022a.
Adverse Events of Special Interest
Adjudicated as Drug-Related ILD/Pneumonitisa
N (%) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any Grade
T-DXd (n=371) 13 (3.5%) 24 (6.5%) 5 (1.3%) 0 3 (0.8%) 45 (12.1%)
TPC (n=172) 1 (0.6%) 0 0 0 0 1 (0.6%)
Left Ventricular Dysfunctionb
N (%) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any Grade
Ejection Fraction Decreased
T-DXd (n=371) 1 (0.3%) 14 (3.8%) 1 (0.3%) 0 0 16 (4.3%)
TPC (n=172) 0 0 0 0 0 0
Cardiac Failurec
T-DXd (n=371) 0 1 (0.3%) 1 (0.3%) 0 0 2 (0.5%)
TPC (n=172) 0 0 0 0 0 0
8% of patients in
the T-DXd arm had
grade 2 or 3 ILD
There were 3
T-DXd–related
deaths due to ILD in
DB-04

TROPiCS-02: Efficacy by HER2 IHC Status
aHER2-low defined as IHC1+ or IHC2+ and ISH–/unavailable.
Rugo HS, Bardia A et al, 2022; Marmé et al, 2022.
Sacituzumab Govitecan in Metastatic Breast Cancer
ITT
SG
(n=272)
TPC
Median PFS, mo
(95% CI)
5.5
(4.2–7.0)
4.0
(3.1–4.4)
HR (95% CI) 0.66 (0.53–0.83), P=0.0003
SG
(n=149)
TPC
(n=134)
Median PFS, mo 6.4 4.2
HR (95% CI) 0.58 (0.42–0.79),
P<0.001
SG
(n=101)
TPC
(n=116)
Median PFS, mo 5.0 3.4
HR (95% CI) 0.72 (0.51–1.00),
P=0.05
PFS
Probability
(%)
0
0 2 4 6 8 10 12
Time (months)
14 16 18 20 22
101
116 53 39 20 14 7 3 1 1 1 1 0
TPC
No. of patients at risk
SG 64 50 27 20 9 4 3 2 1 1 0
10
20
30
40
50
60
70
80
90
100
SG
TPC
Censored
PFS
Probability
(%)
0
0 2 4 6 8 10 12
Time (months)
14 16 18 20 22
149
134 65 43 16 8 4 1 0 0 0 0 0
TPC
SG 99 77 50 38 22 16 8 7 5 5 2
10
20
30
40
50
60
70
80
90
100
SG
TPC
Censored
0
0 3 6 9 12
Time (months)
15 18 21 24
272 148 82 44 22 12 6 3 0
271 105 41 17 4 1 1 0
TPC
SG
10
20
30
40
50
60
70
80
90
100
PFS
Probability
(%)
SG
TPC
Censored
HER2 IHC0 HER2-Lowa
Within the HER2-low population, median PFS with SG vs TPC for the IHC1+ and IHC2+ subgroups was 7.0 vs 4.3 (HR, 0.57) and
5.6 vs 4.0 (HR, 0.58) months, respectively
Median PFS in a sensitivity analysis of the HER2-low subgroup did not show any differences compared with the ITT population
SG Improved PFS vs TPC in HER2 IHC0 and HER2-Low Groups, Consistent With
Outcomes in the ITT Population

ASCENT vs DESTINY-Breast04: Quality of Life
HRQOL = health-related quality of life.
aAssessed in patients who received ≥1 dose of study drug. For global health status and functional scales, a higher score
indicates better quality of life. For symptom scales, a lower score indicates better quality of life.
*P<0.05. **P<0.01.
Loibl et al, 2021; Ueno et al, 2022.
Primary Health-Related
of Life Domains EORTC
C30a
Change from Baseline,
(95% CI)
SG
(n=235)
TPC
(n=233)
Difference
Minimum
Difference
Global Health Status/Quality
Life
0.66
(-2.21, 3.53)
-3.42
(-6.77, -0.08)
4.08
(0.82, 7.35)*
-4
Physical Functioning
1.31
(-1.38, 3.99)
-4.39
(-7.52, -1.26)
5.69
(2.63, 8.76)**
-5
Role Functioning
-2.24
(-6.13, 1.65)
-7.83
(-12.41, -3.25)
5.59
(1.13, 10.05)*
-6
Fatigue
1.97
(-1.20, 5.13)
7.
13 (3.40, 10.87)
-5.17
(-8.81, -1.52)*
+5
Pain
-8.93
(-12.57, -5.30)
-1.89
(-6.18, 2.40)
-7.04
(-11.24, -2.85)**
+6
• In ASCENT, SG demonstrated statistically significant and/or clinically meaningful
improvements relative to baseline in all main HRQOL domains over TPC arm
• In DB-04, T-DXd showed no significant differences vs the TPC arm in global health
status/QOL or fatigue
Fatigue
Global Health Status/QOL
DESTINY-Breast04 Quality of Life
ASCENT Quality of Life

• SG has demonstrated efficacy in the ITT population of patients with mTNBC in a dedicated phase 3 study
regardless of HER2 status
• T-DXd has shown preliminary efficacy data in a small subset of patients with mTNBC in an exploratory
analysis of 58 patients
• Due to differences in patient populations, direct comparisons between any of the study end points
cannot be made
ASCENT DESTINY-Breast04
Population size
Patients with mTNBC: N=529
Of patients with centrally assessed HER2 status:
HER2-IHC 0 = 70% (293/416), 149 treated with SG
HER2-low = 30% (123/416), 63 treated with SG
Patients with mTNBC (n=58; 40 treated with T-DXd); subset of study
population of patients with HER2-low disease (N=557)
Statistical
considerations
Efficacy in patients with mTNBC is the primary end
point of the study
Efficacy in patients with mTNBC is an exploratory end point
Efficacy
Statistically significant and clinically meaningful
improvements in PFS, OS, and ORR with SG versus TPC
regardless of HER2– subtype
Numerical improvements in PFS, OS, and ORR with T-DXd versus TPC
Implications for
mTNBC
SG has demonstrated efficacy in all mTNBC patients
including those with HER2-low and those with HER2-
IHC 0 disease
T-DXd has demonstrated efficacy only in patients with HER2-low
ASCENT vs DESTINY-Breast04 mTNBC Subset
Bardia et al, 2021; Modi et al, 2022b; Hurvitz et al, 2022; Modi et al, 2022a.
Efficacy Overview

Which ongoing investigations
with immunotherapies or
targeted therapies do you feel
have the greatest potential to
impact future practice in TNBC?

SG’s DLT is neutropenia, while DS-1062’s DLTs are maculopapular rash and
stomatitis/mucosal inflammation
DS-1062 has a substantially longer half-life than SG (≈5 days vs 11-14
hours), enabling a more optimal dosing regimen
DS-1062 has a drug-to-antibody ratio of 4 for optimized therapeutic index
Circulating free payload is negligible due to high stability of the linker,
thereby limiting systemic exposure or nontargeted delivery of the payload
High-potency membrane-permeable payload (DXd) that requires Trop2-
mediated internalization for release
Datopotamab Deruxtecan (Dato-DXd)
DLT = dose-limiting toxicity.
Nakada et al, 2019; Okajima et al, 2021; Ocean et al, 2017; Sands et al, 2018; Spira et al, 2021; Lisberg et al, 2020; Heist et al, 2019.
Trop2 ADC in Development

TROPION-PanTumor01: Study Design
RECIST = response valuation criteria in solid tumors;
NSCLC = non–small cell lung cancer; SCLC = small cell lung cancer;
CRPC = castration-resistant prostate cancer.
Bardia et al, 2023.
Dato-DXd in Advanced TNBC
• Advanced/unresectable or metastatic HR–
/HER2– (IHC 0/1+ or IHC2+/ISH–) breast
cancer
• Relapsed or progressed after local standard
treatments
• Unselected for Trop-2 expression
• Age ≥18 years (US) or ≥20 years (Japan)
• ECOG PS 0-1
• Measurable disease per RECIST v1.1
• Stable, treated brain metastases allowed
NSCLC
(0.27 to 10 mg/kg IV Q3W)
TNBC
8 mg/kg IV Q3W (n=2)
HR+/HER2– breast cancer
Other tumor types
(SCLC, bladder, gastric,
esophageal, CRPC, pancreas)
Primary end points
• Safety
• Tolerability
Secondary end points
• Efficacy
• Pharmacokinetics
• Antidrug antibodies

TROPION-PanTumor01: Efficacy
ORR by BICR
All patients: 32%
Topo I inhibitor–naive patients: 44%
mDOR
16.8 months in both groups
mPFS
All patients: 4.4 months
Topo I inhibitor–naive patients:
7.3 months
mOS
All patients: 13.5 months
Topo I inhibitor–naive patients:
14.3 months
AEs: most common TEAEs: stomatitis
(73%), nausea (66%), vomiting (39%)
Dato-DXd in Advanced TNBC
Antitumor Tumor Responses by BICR
Bardia et al, 2023.

TROPION-Breast 02: Study Design
ICC = investigator’s choice chemotherapy; Q4W = every 4 weeks; DFI = disease-free interval.
Dent et al, 2022.
Dato-DXd vs Chemo in 1L mTNBC Not Candidate for Anti–PD-(L)1 Therapy
TROPION-Breast02 is a phase 3, open-label, randomized
study of 1L dato-DXd vs chemotherapy in patients with locally
recurrent inoperable or metastatic TNBC who are not
candidates for anti-PD-(L)1 therapy
N=600
R
1:1
Primary end points
• PFS by BICR per RECIST v1.1
• OS
• ORR and DOR by BICR per RECIST v.1.1
• PFS by investigator assessment per RECIST v1.1
• PFS2
• Geographic location
• DFI history
• PD-L1 status
• Adults with histologically or cytologically documented locally recurrent
inoperable or metastatic TNBC
• No prior chemotherapy or targeted systemic therapy for locally
recurrent inoperable or metastatic breast cancer
• ≥1 measurable lesion (≥10 mm) per RECIST v1.1 that has not been
previously irradiated
• ECOG PS 0-1
• A recent (<3 months prior to screening) formalin-fixed, paraffin-
embedded metastatic (excluding bone) or locally recurrent inoperable
tumor sample
• Not a candidate for PD-(L)1 inhibitor therapy, defined as:
 Patients whose tumors are PD-L1–
 Patients whose tumors are PD-L1+, but have
o Relapsed after prior PD-(L)1 inhibitor therapy for early-
stage breast cancer
o Comorbidities precluding PD-(L)1 inhibitor therapy
o No regulatory access to PD-(L)1 inhibitor therapy
• Eligible for 1 of the listed ICCs (ie, paclitaxel, nab-paclitaxel,
capecitabine, carboplatin, or eribulin mesylate)
ICC
Q3W or Q4W as per protocol directions
(paclitaxel, nab-paclitaxel, capecitabine,
eribulin mesylate, or carboplatin
Dato-DXd
6 mg/kg IV Day 1 Q3W

Patritumab Deruxtecan
GI = gastrointestinal.
Li et al, 2017; Ocana et al, 2013; Krop et al, 2022; Corti et al, 2021.
HER3 is expressed in 30.3%-75.1% of breast cancers; overexpression is associated
with poor prognosis
Patritumab deruxtecan: novel ADC targeting HER3 with topoisomerase I inhibitor
payload capable of bystander antitumor effects
Phase 1/2 trial of patritumab deruxtecan at 1.6-8.0 mg/kg (dose escalation/finding)
or 4.8-6.4 mg/kg IV Q3W (dose expansion), with median follow-up of 31.9 months
(range: 15-56 months)
Phase 1/2 Trial in HER3-Expressing MBC
Patritumab
deruxtecan is
active
regardless of
HER3
expression
6.6% had treatment-related
ILD, including 1 grade 5 ILD
(0.5%)
Most common TEAEs were GI
and hematologic toxicities
Nausea: 68.8%-80.6%
Platelet count decrease:
60.4%-71.4%; neutrophil
count decrease: 62.5%-66.3%
Parameter
HR+/ HER2–
(n=113)
TNBC
(n=53)
HER2-+
(n=14)
HER3 status High and low High High
Confirmed ORR, % 30.1 22.6 42.9
Median DOR, months 7.2 5.9 8.3
Median OS, mo 14.6 14.6 19.5
Median PFS, months 7.4 5.5 11.0

Phase 3 Trial Treatment Arm(s) Population Primary Completion
1L
ASCENT-03
(NCT05382299)
Sacituzumab govitecan vs TPC Metastatic TNBC (N=540) May 2027
ASCENT-04
(NCT05382286)
Sacituzumab govitecan + pembrolizumab vs
TPC + pembrolizumab
Inoperable/metastatic TNBC
(N=440)
February 2027
DESTINY-Breast09
(NCT04784715)
T-DXd ± pertuzumab vs
taxane/trastuzumab/pertuzumab
HER2-positive MBC (N=1,134) March 28, 2025
TROPION-Breast02
(NCT05374512)
Dato-DXd vs TPC
Inoperable/metastatic TNBC ineligible for
ineligible for PD-1/PD-L1 therapy
(N=600)
December 3, 2025
Select Ongoing Phase 3 Trials of ADCs in TNBC
Clinicaltrials.gov, 2023h; Clinicaltrials.gov, 2023g; Clinicaltrials.gov, 2023i; Clinicaltrials.gov, 2023a.

SG
Dato-DXd
ADC2
T-DXd
T-DXd
Dato-DXd
ADC1
T-DXd
ADC Y
ADC X
Critical Question: How Will ADCs Work in Sequence?

Performance of Serial ADCs
Abelman et al, 2023.
Subgroup Analysis of Patients Receiving T-DXd, SG Only
ADC1 ADC2

• Confirmed unresectable locally
locally advanced or metastatic
metastatic disease
• History of HER2-low breast
cancer (any prior primary or
or metastatic tumor) defined
defined as IHC 1+ or 2+/ISH–
2+/ISH–non-amplified
• Most recent pathology: HER2
HER2 IHC 0 or HER2-low
• Measurable disease
• No prior Topo-I inhibitor–-
based therapy
TRADE-DXd
CBR = clinical benefit rate; TTOR = time to overall response.
Patients who received T-DXd/dato-DXd as ADC off-study were
allowed to enroll on ADC1 cohorts.
TReatment of ADC-Refractory Breast CancEr with Dato-DXd or T-DXd
ADC1 ADC2
Primary end point
• ORR
• PFS
• OS
• CBR
• TTOR
• DOR
Baseline
pre-ADC1
biopsy
Post-C2
on-ADC1
biopsy
Baseline
pre-ADC2
biopsy
Optional
post-ADC2
biopsy
Crossover to ADC2
at progression
Crossover to ADC1
at progression
R
1:1
T-DXd
0-1 prior lines
HR+
(Arm A)
HR–
(Arm B)
Dato-DXd
0-1 prior lines
HR+
(Arm C)
HR–
(Arm D)
Dato-DXd
1-2 prior lines
HR+
(Arm E)
HR–
(Arm F)
T-DXd
1-2 prior lines
HR+
(Arm G)
HR–
(Arm H)
Treat until
disease progression
or unacceptable toxicity
= Tumor assessments + blood collection Q9W

BRCAm = BRCA-mutant; dMMR = deficient mismatch repair.
NCCN, 2023.
1L 2L 3L
PD-L1+:
Chemo + pembrolizumab
PD-L1–:
Taxane or platinum
High TMB, MSI-H/dMMR:
Pembrolizumab
HER2-low:
T-DXd
BRCAm:
Olaparib or talazoparib
Eribulin, capecitabine,
gemcitabine, navelbine
Potential
Future
Strategies
Dato-DXd
HER3+ :
Patritumab deruxtecan
Where ADCs Fit Into Treatment of Metastatic TNBC

Other Strategies in TNBC
PI3Ki = phosphoinositide 3-kinase inhibitor.
Clinicaltrials.gov, 2023c; Clinicaltrials.gov, 2023b; Clinicaltrials.gov, 2023d; Clinicaltrials.gov, 2023e; Clinicaltrials.gov, 2023f; Clinicaltrials.gov, 2023j;
Doi et al, 2022; Hamilton et al, 2023; Meric-Bernstam et al, 2022; Meisel et al, 2022; Ono et al, 2022.
Targeted strategies
Akt inhibition: awaiting data from CAPItello-290
Mutant-selective PI3Ki: Loxo (LOXO-783), Relay (RLY-2608), Scorpion
(STX-478), and others
Other immunotherapy strategies
AdvanTIG-211 (ociperlimab/tislelizumab), PRESERVE-2 (trilaciclib)
Novel ADCs
Novel targets: B7-H3 (DS-7300), B7H4 (XMT 1660, AZD8205), LIV1
(ladiratuzumab vedotin), Nectin-4 (enfortumab vedotin)

T-DXd and Sacituzumab Govitecan in Breast Cancer
CINV = chemotherapy-induced nausea and vomiting; LVEF = left ventricular ejection fraction; DDIs = drug-drug interactions;
UGT1A1 = uridine-diphosphate glucuronosyltransferase 1A1.
Enhertu® prescribing information, 2022; Rugo, Bianchini, et al, 2022; Trodelvy® prescribing information, 2023.
Administration Considerations
Consideration T-DXd Sacituzumab Govitecan
Premedication
 CINV: 3-drug combination regimen
(dexamethasone + 5-HT3 receptor
antagonist + NK1 receptor
antagonist)
 Infusion reactions: premedicate with antipyretics, H1
and H2 blockers; consider corticosteroids for those
those with prior infusion reactions
 CINV: 2- to 3-drug combination regimen
(eg, dexamethasone + either 5-HT3 or
NK1 receptor antagonist)
 Some institutions may use only ondansetron
Starting dosage
5.4 mg/kg IV Q3W until progressive
disease/unacceptable toxicity
10 mg/kg IV QW on Days 1 and 8 of 21-day cycles
until progressive disease/unacceptable toxicity
Dose reductions
 First: 4.4 mg/kg
 Second: 3.2 mg/kg
 Third: discontinue
 First: 25% dose reduction
 Second: 50% dose reduction
 Third: discontinue
Key toxicities managed
dose modifications
ILD/pneumonitis, nausea, neutropenia,
neutropenia, thrombocytopenia, LVEF
Neutropenia, nausea, vomiting, diarrhea,
any other high-grade/persistent AEs
DDIs Very limited/not clinically meaningful Avoid coadministering UGT1A1 inhibitors or inducers

T-DXd: Safety Profile
aEjection fraction decrease and cardiac failure data from first interim analysis; drug-related ILD/pneumonitis from second interim analysis.
ABC = advanced breast cancer.
Modi et al, 2022a; Modi et al, 2022b; Hurvitz et al, 2023; Cortés et al, 2022.
DESTINY-Breast04: Drug-Related TEAEs in
≥20% of Patients With HER2-Low ABC
Fatigue
Neutropenia
Anemia
Thrombocytopenia
Transaminases increased
Leukopenia
Patients (%)
Any
Grade
Grade
≥3
T-DXd
Chemo
AE of Special
Interest, %
DESTINY-Breast04:
Low ABC
DESTINY-Breast03:
HER2-Positive MBCa
T-DXd
(n=371)
TPC
(n=172)
T-DXd
(n=257)
T-DM1
(n=261)
Drug-related
ILD/pneumonitis
 Grade 1
 Grade 2
 Grade 3
12.1%
3.5%
6.5%
1.3%
0.6%
0.6%
0%
0%
15%
4%
10%
<1%
3%
2%
1%
<1%
Ejection fraction
decreased
 Grade 1
 Grade 2
 Grade 3
4.3%
0.3%
3.8%
0.3%
0%
0%
0%
0%
2.3%
0%
2.3%
0%
0.4%
0%
0.4%
0%
Cardiac failure
 Grade 1
 Grade 2
 Grade 3
0.5%
0%
0.3%
0.3%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
Nausea
Alopecia
Vomiting
Decreased appetite
Diarrhea
Constipation
80 60 40 20 0 20 40 60
73 5 24
0
48 8 42
5
33 14 51
41
38 0 33
0
34 1 10
0
33 8 23
5
29 2 16
1
24 5 9
1
24 3 23
8
23 6 31
19
22 1 18
2
21 0 0 13
Safety profile of T-DXd was consistent across trials and
disease settings
n=3 grade 5 drug-related ILD/pneumonitis cases with T-
DXd occurred in DESTINY-Breast04
All other AEs of special interest noted above were
grade ≤3 in both trials

Stankowicz et al, 2021; Rugo, Bianchini et al, 2022.
Premedicate with 3-drug regimen for CINV (eg, dexamethasone +
5-HT3 receptor antagonist + NK1 receptor antagonist)
Onset may be delayed: provide patient with take-home antiemetics
(eg, dexamethasone, ondansetron)
Manage with antiemetics, dose reductions; withhold if high-grade until
resolved to grade ≤1
Managing Clinically Significant Nausea and Vomiting With T-DXd

Managing ILD/Pneumonitis With T-DXd
CT = computed tomography; ID = infectious disease;
CBC = complete blood count; BAL = bronchoalveolar lavage;
PFT = pulmonary function test; PK = pharmacokinetic;
PCP = pneumocystis jirovecii pneumonia.
Swain et al, 2022; Enhertu® prescribing information, 2022.
Monitor
 Urge patients to
immediately report
cough, dyspnea,
fever, and/or new
or worsening
respiratory
symptoms
 Monitor for signs/
symptoms of ILD
 Promptly
investigate
evidence of ILD
 Evaluate patients
with suspected ILD
by radiographic
imaging and
assess as follows
 Consider earlier
scans to assess
response and
monitor for ILD
For grade 1
(asymptomatic):
 Hold until resolved to
grade 0
For grades 2-4
(symptomatic):
 Permanently discontinue
Dose Interruptions
Recommended
starting dose
First dose
reduction
Second dose
reduction
Do not reescalate T-DXd dose
after dose reduction is made
5.4 mg/kg
4.4 mg/kg
3.2 mg/kg
Further dose
reduction needed
Permanently
discontinue
Confirm
Assessments should
include:
 High-resolution CT
 Pulmonologist consult;
if indicated, ID consult
 Blood culture and CBC;
other blood tests as needed
 Consider bronchoscopy and
BAL if indicated/feasible
 PFTs and pulse oximetry
 Arterial blood gases,
if indicated
 As soon as ILD suspected,
collect 1 blood sample for
PK assessment, if feasible
 Rule out other causes of ILD
(eg, progression, PCP
infection, other drugs,
radiotherapy)
 All ILD events should be
followed until resolution and
after drug discontinuation
Corticosteroid Treatment
For grade 1 (asymptomatic):
 Consider corticosteroid treatment
(≥0.5 mg/kg prednisolone)
For grade ≥2 (symptomatic):
 Promptly initiate systemic corticosteroid treatment
(≥1 mg/kg prednisolone or equivalent) for ≥14 days
followed by taper for ≥4 weeks
Resume Therapy
(Grade 1 Only)
If resolved in ≤28
days from onset:
 Maintain dose
If resolved >28 days
from onset:
 Reduce dose 1 level

Sacituzumab Govitecan: Safety Profile
Rugo, Bardia, et al, 2022; Bardia et al, 2021.
Safety profile consistent in
HR+/HER2– MBC (TROPiCS-02)
and mTNBC (ASCENT)
No treatment-related cardiac
failure or LVEF observed
Alopecia often observed at higher
rates in real-world practice
Counsel patients on hair loss
Offer wig prescription
TRAEs, n (%)
SG (n=268) TPC (n=249)
All Grade Grade ≥3 All Grade Grade ≥3
Hematologic
Neutropenia 188 (70%) 136 (51%) 134 (54%) 94 (38%)
Anemia 91 (34%) 17 (6%) 62 (25%) 8 (3%)
Leukopenia 37 (14%) 23 (9%) 23 (9%) 13 (5%)
Lymphopenia 31 (12%) 10 (4%) 25 (10%) 8 (3%)
Febrile neutropenia 14 (5%) 14 (5%) 11 (4%) 11 (4%)
Gastrointestinal
Diarrhea 152 (57%) 25 (9%) 41 (16%) 3 (1%)
Nausea 148 (55%) 3 (1%) 77 (31%) 7 (3%)
Vomiting 50 (19%) 1 (<1%) 30 (12%) 4 (2%)
Constipation 49 (18%) 0 36 (14%) 0
Abdominal pain 34 (13%) 2 (1%) 17 (7%) 0
Other
Alopecia 123 (46%) 0 41 (16%) 0
Fatigue 100 (37%) 15 (6%) 73 (29%) 6 (2%)
Asthenia 53 (20%) 5 (2%) 37 (15%) 2 (1%)
Decreased appetite 41 (15%) 1 (<1%) 34 (14%) 1 (<1%)
Neuropathy 23 (9%) 3 (1%) 38 (15%) 6 (2%)
TROPiCS-02: Key TRAEs With SG vs TPC in HR+/HER– MBC

Managing Neutropenia With Approved ADCs
ANC = absolute neutrophil count; G-CSF = granulocyte colony stimulating factor.
Tolaney, personal communication, 2023 Rugo, Bianchini, et al, 2022; Enhertu® prescribing information, 2022; Trodelvy® prescribing information, 2023;
Rugo, Tolaney, et al, 2022; Fleming et al, 2021; Spring et al, 2021.
T-DXd
 Educate on potential for neutropenia, usually
low grade
 Consider G-CSF prophylaxis if history of
prior neutropenic complications
 Monitor regularly and withhold if ANC <1,000/µL or
neutropenic fever
 Manage with G-CSF; dose reductions for grade 4
neutropenia or grade 3 febrile neutropenia
 Educate on potential for severe neutropenia
 Monitor regularly and withhold if ANC <1,500/µL on
Day 1 or <1,000/µL on Day 8, or neutropenic fever
 Manage with G-CSF and dose reductions for grade 4
lasting ≥7 days or grade ≥3 febrile neutropenia
 When making dose reductions, consider patient’s bone
marrow reserve, age, frailty, etc
 Use anti-infective treatment for febrile neutropenia
 Suspect UGT1A1*28 genotype if prolonged
neutropenia unresponsive to treatment
Sacituzumab Govitecan
G-CSF for SG-Related Neutropenia—Consider Either:
1. Short-acting G-CSF on Days 2-4 and long-acting G-
CSF on Day 9, or
2. Just long-acting G-CSF on Day 9

Managing Diarrhea With Sacituzumab Govitecan
Fleming et al, 2021; Rugo, Tolaney et al 2022; Trodelvy® prescribing information, 2023; Spring et al, 2021.
Educate patients about potential for severe diarrhea and about
loperamide before first dose
Prophylaxis not recommended unless prior history of diarrhea
For early diarrhea of any severity, administer atropine
For late diarrhea, rule out infectious etiologies and administer
loperamide
Manage with fluids, electrolyte substitution, dose reductions;
withhold for grade ≥3 until resolution

Case Study 1: Ms. KQ
56-year-old woman presented with de novo metastatic TNBC with a left-
sided breast mass, ipsilateral enlarged axillary lymph node, and liver and
lung metastases
Breast and ipsilateral lymph node = ER–, PR–, HER2 1+
Biopsy of the liver confirmed metastatic TNBC
Her tumor was found to be PD-L1+
Germline genetic testing did not reveal a BRCA mutation
She received first line paclitaxel + pembrolizumab and had a good
response, but after 8 months, developed disease progression with growth of
liver metastases

Case Study 1: Ms. KQ (cont.)
Image courtesy of Ira Bleiweiss, MD.
PD-L1+

Case Study 1: Ms. KQ (cont.)
a. Olaparib
b. Carboplatin
c. Sacituzumab govitecan
d. Trastuzumab deruxtecan
e. Capecitabine
What Therapy Do You Recommend?

Case Study 2: Ms. TL
L = left; FNA = fine needle aspiration; ddAC-T = dose-dense doxorubicin/cyclophosphamide/paclitaxel.
36-year-old woman initially presented with 3.5-cm L breast mass with
an enlarged axillary lymph node 2 years ago
Breast biopsy revealed ER–, PR–, HER2 1+ invasive ductal
carcinoma
FNA was positive for malignant cells
She received preoperative ddACT chemotherapy
At surgery, she was found to have a partial CR

Case Study 2: Ms. TL
HER2 0

Case Study 2: Ms. GB
HER2 1+

Case Study 2: Ms. TL (cont.)
AST = aspartate aminotransferase; ALT = alanine transaminase.
Germline genetic testing was done, and she was found to have a
BRCA1 mutation
2 years after surgery, she was found to have elevated transaminases
(AST 75 U/L, ALT 80 U/L), and imaging revealed liver metastases
Biopsy of the liver was consistent with her breast primary, ER–, PR–,
HER2 1+
PD-L1 testing was done with 22C3 yielding CPS >10

Primary TNBC, Extensive Necrosis

PD-L1+ ?

Image courtesy of Ira J. Bleiweiss, MD.
Liver Biopsy

Image courtesy of Ira J. Bleiweiss, MD.
PD-L1–

Original Axillary Node +

PD-L1+

a. Olaparib
b. Carboplatin
c. Sacituzumab govitecan
d. Trastuzumab deruxtecan
e. Paclitaxel
f. Carboplatin/gemcitabine/pembrolizumab
What Therapy Do You Recommend?

She starts on carbo/gem/pembro and has a nice response for 12
months, but then has disease progression in her liver
What do you now recommend?
a. T-DXd
b. Sacituzumab govitecan
c. Paclitaxel
d. Paclitaxel + pembrolizumab
e. Olaparib

What do you now recommend?
a. T-DXd
b. Sacituzumab govitecan
c. Paclitaxel
d. Paclitaxel + pembrolizumab
e. Olaparib

Key Takeaways
Triple-negative breast cancers are generally poorly differentiated duct
carcinomas
Rare variants of triple-negative invasive breast carcinomas exist,
many of which have a good prognosis
A pathology report detailing a well differentiated breast carcinoma
which is triple-negative should raise a red flag as it likely incorrect and
deserves investigation

Key Takeaways (cont.)
Key biomarker information is needed to determine therapy
recommendations in TNBC:
PDL1, HER2-low, BRCAm, PALB2m, TMB, NTRK, MSI
First-line therapy with chemo + pembro is standard for PDL1+mTNBC
Will need to understand how to approach patients who recur after adjuvant
pembro
ADC + immunotherapy may become a new first-line standard
ADCs currently are the second-line standard
For HER2-low patients, slight preference for sacituzumab govitecan over TDXd
given robust phase 3 data
Sequencing ADCs is currently reasonable, but more data is needed

Questions for the Faculty?
Download the Triple-Negative Breast Cancer
Essentials Pocket Guide App!
After scanning the QR code, follow these steps to
add to your home screen:
FOR IPHONE:
Click the Share arrow on your screen
Scroll to the bottom & click ‘Add to Home Screen’
FOR ANDROID:
Click the 3 dots on your screen
Click ‘Install App’
This TNBC app includes:
Guideline summaries on evidence-based
management of TNBC
Treatment and supportive care information
Answers to FAQs
Further Q&As with the expert faculty

References
Abelman RO, Hartley-Blossom Z, Fell GG, et al (2023). Sequential use of antibody-drug conjugate after antibody-drug conjugate for patients with metastatic breast cancer: ADC after ADC (A3)
study. J Clin Oncol, 41(suppl_16):1022. DOI:10.1200/JCO.2023.41.16_suppl.1022
Allison KH, Hammond MEH, Dowsett M, et al (2020). Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP guideline update. J Clin Oncol, 38(12):1346-1366.
DOI:10.1200/JCO.19.02309
Ambrogi F, Fornili M, Boracchi P, et al (2014). Trop-2 is a determinant of breast cancer survival. PLoS One, 9(5):e96993. DOI:10.1371/journal.pone.0096993
American Cancer Society (2023). Triple-negative breast cancer. Available at: https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/types-of-breast-
cancer/triple-negative.html
Amin MB, Edge S, Green F, et al (2017). AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer.
Bardia A, Hurvitz SA, Tolaney SM, et al (2021). Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med, 384(16):1529-1541. DOI:10.1056/NEJMoa2028485
Bardia A, Krop I, Meric-Bernstam F, et al (2023). Datopotamab deruxtecan (Dato-DXd) in advanced triple-negative breast cancer (TNBC): updated results from the phase 1 TROPION-
PanTumor01 study. Cancer Res, 83(suppl_5). Abstract P6-10-03. DOI:10.1158/1538-7445.SABCS22-P6-10-03
Bardia A, Tolaney SM, Loirat D, et al (2020). LBA17 ASCENT: a randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with
previously treated metastatic triple-negative breast cancer (mTNBC). Annals Oncol ESMO, 31(suppl_4); 1149-1150. DOI:10.1016/j.annonc.2020.08.2245
Bardia A, Tolaney SM, Loirat D, et al (2022). Sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (pts) with previously treated, metastatic triple-negative breast
cancer (mTNBC) [oral presention]: final results from the phase 3 ASCENT study. J Clin Oncol, 40(suppl_16); 1071-1071. DOI:10.1200/JCO.2022.40.16_suppl.1071
Bauer KR, Brown M, Cress RD, et al (2007). Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-netative invasive breast cancer, the so-
called triple-negative phenotype: a population-based study from the California cancer registry. Cancer, 109(9):1721-1728. DOI:10.1002/cncr.22618
Carey LA, Loirat D, Punie K, et al (2022). Sacituzumab govitecan as second-line treatment for metastatic triple-negative breast cancer-phase 3 ASCENT study subanalysis. NPJ Breast Cancer,
8(1):72. DOI:10.1038/s41523-022-00439-5
Cardillo TM, Govindan SV, Sharkey RM, et al (2015). Sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate: characterization and efficacy in pancreatic, gastric,
and other cancers. Bioconjug Chem, 26(5):919-31. DOI:10.1021/acs.bioconjchem.5b00223

References (cont.)
Clinicaltrials.gov (2022). Trial of sacituzumab govitecan in participants with refractory/relapsed metastatic triple-negative breast cancer (TNBC) (ASCENT). NLM identifier: NCT02574455.
Clinicaltrials.gov (2023a). A study of dato-DXd versus investigator’s choice chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer, who are not
candidates for PD-1/PD-L1 inhibitor therapy (TROPION-Breast02). NLM identifier: NCT05374512.
Clinicaltrials.gov (2023b). A study of LOXO-783 in patients with breast cancer/other solid tumors (PIKASSO-01). NLM identifier: NCT5307705.
Clinicaltrials.gov (2023c). Capivasertib+paclitaxel as first line treatment for patients with locally advanced or metastatic TNBC (CAPItello-290). NLM identifier: NCT03997123.
Clinicaltrials.gov (2023d). First-in-human study of mutant-selective PI3K⍺ inhibitor, RLY-2608, as a single agent in advanced solid tumor patients and in combination with fulvestrant in patients
with advanced breast cancer. NLM identifier: NCT05216432.
Clinicaltrials.gov (2023e). First-in-human study of STX-478 as monotherapy and in combination with other antineoplastic agents in participants with advanced solid tumor. NLM identifier:
NCT05768139.
Clinicaltrials.gov (2023f). Phase II study evaluating the efficacy and safety of ociperlimab in combination with tislelizumab and chemotherapy as first-line treatment for participants with advanced
triple negative breast cancer (AdvanTIG-211). NLM identifier: NCT05809895.
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