The treatment for mTNBC is evolving with the identification of biomarkers and clinical trials revealing new treatment options. Join us to hear from our expert guests, Dr. Paolo Tarantino, an advanced research fellow at Dana-Farber Cancer Institute and at Harvard Medical School, and Dr. Ana Garrido-Castro, Breast Medical Oncologist at Dana-Farber Cancer Institute (DFCI) and Assistant Professor of Medicine at Harvard Medical School.They will present the important changes in genetic/ biomarker diagnostics, immunotherapy as well as emerging therapies. This presentation will also highlight racial disparities and how TNBC disproportionately affects the Black community. Register now and discover your clinical options. Feel free to bring any questions you may have for discussion after the presentation.

1. Paolo Tarantino, MD
Research Fellow, Breast Oncology Center
Dana-Farber Cancer Institute
Future directions for the treatment of
metastatic TNBC

2. Adapted from Wolff A et al. JCO 2018
DISCLOSURES
Consulting/ Advisory role: AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Novartis
Speaker: Roche

3. Adapted from Wolff A et al. JCO 2018
The path towards targeted chemotherapies

4. ASCO 18 & 19
Modi S et al ASCO18; Saura C et al ASCO 18
T-DXd in HER2-low MBC T-DCz in HER2-low mTNBC

5. CHARACTERIZATION OF HER2-LOW BC
HER2-low  tumors with a HER2 IHC score of 1+ or 2+
with negative ISH assay
With this definition, 45-55% of all BC are HER2-low
Tarantino P et al. JCO 2020
TNBC
HER2-low HER2-zero
39% HER2-low
(n=274/697 in our
COQD database)

6. NOVEL CONJUGATES FOR HER2-LOW BC
- High DAR
- Cleavable Linker
- Novel payloads
N N
N N
N
N

7. PFS and OS in HR− (Exploratory Endpoints)
Modi S. et al. Presented at ASCO 2022

8. A range of ongoing ADC trials in both early and metastatic TNBC
have the potential to impact on the treatment landscape
Read out
Ongoing
ESR
Upcoming
NEOADJUVANT ADJUVANT 1L 2L 3L
TROPION-Breast02
Phase III
Dato-DXd vs. TPC
TROPION-Breast03
Phase III
Dato-DXd vs. Dato-DXd + durvalumab vs.
capecitabine ± pembrolizumab
DESTINY-Breast04* in HER2-low
Phase III
T-DXd vs. TPC
I-SPY
Phase II
Dato-DXd ± durvalumab
BEGONIA
Phase Ib/II
Dato-DXd + durvalumab
TROPION-PanTumor01
Phase I
Dato-DXd after T-DXd cohort 2L+
ASCENT-04
Phase III
SG + pembrolizumab
vs. TPC + pembrolizumab
ASCENT-05
Phase III
SG + pembrolizumab
vs. TPC
ASCENT-03
Phase III
SG vs. TPC
SASCIA
Phase III
SG vs. TPC
RC48-ADC in HER2-low
Phase III
RC48-ADC vs. TPC
Given the range of ongoing ADC trials in TNBC, there is a need to investigate sequencing of such agents

9. Targeting Trop2 with Datopotamab-DXd

10. Dato-DXd is an emerging Trop-2-targeting ADC with initial efficacy reported in
the TROPION-PanTumor01 study of heavily pre-treated patients with solid
tumours
Eligibility criteria
• Advanced / metastatic
HR-negative/HER2-negative
breast cancer (TNBC)
• Relapsed / progressed on standard treatment
• Unselected for TROP2 expression
• ECOG PS 0–1
• Measurable disease (per RECIST v1.1)
• Stable, treated BMs allowed
NSCLC
Dato-DXd 0.27–10 mg/kg IV Q3W
Primary endpoint
• Safety and tolerability
Secondary endpoints
• Maximum concentration
(Cmax)
• Time at which Cmax is
reached
TNBC
Dato-DXd 8 mg/kg IV Q3W (n=2);
6 mg/kg IV Q3W (n=42)
HR-positive/HER2-negative BC
Dato-DXd 6 mg/kg IV Q3W (n=41)
Other tumour types
(SCLC, bladder, gastric, oesophageal, CRPC, pancreas)
Study schema

11. In heavily pre-treated patients with advanced TNBC, Dato-DXd showed
encouraging and durable efficacy responses with a generally manageable
safety profile
The most common TEAEs were stomatitis and nausea, and no cases
of ILD/pneumonitis or neutropenia were reported
ORR by BICR was 32% in all patients and 44% in Topo I inhibitor-naïve patients
with measurable disease at baseline
†
Anti-tumour responses by BICR Safety

12. The role of first-line datopotamab deruxtecan will be further validated in
TROPION-Breast02
Eligibility criteria
• Metastatic or locally recurrent unresectable TNBC
• No prior chemotherapy or targeted systemic therapy for metastatic TNBC
• Not a candidate for PD-1/PD-L1 inhibitor therapy
• Measurable disease as defined by RECIST v1.1
• ECOG PS 0–1
• Adequate haematologic and end-organ function
Primary endpoints
• PFS
• OS
Key secondary endpoints
• ORR
• DOR
• PFS by IA
• TTD
• PROs
• Safety
Dato-DXd
6 mg/kg IV Q3W
TPC†
TROPION-Breast02 study schema2
TROPION-Breast03 is also investigating Dato-DXd (vs. investigator’s choice of therapy) in the post-neoadjuvant setting

13. ASCENT-03/04 follow on from the ASCENT trial and are investigating SG in
earlier lines of TNBC treatment
Eligibility criteria
• Previously untreated, inoperable, locally advanced or mTNBC
• PD-L1− tumours (CPS<10, IHC 22C3 assay) OR
• PD-L1+ tumours (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
Primary endpoints
• PFS by BICR per RECIST v1.1
Secondary endpoints
• OS by BICR per RECIST v1.1
• ORR by BICR per RECIST v1.1
• DOR by BICR per RECIST v1.1
• TTR by BICR per RECIST v1.1
• Safety
• TTD
Sacituzumab govitecan + pembrolizumab
10 mg/kg IV on D1 and 8 of 21D cycles, and 200 mg IV on D1 of 21D
cycles, respectively
TPC + pembrolizumab
ASCENT-03 study schema1
Eligibility criteria
• Previously untreated, inoperable, locally advanced, or mTNBC
• PD-L1+ (CPS ≥10, IHC 22C3 assay)
• ≥6 months since treatment in the curative setting
• Prior anti-PD-(L)1 agent allowed in the curative setting
• PD-L1 and TNBC status centrally confirmed
Primary endpoints
• PFS by BICR per RECIST v1.1
Secondary endpoints
• OS by BICR per RECIST v1.1
• ORR by BICR per RECIST v1.1
• DOR by BICR per RECIST v1.1
• TTR by BICR per RECIST v1.1
• Safety
• TTD
Sacituzumab govitecan + pembrolizumab
10 mg/kg IV on D1 and 8 of 21D cycles, and 200 mg IV on D1 of 21D
cycles, respectively
TPC + pembrolizumab
ASCENT-04 study schema2

14. Evolving Treatment Algorithm for Metastatic TNBC
1L 2L 3L
PD-L1+:
CT + pembrolizumab
PD-L1-:
Taxane or platinum
Sacituzumab govitecan
High TMB, MSI-H/dMMR:
Pembrolizumab
HER2 low:
T-DXd
BRCAm:
Olaparib or talazoparib
Eribulin, capecitabine,
gemcitabine, navelbine
Dato-DXd
?

15. What other target
on the horizon?
HER3
LIV1
NECTIN4
CEACAM
MESOTHELIN
FRα
B7H4 CD166 CD71
MUC1

16. HER3

17. HER3 in breast cancer
HER3 is expressed in >95% of breast
cancers, with half showing a strong
overexspression
Luthala S. et al. BMC Cancer 2018

18. HER3-DXd

19. Phase 2 trial of HER3-DXd for patients with HER2- MBC

20. Phase 2 trial of HER3-DXd for patients with HER2- MBC

21. Future frontiers
Tarantino P et al. Cancer Res 2022

22. SPECULATIONS
Choosing which ADC to prioritize will soon rely on cross-trials
comparisons. But could a refined biomarker assessment change
the paradigm in the future?
EXAMPLE: metastatic TNBC (ER: 0%, PgR: 0%, HER2-negative)
Hypotetical expanded biomarker testing :
- HER2 80%, other targets low  prioritize T-DXd?
- TROP2 90%, other targets low  prioritize Saci/Dato-DXd?

23. OPTIMIZING THE MANAGEMENT OF TOXICITIES
Tarantino P et al. Nat Rev Clin Onc 2023

24. OPTIMIZING THE MANAGEMENT OF TOXICITIES
Tarantino P et al. Nat Rev Clin Onc 2023

25. WHAT ABOUT IMMUNOTHERAPY?
Debien et al Breast NPJ 2023; Courtesy of A. Giordano

26. COMBINATION STRATEGIES
Courtesy of A. Giordano

27. Combining Dato-DXd + durvalumab (PD-L1 inh) showed impressive activity
Confirmed ORR: 79% with 2 complete responses
and most responses being durable (100%
ongoing at 6 months).
Most common Aes: nausea [55%] and stomatitis
[51%]). No cases of ILD.

28. Similarly promising outcomes for 1L T-DXd + durvalumab

29. Targeting LIV1 with ladiratuzumab vedotin + pembro
Han H. SABCS 2019; Courtesy of A. Giordano

30. PARP INHIBITORS + IO
Han H. SABCS 2019; Courtesy of A. Giordano

31. TOPACIO: PHASE 2 TRIAL OF NIRABARIB + PEMBRO
Vinayak et al JAMA Onc 2019; Courtesy of A. Giordano

32. Is there a role for PARPi + IO maintainance for mTNBC?
Courtesy of A. Giordano

33. CONCLUSION
Several ADCs have recently expanded the treatment arsenale for TNBC, demonstrating relevant activity in
chemotherapy-refractory settings
Encouraging activity has been observed with Dato-DXd, both as monotherapy and in combo with IO
SG and Dato-DXd are currently being tested in the 1L setting, and may modify our treatment algorithms in the next
future
ADCs, PARP inhibitors and additional combination strategies are being experimented to enhance the activity of
immunotherapy in TNBC
Together with developing new agents, it will be critical to improve the management of their side effects and identify
appropriate biomarkers of response and resistance

34. Thank you for your
attention!
EMAIL
paolo_tarantino@dfci.harvard.edu
Twitter: @PTarantinoMD
Naples, Italy