Antibody drug conjugates (ADC’s), a novel class of anticancer agents, have been around for decades but recently great strides have been made in metastatic breast cancer. Next generation ADC’s, sometimes referred to as ' Trojan Horses' have shown promising efficacy in all subtypes of MBC. Join Dr. Erika Hamilton, Director of Breast Cancer and Gynecologic Cancer Research at Sarah Cannon Research Institute, and partner with Tennessee Oncology PLCC, as she presents an overview of ADC’s, biomarkers and clinical mapping, current treatment options, as well as the promising trials to keep an eye on. There will be time for your questions throughout the presentation.

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Antibody drug conjugates for
metastatic breast cancer (MBC)
Erika Hamilton, MD
Director, Breast Cancer Research
Sarah Cannon Research Institute
Nashville, TN 37203

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COI disclosures
Consulting Advisory Role (to institution only):
Arcus, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Greenwich LifeSciences, iTeos, Janssen, Lilly, Loxo, Mersana, Novartis, Olema
Pharmaceuticals, Orum Therapeutics, Pfizer, Relay Therapeutics, Roche/Genentech, SeaGen, Stemline Therapeutics, Tubulis, Verascity
Science
Contracted Research/Grant (to institution only):
Abbvie, Acerta Pharma, Accutar Biotechnology, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, ArQule, Artios, Arvinas,
AstraZeneca, AtlasMedx, BeiGene, Black Diamond, Bliss BioPharmaceuticals, Boehringer Ingelheim, Cascadian Therapeutics, Clovis,
Compugen, , Context Therapeutics, Cullen-Florentine, Curis, CytomX, Daiichi Sankyo, Dana Farber Cancer Inst, Dantari, Deciphera,
Duality Biologics, eFFECTOR Therapeutics, Ellipses Pharma, Elucida Oncology, EMD Serono, FujiFilm, G1 Therapeutics, H3 Biomedicine,
Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, Infinity Pharmaceuticals , InvestisBio, Jacobio, Karyopharm, K-
Group Beta, Kind Pharmaceuticals, Leap Therapeutics, Lilly, Loxo Oncology, Lycera, Mabspace Biosciences, Macrogenics, MedImmune,
Mersana, Merus, Millennium, Molecular Templates, Novartis, Nucana, Olema, OncoMed, Onconova Therapeutics, Oncothyreon, ORIC
Pharmaceuticals, Orinove, Orum Therapeutics, Pfizer, Pharma Mar, Pieris Pharmaceuticals, Pionyr, Immunotherapeutics, Plexxikon,
Prelude Therapeutics, Profound Bio, Radius Health, Regeneron, Relay Therapeutics, Repertoire, Immune Medicine, Rgenix,
Roche/Genentech, SeaGen, Sermonix Pharmaceuticals, Shattuck Labs, StemCentRx, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro,
Tolmar, Torque Therapeutics, Treadwell Therapeutics, Verastem, Vincerx Pharma, Zenith Epigenetics, Zymeworks

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Structure of an antibody drug conjugate (ADC)
Antigen-
Binding Site
mAb
Targets tumor-specific or
tumor-associated antigens
Potent Cytotoxic Payload
Amount of payload varies
among ADCs
Stable Linker
Releases payload in tumor
cell ± surrounding
microenvironment
Tumor Antigen
@Erikahamilton9
Antibody drug conjugates
 have 3 components (antibody, linker, payload)
 are designed to deliver cytotoxic payload
directly to targeted tumor cell
 have increased therapeutic index compared
to either antibody or payload component alone

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Canonical MOA of an ADC
@Erikahamilton9
Figure from: Tolcher A, Hamilton E & Coleman RL Cancer Treat. Rev 2023

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FDA approved ADCs
@Erikahamilton9
T-DM1
Roche
Sacituzumab
Gilead
T-DXd
DSI /AZ
2013 2019 2020
3 different ADCs approved for the treatment of breast cancer
T-DM1: targets HER2
T-DXd: targets HER2
SG : targets TROP2

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Trastuzumab emtansine (T-DM1)
@Erikahamilton9
HER2 antibody (trastuzumab) attached to DM1 payload
DM1, a maytansinoid, ~20-200X more potent than taxanes and
vinca alkaloids
MCC linker (non cleavable) designed to provide a more stable
bond between trastuzumab and the active cytotoxic agent
- goal of minimizing systemic exposure in circulation
Figure from: Lo Russo PM et al. Clin Cancer Res 2011

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T-DM1: 1st ADC to receive FDA approval for solid tumors (2013)
@Erikahamilton9
Study name EMILIA TH3RESA
Treatment T-DM1 vs cape/lapatinib T-DM1 vs Treatment of physician's choice
Patient population
HER2+ MBC treated with prior trastuzumab
and taxane
>2 lines of anti-HER2 therapy for HER2+ MBC
Study treatment T-DM1 Cape/lapatinib T-DM1
Treatment of
physician's choice
Median PFS
(months)
9.6 6.4 6.2 3.3
Media OS (months) 30.9 25.1 Not reached 14.9
Approved for HER2+ MBC after prior treatment with trastuzumab and taxane

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New/potent ADCs with bystander killing effect
@Erikahamilton9
ADC binding to
receptor
A high drug-to-antibody ratio
increases antitumoral efficacy
despite low antigen density
on tumor cells
Release of drug payload from antibody after
antigen binding, before internalization
Release of drug payload into
intercellular space because of high
drug membrane permeability
Drug payload release after linker
cleavage by lysosomal enzymes
Internalization
by endocytosis
Cytotoxic effect
induced by drug payload
ADC
Drug payload
Tumor cell
Classical ADC
Mode of Action
Bystander Killing Effect
Figure from: Rinnerthaler G et al. Int J Mol Sci. 2019;20:1115

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Tratuzumab deruxtecan (T-DXd): novel HER2 ADC
@ErikaHamilton9
Humanized anti-HER2 IgG1
mAb1-3
Deruxtecan1,2
Topoisomerase I Inhibitor payload (DXd=DX-8951f
derivative)
Cleavable Tetrapeptide-Based
Linker
T-DXd is an ADC composed of 3 components1,2:
• A humanized anti-HER2 IgG1 mAb with the same amino
acid sequence as trastuzumab, covalently linked to:
• A topoisomerase I inhibitor payload, an exatecan
derivative, via
• A tetrapeptide-based cleavable linker
Payload mechanism of action:
topoisomerase I inhibitora,1,2
High potency of payloada,1,2
High drug-to-antibody ratio ≈ 8a,1,2
Payload with short systemic half-lifea,1,2
Stable linker-payloada,1,2
Tumor-selective cleavable linkera,1,2
Bystander antitumor effecta,1,4
1. Nakada T, et al. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. 2. Ogitani Y, et al. Clin Cancer Res. 2016;22(20):5097-5108. 3.
Trail PA, et al. Pharmacol Ther. 2018;181:126-142. 4. Ogitani Y, et al. Cancer Sci. 2016;107(7):1039-1046.
aThe clinical relevance of these features is under investigation.
ADC, antibody-drug conjugate; IgG1, immunoglobulin G1; mAB, monoclonal antibody.

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Trastuzumab emtansine Trastuzumab deruxtecan
Structure
Antibody Trastuzumab Trastuzumab
Linker Non-cleavable Cleavable
Drug-antibody ratio 3.5:1 8:1
Cytotoxic moiety Maytansine derivative Exatecan derivative
MOA of cytotoxic moiety Microtubule inhibitor Topoisomerase 1 inhibitor
Diffusible cytotoxic moiety No Yes
Bystander killing effect No Yes
Targets HER2+ tumors Yes Yes
Targets HER2-low tumors No Yes
T-DM1 vs T-DXd

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Sacituzumab
govitecan
(SG)
@ErikaHamilton9
First-in-class TROP2 directed ADC
Approved for treatment of metastatic TNBC and HR+/HER2- MBC

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Overview of current treatment with ADCs
for HER2+ MBC

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Current treatment algorithm for HER2+ MBC
1st line
2nd line
3rd line
Taxane + trastuzumab + pertuzumab
Trastuzumab emtansine (T-DM1)
Capecitabine + lapatinib
Margetuximab + chemo (SOPHIA)
Capecitabine + neratinib (NALA)
Trastuzumab deruxtecan (T-DXd)
Tucatinib + trastuzumab + capecitabine
4th line &
later
Clinical trials!!

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Key measures of efficacy in oncology clinical trials
• Overall response rate (ORR):
The percentage of patients whose cancer shrinks or disappears after treatment
• Duration of response (DoR):
The length of time from when a tumor began responding to treatment to the time the tumor
grows/spreads
• Progression-free survival (PFS):
The average length of time after the start of treatment in which a person is alive, and their cancer does
not grow or spread
• Overall survival (OS):
The average length of time patients are alive after the start of treatment

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DESTINY Breast01: Efficacy and safety
Change from baseline in tumor size
and Nausea
Trastuzumab deruxtecan (T-DXd) was approved by the FDA on Dec 20, 2019 for treatment of HER2+ MBC
after >2 prior anti-HER2 regimens
Krop I et al. SABCS 2019, GS1-03
Phase 2 trial that evaluated single agent T-DXd in HER2+ MBC previously treated with T-DM1

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DESTINY Breast03: Ph 3 trial of T-DXd vs T-DM1 in 2L HER2+ MBC
Cortes J et al. ESMO 20

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DESTINY Breast03: Significant improvement in PFS with T-DXd
vs T-DM1
Cortes J et al. ESMO 2021
Progression-free survival Best overall response
ORR: 79.7%
ORR: 34.2%
Trastuzumab deruxtecan (T-DXd) was approved by FDA on May 6, 2022 for treatment of HER2+ MBC
after 1 prior anti-HER2 regimen for MBC or relapse <6 months from (neo)adjuvant anti-HER2 treatment

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Overview of current treatment with
ADCs for HR+ MBC

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HER2: Continuum of expression of in breast cancer
Penault-Llorca F. ESMO E-learning module
HER2-low
HER2 IHC 2+/ISH- OR IHC 1+/ISH – or untested

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Frequency of HER2 IHC 0, 1+, 2+ in breast cancer
HR+ (5563 cases) TNBC (607 cases)
Penault-Llorca F. ESMO E-learning module
~75% HER2-low ~49% HER2-low

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T-DXd: Activity in HER2-low MBC
Modi S et al. JCO 2020
Best percent change in tumor size
Significant anti-tumor activity in HER2 IHC 2+ and 1+ tumors
Confirmed ORR: 37%
Confirmed DCR: 87%
Median DoR: 10.4 months
Median PFS: 11.1 months

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DESTINY Breast04 Schema
Modi S et al. Plenary session ASCO 2022
Patient population
HR+/HER2-low All patients
>3 priors for MBC 66% 62%
2 prior lines of chemo 40% 43%
Prior CDK 4/6i 70.5% 64.5%

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DESTINY Breast04: Progression-free survival
Primary EP
Modi S et al. Plenary session ASCO 2022

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DESTINY Breast04: Overall Survival
Modi S et al. Plenary session ASCO 2022

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DESTINY Breast04: Summary
Modi S et al. Plenary session ASCO 2022
• In pts with HER2-low MBC, trastuzumab deruxtecan improved
o Median PFS by 4.8 months (HR 0.50, p<0.0001)
o Median OS by 6.6 months (HR 0.64, P=0.0010)
o No new safety signals; there was an overall positive benefit-risk
These results establish T-DXd as the new SOC for HER2-low MBC
T-DXd approved by the FDA for treatment of MBC for the newly defined
“HER2-low” subtype on August 5, 2022

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Sacituzumab govitecan (SG): Trop2 - directed ADC in HR+/HER2- MBC
Rugo H et al. ASCO 2022
o Significant improvement in mPFS with SG (HR 0.66, P<0.001)
o Significant improvement in OS with SG (HR 0.79, P=0.020)
o A posthoc subgroup analysis evaluated efficacy in the HER2-low subgroup

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Current treatment algorithm for HR+/HER2- MBC
1st line
2nd line
3rd line
CDK4/6i + AI/Fulvestrant
Trastuzumab deruxtecan (T-DXd)*
PIK3CA mutant
Alpelisib + ET
Chemotherapy
4th line &
later Sacituzumab govitecan
gBRCA mutant
Olaparib / Talazoparib
ESR1 mutant
Elacestrant
Everolimus + ET
Fulvestrant (if not used
previously)
Visceral crisis
Chemotherapy
Consider Clinical trials if available!!
*HR+/HER2low

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Overview of current treatment with
ADCs for mTNBC

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ASCENT : Phase 3 confirmatory trial
@ErikaHamilton9
Bardia A et al. ESMO 2021; NEJM 2021
Sacituzumab govitecan received accelerated approval from FDA (April 2020) for pts with metastatic TNBC
treated with at least 2 prior therapies for MBC. Approval was based on a single arm trial of mTNBC (n=108)
ASCENT- phase 3 trial study design

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ASCENT : PFS & OS
@ErikaHamilton9
Bardia A et al. ASCO 2022
Trial demonstrated statistically significant & clinically meaningful improvement in PFS and OS over single-agent chemotherapy
In April 2021, the FDA granted regular approval to Sacituzumab govitecan for pts with mTNBC who
have received two or more prior systemic therapies, at least one of them for metastatic disease

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ASCENT : Clinical benefit irrespective of Trop-2 expression
@ErikaHamilton9
Bardia A et al. ASCO 2022

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Current treatment algorithm for mTNBC
1st line
2nd line
3rd line
PD-L1 CPS >10
Chemotherapy +
pembrolizumab
4th line &
later
Consider Clinical trials if available!!
Chemotherapy
gBRCA mutant
Olaparib / Talazoparib
PD-L1 CPS <10
Chemotherapy
Trastuzumab
deruxtecan*/
Sacituzumab govitecan
Trastuzumab
deruxtecan*/
Sacituzumab govitecan
Sacituzumab govitecan
Trastuzumab
deruxtecan*/
Sacituzumab govitecan
Sacituzumab govitecan
Trastuzumab
deruxtecan*/
Sacituzumab govitecan
Chemotherapy
*HR+/HER2low

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Trastuzumab
emtansine
• Alopecia
• Thrombocytopenia
Common toxicities with FDA approved ADCs for MBC
Trastuzumab
deruxtecan
• Nausea
• Fatigue
• Vomiting
• Neutropenia
• Interstitial lung disease
(ILD)
Sacituzumab
govitecan
• Diarrhea
• Nausea
• Vomiting
• Neutropenia
@Erikahamilton9

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Management of ILD with T-DXd
Tarantino P & Tolaney SM JCO Onc Prac 2023
Careful patient selection
during screening to
optimize monitoring
strategies
Continue monitoring
during treatment to
exclude signs/symptoms
of ILD
Monitor using high
resolution chest CT
Baseline scan
recommended, with repeat
scans every 6-12 weeks
Minimizing risk of ILD
involves teamwork -
educating patients and
the care team is essential
Multidisciplinary
management is required
once ILD is suspected
T-DXd should be
interrupted if ILD is
suspected
T-DXd can be restarted
only in case of
asymptomatic ILD that
has fully resolved
Corticosteroids are
the mainstay of treatment
and the dose should be
tailored to toxicity grade

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Antiemetic prophylaxis recommendations
@ErikaHamilton9
 Use pre-medications to manage nausea
 Prescribe anti nausea medication for use during treatment
Bianchini G. et al., Cancers 2022, 14(4), 1022; https://doi.org/10.3390/cancers14041022

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Ongoing trials with ADCs for MBC

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Moving T-DXd to 1st line MBC
DESTINY Breast07 (NCT04538742) Enrollment closed
T-DXd combinations with chemotherapy, immunotherapy and endocrine therapy in 1-2L setting in HER2+ MBC
DESTINY Breast09 (NCT04784715)

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DESTINY Breast06: T-DXd for HER2 low and ultra low MBC
DESTINY Breast08 (NCT04556773) Enrollment closed
T-DXd combinations with chemotherapy, immunotherapy and endocrine therapy in 1-2L HER2-low MBC
NCT04494425 Enrollment closed – results anticipated in Q4 2023 /Q1 2024

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TROPION Breast02: Dato-DXd for 1L mTNBC
 Metastatic TNBC
No prior systemic therapy for MBC
Not a candidate for PD-(L)1
therapy
Central testing to confirm PD-L1
status
Measurable disease per RECIST
v1.1
Dato-DXd
6mg/kg IV Q3 weeks
Investigator choice of
Chemotherapy*
1:1
N=600
• Datopotamab DXd (Dato-DXd) is a TROP2 targeting ADC
• Trop 2 is highly expressed in breast cancer and its expression is associated with poor prognosis
*If no prior taxane or DFI >12 months: paclitaxel or nab-paclitaxel
If prior taxane or DFI <12 months: Eribulin, Capecitabine, Carboplatin
NCT05374512

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ASCENT-03 and -04: Sacituzumab govitecan for 1L mTNBC
• Sacituzumab Govitecan (SG) is a TROP2 targeting ADC
ASCENT-03: PD-L1 neg or PD-L1+ and rcvd CPI for EBC
ASCENT-04: PD-L1+ tumor
CPI: checkpoint inhibitor

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Patritumab deruxtecan in HER2+ MBC after PD on prior ADC
Part Z (N = 21)
*T-DXd does not have to be
the most recent line of tx
 HER2+ MBC
 At least 2 prior anti-HER2 therapies, one of which
must be T-DXd*
 No prior tx with any HER3-targeting agent
 No prior tx with an ADC that contains an exatecan
derivative except for T-DXd
Patritumab deruxtecan
5.6mg/kg IV q 3 weeks
Patritumab deruxtecan is a HER3 targeting ADC with promising activity in HER2- MBC
irrespective of HER3 expression in the tumor
Measurable disease per RECIST v1.1 (bone only excluded)
HR+ /HER2- MBC:
ER/PR >1% and HER2 IHC 0 or 1+ or IHC2+ and ISH negative
Prior tx with ET+ CDK 4/6i; unlimited ET but only 2 prior chemo
Prior T-DXd and/or Sacituzumab govitecan
mTNBC:
1-5 prior lines of chemo for MBC
Prior T-DXd and/or Dato-DXd
Patritumab deruxtecan
5.6mg/kg IV q 3 weeks
Part B (N = 40)
NCT04699630

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Thank You