Nuevas definiciones, la nueva clasificación

inmuno-histoquímica del cáncer de mama.

Sandra Ximena Franco, MD
Directora Clínica, CTIC
Medellín, Enero 27, 2024
 Conflicts of interest

• Clinical research support to the institution : Pfizer, Roche,

Novartis, MSD y Abbvie, Bristol
• Advisory boards: Pfizer, Roche y Novartis, Astra-Zeneca,
MSD,Eli Lily
• Speaker events: Roche, Novartis, Pfizer, Astra-Zeneca, Dr.
Reddy´s, BI, Amarey, Lilly.
 Evolution in Breast Cancer Classification

Morphological Immunohistochemical DNA microarray Multi-omic Immunome

Diagnosis assessment analysis analysis analysis
Classical Protein Gene Expression (epi) DNA, RNA, Immune-cell
Diagnosis Expression Profiling Protein Profiling Profiling
Ductal infiltrating ErbB2 over expressing Partial two-dimensional Multi dimensional analysis Integration cellular,
carcinoma of breast with breast tumour cluster analysis of integration of cytokine
high grade of nuclear 17 breast tumours tumours leading to Pathway analysis
atypia Pathway analysis
Adapted from: Baselga J & Norton L. Cancer Cell. 2002;1(4):319–22;
TCGA, Available at: https://www.cancer.gov/about-nci/organization/ccg/research/structural-
genomics/tcga. Accessed September 2019
Overview of HER2 in Breast Cancer
▪ ~15% of breast cancer
are considered HER2 14%
4% 7%
“positive”
10% HR+/HER2- (68%)
▪ HER2 gene amplification HR-/HER2- (10%)
HR+/HER2+ (10%)
and/or HER2 protein 10% HR-/HER2+ (4%)
overexpression is linked to a 68% Unknown (7%)
more aggressive phenotype
▪ HER2 is a validated
therapeutic target

Slamon. Science. 1987;235:177. Ran. Onco Targets Ther. 2020;13:4385. seer.cancer.gov/statfacts/html/breast-subtypes.html.

Current Binary Classification of HER2 in
Breast Cancer

HER2 Score HER2 Score HER2 Score HER2 Score

0 1+ 2+ 3+
ISH

Not Amp Equivocal Amp

HER2 Negative HER2 Positive

Adapted from: Marchiò. Semin Cancer Biol. 2021:72:123.

Targeted Therapies for HER2+ Breast Cancer
HER2-Targeted mAbs HER2-Targeted ADCs
Trastuzumab T-DM1
Margetuximab Pertuzumab T-DXd
HER3 HER2 HER2
HER2 Trastuzumab
HER2
duocarmazine

P P P hsp90
P Lapatinib MK-2206
Alpelisib inhibitor
HER2-Targeted Neratinib PI3K Proteasome P
Tucatinib BEZ235 T-DM1
TKIs hsp90
AKT T-DXd
Breakdown Trastuzumab
Everolimus
mTOR of HER2 P duocarmazine
Temsirolimus
Endosome

T-DM1
T-DXd
Trastuzumab
duocarmazine
Gajria. Expert Rev Anticancer Ther. 2011;11:263. Pernas. Ther Adv Med Oncol. 2019;11:1758835919833519.
 Traditional View of HER2-Positive Breast
Cancer

HER2
Positive

HER2 Negative
• Tumors lacking ERBB2
overexpression or amplification are
collectively defined as HER2
negative
Wolff A et al. J Clin Oncol. 2018;36:2105-2122.
Over half of breast cancers currently categorized as HER2
negative express low levels of HER2, which may be clinically
meaningful1
Current paradigm Future paradigm

Guidelines recommend ‘HER2 positive2’ HER2+ HER2+

assessment of HER2 status
in all newly diagnosed
patients with BC and those HR+/HER2−
patients who develop
metastatic disease3
HR+/HER2−
Currently ~50% of patients
HR+/
‘HER2 negative1,2’ with BC have
Low HER2
(~85%) tumors that express
low levels of
HER21,4

HR-/Low HER2
HER2-
HR−/HER2− HR−/HER2−
(IHC 0)

1. Tarantino P, et al. J Clin Oncol. 2020;38(17):1951-1962; 2. Burstein HJ. N Engl J Med. 2005;353(16):1652-1654; 3. Wolff AC, et al. J Clin Oncol. 2018;36(20):2105-2122. 4.
Marchiò C, et al. Semin Cancer Biol. 2021;72:123-135

8
Proposed Paradigm of Identifying Low HER2
Expression in BC
IHC 01,a IHC 1+ IHC 2+ IHC 3+
No staining OR faint, Faint Weak to moderate Intense
incomplete staining in incomplete staining in complete staining in complete staining in
≤10% of tumor cells >10% of tumor cells >10% of tumor cells >10% of tumor cells

Equivocal
ISH ISH
Negative Positive

HER2 negative
HER2 negative Low HER2 expression HER2 positive

• Low HER2 expression is proposed as a HER2 IHC score of 1+ or 2+/ISH negative2 HER2-
• Evidence-to-date is insufficient for defining low HER2 expressing BC as an individual subtype2(IHC 0)

aAn IHC s core of 0 ma y refl ect a n a rtifactual limitation of the technique ra ther tha n the total a bsence of HER2 protein on the me mbrane, which could be defined as l ow HER2 expression.2
1. Wol ff AC, et a l . J Clin Oncol. 2018;36(20):2105-2122; 2. Ta ra nti no P, et a l . J Clin Onc. 2020;38(17):1951-1962.

9
Overall Survival Outcomes:
HER2-low vs HER2 0
Retrospective Cohort Study: National Cancer Data Base (2010-2019)
N=1,136,016

Large Cohort With Only Potential Marginal Differences in Survival

Peiffer D et al, SABCS 2022

HER2-low and benefit to iCDK 4/6 in the metastatic setting
MDACC (n=918)

No difference in PFS and OS among pts getting ET+ cdk 4/6i in the 1L setting

Mouabbi J et al, SABCS 2022

 Phase 2 DAISY Trial of T-DXD:
Activity seen in HER2 IHC 0 Cohort

IHC 0 Cohort med DoR: 6.8mo (CI: 2.8; NR) ; med PFS: 4.2mo (CI: 2.0; 5.7)

Dieras, V et a; SABC 2021

Evolution of HER2-low Status in
Primary vs. Mets

Approx. 30% of HER2 0 → HER2 Low

Approx. 30% of HER2 Low→ HER2 0

2/23/2024 Response and Resistance to ADCs Zhang et al, ASCO 2023 13

HER2-low mBC: Unmet Clinical Need
Current Standard of Care
HER2 negative
(IHC 0, IHC 1+, IHC 2+/ISH−)
HER2-low
HR+a
Endocrine therapy (ET)
ET combinations
PARP inhibitors (gBRCA+)
Chemotherapy
• HER2-low mBC is defined by IHC scores of 1+ or 2+/ISH−
– This is a heterogenous population with a high prevalence of HR
coexpression and without a distinct biology
• HER2-low mBC is treated as HER2− mBC, with limited options for
later lines of therapy1-4
– Current HER2 targeted therapies are not effective for patients with
tumors that express lower levels of HER2
HR−b • Therapeutic options for patients with HR+/HER2− mBC after
CDK4/6i progression have limited efficacy
Checkpoint inhibitors (PD-L1+)
PARP inhibitors (gBRCA+) – Real-world studies suggest a PFS of <4 months after progressive disease
Sacituzumab govitecan with CDK4/6i5
• Limited benefit exists for patients who progress after multiple lines
of chemotherapy
– In a pooled analysis of patients with HER2− mBC, eribulin and
capecitabine provide minimal benefit, with a mPFS of ~4 months and
mOS of ~15 months6

CDK4/6i, cyclin-dependent kinase 4/6 inhibitors; gBRCA+, germline breast cancer gene positive; HER2, human epidermal grow th factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast
cancer; mOS, median overall survival; PARP, poly (ADP-ribose) polymerase; PD-L1, programmed death ligand 1; mPFS, median progression-free survival; T-DXd, trastuzumab deruxtecan.
aImmunoreactive for estrogen or progesterone receptor in ≥1% tumor cell nuclei. b Immunoreactive for estrogen or progesterone receptor in <1% tumor cell nuclei.

1. Tarantino P, et al. J Clin Oncol. 2020;38(17):1951-1962. 2. Aogi K, et al. Ann Oncol. 2012;23:1441-1448. 3. Eiger D, et al. Cancers (Basel). 2021;13(5):1015. 4. Fehrenbacher L, et al. J Clin Oncol. 2019;38(5):444-453. 5. Mo H, et al. Clin Breast
Cancer. 2022;22:143-148. 6. Kaufman PA, et al. J Clin Oncol. 2015;33:594-601.

14
T-DXd MOA, Bystander Effect, and Rationale for
Targeting HER2-low mBC Neighboring
Tumor Cell
T-DXd binds to
T-DXd1,2 HER2
Tumor Cell
Tumor cell
8:1 drug-to- death
antibody ratio
T-DXd
internalized
Topoisomerase I
inhibitor enters
Cleavable linker nucleus
Highly potent Membrane-
Linker cleaved, permeable
topoisomerase I
releasing payload results in
inhibitor payload topoisomerase I bystander effect
inhibitor

T-DXd HER2 protein

Internalization of T-DXd leads to release of the DXd payload and
Topoisomerase I inhibitor payload
subsequent cell death in the target tumor cell and neighboring
Adapted with permission from Modi S, et al. J Clin Oncol 2020;38:1887-96. CC BY ND 4.0.
tumor cells through the bystander effect1,2

• Results from a phase 1b study have reported efficacy of T-DXd in heavily pre-treated patients (N = 54) with HER2-low mBC, with
a mPFS of 11.1 months and an ORR: 37.0%3

15
1. Nakada T, et al. Chem Pharm Bull. 2019;67:173-85. 2. Ogitani Y, et al. Clin Cancer Res. 2016;22:5097-108. 3. Modi S, et al. J Clin Oncol 2020;38:1887-96.
 ADC Characteristic Differences Between T-DXd and T-DM1

Trastuzumab Trastuzumab
T-DXd1-4,a ADC Attributes T-DM13-5
deruxtecan emtansine
(T-DXd)1 Topoisomerase I (T-DM1)5
Payload MoA Anti-microtubule
inhibitor

~8:1 Drug-to-antibody ratio ~3.5:1

Tumor-selective cleavable
Yes No
linker?
Evidence of bystander
Yes No
anti-tumor effect?

aThe cl inical relevance of these features is under i nvestigation.

1. Na kada T et al. Chem Pharm Bull (Tokyo). 2019;67:173-85. 2. Ogi ta ni Y et al. Clin Cancer Res. 2016;22:5097-108. 3. Tra i l PA et a l. Pharmacol Ther. 2018;181:126-42.
4. Ogi tani Y et al. Cancer Sci. 2016;107:1039-46. 5. LoRus so PM et a l. Clin Cancer Res. 2011;17:6437-47.

ES-19125 (JUNIO 2022) El Departamento Médico de AstraZeneca proporciona esta inf ormación en respuesta a su solicitud y no tiene por objetiv o su copia y /o dif usión integral.
17
En caso de reproducir este material, deberá de adaptarse (patrón y contenido) prev io a su dif usión. Para obtener más inf ormac ión, comuníquese con el Departamento Médico de AstraZeneca.
DS8201-A-J101 is an early (Phase I) dose
expansion study
Dose escalation (Part 1; Japan Only) Dose expansion (Part 2; Japan/US) b
Breast cancer or gastric/GEJ adenocarcinomaa

6 pts
2a Breast cancer (N = 103)
T‐DM1 pre-treated, HER2-positive
RD 8.0 mg/kg

Administered IV Q3W
2b
6.4 mg/kg RD Gastric cancer (N = 41)
6 pts Trastuzumab pre-treated, HER2-positive (IHC3+ or IHC 2+/ISH+)
5.4 mg/kg 6 pts

2c HER2-low breast cancer (N = 40)

HER2-low expressing (IHC 2+/ISH‐, IHC 1+/ISH‐, or IHC 1+/ISH untested)
3.2 mg/kg 3 pts
Pharmacologically active

2d
level Non-breast or gastric cancer (N = 60)
1.6 mg/kg 3 pts HER2 expressing or mutant solid tumours

2e
Minimum effective PK cohort breast cancer (N = 21) (Japan only)
0.8 mg/kg 3 pts
level HER2-positive or low (IHC 1+, IHC2+, IHC 3+, and/or ISH+)

• T-DXd is not licensed in all of these cancers. Please note that off-licence posologies were included in this trial. The recommended dose of T-DXd is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease
progression or unacceptable toxicity.

• a
Subjects in part 1 were not required to have HER2-positive (IHC 3+ or IHC2+/ISH+) tumours.
bThe RD for expansion based on part 1 is 5.4 or 6.4 mg/kg. Part 2a and 2c doses are 5.4 or 6.4 mg/kg Q3W. Parts 2b, 2d and 2e doses are 6.4 mg/kg Q3W. HER2 status was assessed on archival tissue.

• GEJ=gastroesophageal junction; HER2=human epidermal growth factor receptor 2; IHC=immunohistochemistry; ISH=in-situ hybridization; IV=intravenous; PK=pharmacokinetic; Q3W=every 3 weeks; RD=recommended dose;
T-DM1=trastuzumab emtansine; US=United Sates.

• 1. Doi T, et al. Lancet Oncol 2017;18:1512–1522; 2. Iwata H et al. ASCO Annual Meeting 2018. Abstract 2501; 3. Modi S, et al. – supplementary. 2020. J Clin Oncol 38:1887–1896; 4.Tsurutani J et al. Cancer Discov. 2020;10(5):688–701.
 DESTINY-Breast04: Phase 3 Study of T-DXd for HER2-low mBC
An open-label, multicenter study (NCT03734029)

T-DXd
• Centrally HER2 Low MBC 5.4 mg/kg Q3W
(IHC 1+ or IHC 2+/ISH−) (n = 373) Primary endpoint
• PFS by BICR (HR+)
HR+ ≈ 480
• 1-2 prior lines of chemo R HR− ≈ 60
or relapse <6mo of adj CTx 2:1 Key secondary endpointsd
TPC • PFS by BICR (all patients)
• HR+ disease considered Capecitabine, eribulin,
• OS (HR+ and all patients)
gemcitabine, paclitaxel,
endocrine refractory nab-paclitaxelc
(n = 184)

Stratification factors
• Centrally assessed HER2 statusb (IHC 1+ vs IHC 2+/ISH−)
• 1 vs 2 prior lines of chemotherapy
• HR+ (with vs without prior treatment with CDK4/6 inhibitor) vs HR−

BICR, blinded independent central review; CDK, cyclin-dependent kinase; HER2, human epidermal grow th factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer; OS, overall
survival; PFS, progression-free survival; Q3W, every three w eeks; T-DXd, trastuzumab deruxtecan; TPC, treatment of physician’s choice.
aIf patients had HR+ mBC, prior endocrine therapy w as required. bPerformed on adequate archived or recent tumor biopsy per ASCO/CAP guidelines using the VENTANA HER2/neu (4B5) investigational use only [IUO] Assay system. c TPC w as

administered accordingly to the label. dOther secondary endpoints included ORR (BICR and investigator), DOR (BICR), PFS (investigator), and safety; efficacy in the HR− cohort w as an exploratory endpoint.

Modi S, et al. N Engl J Med. 2022 Jul 7;387(1):9-20.

 DESTINY-Breast04: Efficacy Endpoints

PFS in all patients OS in all patients

T-DXd showed unprecedented improvement in efficacy for patients with HER2-low mBC

• Modi S, et a l. Presented at: ASCO 2022 Annual Meeting; June 3-June 7, 2022; Chi cago, IL; Modi S et al, NEJM 2022.
 DB-04 : Efficacy in HR− HER2 Low Cohort
(Exploratory)

Progression Free Survival HR: 0.46 Overall Survival HR: 0.48

95% CI, 0.24-0.89 95% CI, 0.24-0.95
100 100
Progression-Free Survival Probability (%)

80 80

Overall Survival Probability (%)

60 60

40 40

20 20

0 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 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 Months
No. at Risk No. at Risk
T-DXd (n=40): 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 T-DXd (n=40): 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
TPC (n=18): 18 17 11 7 6 4 3 3 2 2 2 2 2 2 1 1 1 1 1 1 0 TPC (n=18): 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 mPFS: 8.5 mo TPC mPFS: 2.9 mo T-DXd mOS: 18.2 mo TPC mOS: 8.3 mo

Modi S, et al. N Engl J Med. 2022 Jul 7;387(1):9-20.

Impacto de la clasificación Her 2 low en el
tratamiento

.
 ES-7066 (ENERO 2022)

Desarrollo Clínico T-DXd Breast Cancer

 ES-17066 (ENERO 2022)
DESTINY-Breast07 (D967JC00001) Enrolling
Study of Trastuzumab Deruxtecan in Combination With Other Anti-Cancer Agents for Patients
With HER2+, Advanced or Metastatic Breast Cancer1
A phase 1b/2, multicenter, open-label, modular, dose-finding and dose expansion study to explore the safety,
tolerability, and anti-tumor activity of trastuzumab deruxtecan (T-DXd) in combination with other anti-cancer agents in
patients with metastatic HER2+ breast cancer (North America, South America, Europe, Asia, Australia)
Study Design Part 1: Dose Finding Part 2: Dose Expansionb
• Advanced or metastatic breast cancer Module 0: Primary Endpoint
• ECOG PS 0-1 Module 1: T-DXd
T-DXd + Durvalumaba • AEs and serious AEs, RP2D – Part 1
• HER2+ (IHC 3+ or IHC 2+/ISH +) Module 1:

(dependent on available RP2D and Sponsor prioritization

(N ≈ 350) T-DXd + Durva lumab • AEs and serious AEs – Part 2

Randomization to open modules

Part 1: Module 2: Module 2:
Secondary Endpoints
Sponsor Assigned
• ≥2 nd Line T-DXd + Pertuzumab T-DXd + Pertuzumab

Module 3:
• Objective response rate (ORR) - Part 2
Part 2: T-DXd + Pa cl itaxel • Duration of Response (DoR) - Part 2
• 1 st Line Module 3:
• Stratified by: T-DXd + Paclitaxel Module 4: • Progression-free survival (PFS) - Part 2
o PD-L1 expression (positivec vs T-DXd + Durva lumab + Pa clitaxel
• Progression-free survival 2 (PFS2) - Part 2
negative) Module 5:
o HR status (positive vs negative) Module 4: T-DXd + Tuca tinib • Overall survival (OS) - Part 2
o Disease status (recurrent vs de novo) T-DXd + Durvalumab + Paclitaxel
Module 6:
T-DXd + Tucatinib in patients with active BM
New combination treatment modules
may be added via protocol amendment Module 7:
T-DXd i n patients with active BM
1. André F, et al. Presented at: San Antonio Breast Cancer Symposium (SABCS)
2020 Virtual Meeting. December8-12 [poster OT-03-04]. New combination treatment modules may be
added via protocol amendment
ClinicalTrials.gov Identifier: NCT04538742
a Dose finding for module 1 may not be necessary due to potential recommended phase 2 dose (RP2D) determination in a separate study (BEGONIA; NCT03742102); b The part 2 dose-expansion phase will use the RP2D determined in part 1; c PD-L1 positive is defined
as IHC ≥1%.

25
DESTINY-Breast08: Trial of T-DXd Combinations in
HER2-Low Advanced Breast Cancer
‒ Nonrandomized phase I study
Part 1: Dose-finding phase Part 2: Dose-expansion phase
Module 1: T-DXd + capecitabine (HR+ or HR-) Allocation to
HR+* or HR-†,
open
Central assignment

HER2-low Module 2‡: T-DXd + durvalumab + paclitaxel (HR+ or HR-)

(IHC1+ or modules
IHC2+/ISH-) Module 3: T-DXd + capivasertib (HR-) depending
advanced BC;
ECOG PS 0/1 Module 4: T-DXd + anastrozole (HR+) on available
(N = 139) RP2D from
Module 5: T-DXd + fulvestrant (HR+) Part 1
*Received ≥1 prior line of endocrine therapy and ≥1 prior line of CT for
▪ Primary endpoint: safety MBC. †Received ≥1 prior line of CT for MBC. ‡Patients who have received
▪ Key secondary endpoint: ORR, PFS, DoR, OS, CT in the neoadjuvant or adjuvant setting are eligible, as long as they
immunogenicity have had a disease-free interval of >12 months.

Can the potential of T-DXd be maximized via combinations?

NCT04556773.
TRIO-US B-12 (TALENT): Neoadjuvant HER2 Low Trial

Arm A (N=29):
Study Population: T-DXd 5.4mg/kg
• HR+
• HER2-low (by local Treatment: 6 or 8 cycles * + EOT Surgery
and/or central review)
Arm B (N=29):
• Stage II-III operable
T-DXd 5.4mg/kg + anastrozole
(+GnRH analog for
men/premenopausal women)

Tissue acquisition from archival tissue or biopsy at baseline and biopsy

between C1D17-C1D21, and tissue at time of surgical resection
All tissue collected for study: pathology centrally reviewed HER2 and Ki67

* Originally, 6 cycles of treatment were given but in 02/2022, an amendment increased the number of treatment cycles
from 6 to 8 for newly enrolled participants, or those who had not yet had surgery.

Presented by Bardia A, Hurvitz S; SABC 2022

DESTINY-Breast06: T-DXd in Chemotherapy Naive
and HER2-Ultralow Advanced/Metastatic Breast Cancer
▪ Randomized, open-label phase III study
Stratified by: prior CDK4/6 inhibitor; HER2 IHC 2+ vs 1+ vs 0;
prior taxane in non-metastatic setting.

Patients with advanced/metastatic breast

T-DXd
cancer with progression on 2 previous
(n = 425)
endocrine therapy; restricted to HR+ Until PD or
Disease; HER2 low (IHC1+, or 2+) or HER2 toxicity
ultralow (IHC* >0 <1+) based on central Chemotherapy
IHC assessment at diagnosis of first (n = 425)
metastatic disease or later
(N = 850) *Investigator’s choice chemotherapy may consist of
capecitabine, paclitaxel, or nab-paclitaxel.
▪ Secondary endpoints: PFS (per INV) in HER2 1+/2+, ORR and
▪ Primary endpoint: PFS (per BICR) in HER2 IHC 1+/2+
DoR in HER2 1+/2+and ITT, safety and tolerability, symptoms,
▪ Key secondary endpoint: OS in HER2 IHC 1+/2+ functioning and QoL
population, PFS and OS in ITT ▪ Exploratory: OS in HER2 IHC 1+/2+ population

*HER2 IHC >0 defined by any IHC staining up to 10% of tumor

NCT04494425. cells. Futility analysis in HER2 IHC 0+ cohort will be done.
DESTINY Breast-15: Phase 3b Study of T-DXd in HER2 LOW
and HER2 IHC 0 MBC

Modi S et al, SABC 2023

 Phase I Trial: Efficacy of Trastuzumab Duocarmazine in
HER2-Positive and HER2-Low Metastatic Breast Cancer
HER2+ MBC HR+/HER2-Low MBC HR-/HER2-Low MBC
100
Best Change in Tumor Size

80 ORR: 33% ORR: 28% ORR: 40%

From Baseline (%)

60 Median PFS: 7.6 mo Median PFS: 4.1 mo Median PFS: 4.9 mo

40
20
0 ***** *
-20
-40
-60
-80
-100

Patients (n = 48) Patients (n = 32) Patients (n = 15)

*Indicates best percentage change of 0%.

▪ Median number of previous systemic treatments: HER2+, 6; HR+/HER2 low, 7;

HR-/HER2-low, 4
Bannerji. Lancet Oncol. 2019;20:1124. Slide credit: clinicaloptions.com
HER2-Targeted ADC: Trastuzumab Duocarmazine (SYD985)

▪ HER2 antibody with same

amino acid sequence as Trastuzumab-vc-seco-duocarmycin-hydroxybenzamide-azaindole
trastuzumab Antibody Linker Prodrug
Trastuzumab Maleimide Protease- Self- Seco-duocarmycin
linker cleavable elimination prodrug
▪ Proteolytic cleavage of linker spacers
linker in tumor Valine
Citrulline
PABC Cyclization
spacer
microenvironment leads to O NH2
activation of prodrug O
HN CI

payload S N O
H
N
O
H
N N
O N O H
H O N N OH
N
▪ Active toxin (DUBA)
O O O N O O
N
SYD985 O O
OH O
~2.8
alkylates DNA, kills dividing
and nondividing cells
▪ Bystander killing effect
Dokter. Mol Cancer Ther. 2014;13:2618. Elgersma. Mol Pharm. 2015;12:1813. Slide credit: clinicaloptions.com
 Pooled Analysis of 2 Phase I Trials of Disitamab Vedotin in
Patients With HER2-Low Advanced BC
Disitamab vedotin (RC48)1 Out of 48 patients with HER2-low mBC2:
NH2
O NH O ▪ ORR: 39.6%
HN O N H O
O
N
N
N
O ▪ mPFS: 5.7 mo
O O NH O
O O O HER2-low expressing
S O N
N N H HO 100 IHC1+
H

Percent Change From Baseline (%)

O
80 IHC2+ FISH-
MC Val-Cit PAB MMAE
60
Antibody Linker Cytotoxic Drug 40
20
*
0
-20
-40
-60
-80
-100
*Percent change from baseline of target lesion is 0%.

1. Shi. Drug Deliv. 2022;29:1335. 2. Wang. ASCO 2021;Abstr 1022. Slide credit: clinicaloptions.com
 HER2-Low Breast Cancer
• A large proportion of all breast cancers: approximately 50%-55%
• Predominantly HR positive: approximately 85%-90%
• Discordant HER2 scoring by IHC and fluctuating expression occurs over
time

HER2-low breast cancer is not a unique subtype

but a TARGETABLE subgroup

Fernandez. JAMA. 2022;8:607. Miglietta. NPJ Breast Cancer. 2021;7:137. Tarantino. ESMO Breast 2022.
Abstr 1MO. Tarantino. JCO. 2020;38:1951. Schettini. ESMO Breast. 2020. Abstr 23P.
Gracias por su atención