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Next-Generation HER2-Targeted Antibody–Drug Conjugates in Breast Cancer

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Human epidermal growth factor receptor 2 (HER2) tyrosine kinase is overexpressed in 20% of breast cancers and associated with a less favorable prognosis compared to HER2-negative disease. Patients have traditionally been treated with a combination of chemotherapy and HER2-targeted monoclonal antibodies such as trastuzumab and pertuzumab. The HER2-targeted antibody–drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) represent a novel class of therapeutics in breast cancer. These drugs augment monoclonal antibodies with a cytotoxic payload, which is attached by a linker, forming the basic structure of an ADC. Novel combinations and sequential approaches are under investigation to overcome resistance to T-DM1 and T-DXd. Furthermore, the landscape of HER2-targeted therapy is rapidly advancing with the development of ADCs designed to attack cancer cells with greater precision and reduced toxicity. This review provides an updated summary of the current state of HER2-targeted ADCs as well as a detailed review of investigational agents on the horizon. Clinical trials are crucial in determining the optimal dosing regimens, understanding resistance mechanisms, and identifying patient populations that would derive the most benefit from these treatments. These novel ADCs are at the forefront of a new era in targeted cancer therapy, holding the potential to improve outcomes for patients with HER2-positive and HER2-Low breast cancer.
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Citation: Zimmerman, B.S.; Esteva, F.J.
Next-Generation HER2-Targeted
Antibody–Drug Conjugates in Breast
Cancer. Cancers 2024,16, 800. https://
doi.org/10.3390/cancers16040800
Academic Editors: Michael Bohlmann,
Ralf D. Hofheinz and Sylvie Lorenzen
Received: 7 January 2024
Revised: 13 February 2024
Accepted: 14 February 2024
Published: 16 February 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
cancers
Review
Next-Generation HER2-Targeted Antibody–Drug Conjugates in
Breast Cancer
Brittney S. Zimmerman 1,2 and Francisco J. Esteva 1, 2, *
1Northwell, New Hyde Park, NY 11042, USA; bzimmerman2@northwell.edu
2Northwell Health Cancer Institute, Lake Success, NY 11042, USA
*Correspondence: festeva@northwell.edu
Simple Summary: Human epidermal growth factor receptor 2 (HER2) is amplified or overexpressed
in approximately 20% of breast cancer cases. This overexpression is correlated with a more aggressive
form of the disease and predicts a less favorable prognosis. Historically, the standard treatment
for patients with HER2-positive breast cancer has involved chemotherapy in combination with
monoclonal antibodies that target the HER2 receptor, notably trastuzumab and pertuzumab. However,
resistance to these drugs has been ubiquitous, presenting challenges in the management of the
disease. Antibody–drug conjugates (ADCs) represent a promising therapeutic category for the
treatment of breast cancer. Trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd)
are currently approved ADCs. These molecules have been pivotal, demonstrating superior clinical
outcomes over previous conventional treatments in HER2-positive breast cancer (T-DM1, T-DXd)
and HER2-Low (T-DXd). However, drug resistance remains an unresolved problem, and there is
interest in developing better-tolerated and more effective therapeutics for breast cancer. This review
focuses on the emergence of innovative HER2-targeted ADCs, including those currently undergoing
investigation in clinical trials.
Abstract: Human epidermal growth factor receptor 2 (HER2) tyrosine kinase is overexpressed in 20%
of breast cancers and associated with a less favorable prognosis compared to HER2-negative disease.
Patients have traditionally been treated with a combination of chemotherapy and HER2-targeted mono-
clonal antibodies such as trastuzumab and pertuzumab. The HER2-targeted antibody–drug conjugates
(ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) represent a novel class
of therapeutics in breast cancer. These drugs augment monoclonal antibodies with a cytotoxic pay-
load, which is attached by a linker, forming the basic structure of an ADC. Novel combinations
and sequential approaches are under investigation to overcome resistance to T-DM1 and T-DXd.
Furthermore, the landscape of HER2-targeted therapy is rapidly advancing with the development
of ADCs designed to attack cancer cells with greater precision and reduced toxicity. This review
provides an updated summary of the current state of HER2-targeted ADCs as well as a detailed
review of investigational agents on the horizon. Clinical trials are crucial in determining the optimal
dosing regimens, understanding resistance mechanisms, and identifying patient populations that
would derive the most benefit from these treatments. These novel ADCs are at the forefront of a
new era in targeted cancer therapy, holding the potential to improve outcomes for patients with
HER2-positive and HER2-Low breast cancer.
Keywords: HER2; antibody–drug conjugates; breast neoplasms; targeted therapy; trastuzumab
deruxtecan; trastuzumab-DM1; drug resistance
1. Introduction
Breast cancer is the most common malignancy among women and a leading cause of
cancer-related deaths worldwide [
1
]. There are three main molecular subtypes of breast
cancer, which differ significantly in natural history, prognosis, and treatment options. These
Cancers 2024,16, 800. https://doi.org/10.3390/cancers16040800 https://www.mdpi.com/journal/cancers
Cancers 2024,16, 800 2 of 21
are commonly known as hormone receptor-positive/HER2-negative (luminal A, luminal
B), human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative [
2
]. The
HER2 protein is overexpressed in 20–30% of breast cancers and is historically associated
with higher cancer recurrence rates and shorter disease-free and overall survival when com-
pared with HER2-negative breast cancers [
3
]. HER2 is a member of the epidermal growth
factor receptor (EGFR) family of receptor tyrosine kinases, which includes EGFR/HER1,
HER2, HER3, and HER4. These receptors play a significant role in cell growth and dif-
ferentiation. Overexpression of HER2 is linked to upregulated cell proliferation and the
development of several cancers, including breast, gastric, and ovarian cancer [
3
,
4
]. Identifi-
cation of the HER2 status is achieved by two methods: immunohistochemistry (IHC) and
fluorescence in situ hybridization (FISH). All patients with invasive breast cancer have the
tumor evaluated first by IHC (graded from 0 to 3+), followed by validation with FISH for
borderline (IHC 2+) results. Patients with tumors that are IHC 3+- or FISH-positive tend
to respond to anti-HER2 therapies. HER2 testing methodologies have evolved over time,
including different ways of assessing HER2 protein expression using immunohistochem-
istry with novel scoring systems (e.g., H-score). HER2-Low breast cancer represents a new
subset of breast cancers that may respond to HER2 ADC therapy. The development and
validation of quantitative assays to determine HER2 protein levels in breast cancer tissue
samples is an area of active investigation [5].
The approval of trastuzumab, a monoclonal antibody targeting HER2, in 1998 marked
a significant advancement in the therapeutic landscape for HER2-positive breast cancer [
6
].
Subsequently, there has been a substantial increase in the clinical development of innovative
therapies aimed at this specific breast cancer subtype [
7
]. The strategic incorporation of
monoclonal antibodies and tyrosine kinase inhibitors, along with chemotherapy, endocrine
therapy, and immunotherapy, has profoundly transformed the clinical outcomes for indi-
viduals diagnosed with HER2-positive breast cancer [
8
]. This paradigm shift has occurred
at both the early and advanced stages of the disease [9].
While monoclonal antibodies and tyrosine kinase inhibitors represent major advances
in the treatment of HER2-positive breast cancer, a significant number of patients with early
breast cancer develop metastatic disease despite adjuvant systemic therapy. Furthermore,
the development of progressive disease in the metastatic setting and the lack of curative
therapies remain unmet needs. Understanding molecular mechanisms of resistance in
HER2-positive breast cancer cells, together with improvements in technology, led to the
development of antibody–drug conjugates (ADCs). These drugs represent an advanced
modality in oncological treatment, integrating the specificity of monoclonal antibodies with
the cytotoxic power of potent drugs, also known as “payloads”, using specific linkers [
10
].
As targeted therapeutics, ADCs are designed to selectively hone in on and neutralize cancer
cells expressing antigens, specifically the HER2 antigen (for purposes of this review). This
targeted approach amplifies treatment efficacy while minimizing the widespread adverse
effects typically associated with conventional chemotherapy.
The chemical structure of ADCs consists of three integral elements: a monoclonal
antibody, a chemical linker with stability or cleavability properties, and a cytotoxic pay-
load/agent (Figure 1).
Cancers 2024,16, 800 3 of 21
Cancers 2024, 16, x FOR PEER REVIEW 3 of 22
Figure 1. ADC components. Abbreviations: DAR: drug-to-antibody ratio; DM1: derivative of may-
tansine 1; DM4: derivative of maytansine 4; MMAF: monomethyl auristatin F; MMAE: monomethyl
auristatin E.
The engineered monoclonal antibody (e.g., trastuzumab) is designed to detect and
bind to an antigen expressed on the surface of cancer cells (i.e., HER2) [11]. Following
aachment, the antibody–drug complex is internalized via receptor-mediated endocytosis
[12]. While pinocytosis may also facilitate ADC uptake in the absence of the target antigen,
the conjugated antibody’s considerable size and hydrophilic character signicantly miti-
gate nonspecic absorption, thereby augmenting the specicity and safety of ADCs [13].
Upon cellular entry, the ADC is tracked to endosomes and lysosomes, where enzymatic
cleavage of the linker ensues, resulting in the release of the cytotoxic payload. This release
enables the drug to unleash its cell-killing potential (Figure 2). The therapeutic agents em-
ployed in ADCs are diverse, ranging from microtubule disruptors to topoisomerase in-
hibitors. A pivotal feature of ADCs is the “bystander eect,” wherein the liberated toxins
can permeate and exterminate neighboring tumor cells that may not express the target
antigen, thereby increasing the antitumor eect [14].
Figure 1. ADC components. Abbreviations: DAR: drug-to-antibody ratio; DM1: derivative of may-
tansine 1; DM4: derivative of maytansine 4; MMAF: monomethyl auristatin F; MMAE: monomethyl
auristatin E.
The engineered monoclonal antibody (e.g., trastuzumab) is designed to detect and
bind to an antigen expressed on the surface of cancer cells (i.e., HER2) [
11
]. Following
attachment, the antibody–drug complex is internalized via receptor-mediated endocyto-
sis [
12
]. While pinocytosis may also facilitate ADC uptake in the absence of the target
antigen, the conjugated antibody’s considerable size and hydrophilic character significantly
mitigate nonspecific absorption, thereby augmenting the specificity and safety of ADCs [
13
].
Upon cellular entry, the ADC is trafficked to endosomes and lysosomes, where enzymatic
cleavage of the linker ensues, resulting in the release of the cytotoxic payload. This release
enables the drug to unleash its cell-killing potential (Figure 2). The therapeutic agents
employed in ADCs are diverse, ranging from microtubule disruptors to topoisomerase
inhibitors. A pivotal feature of ADCs is the “bystander effect,” wherein the liberated toxins
can permeate and exterminate neighboring tumor cells that may not express the target
antigen, thereby increasing the antitumor effect [14].
Cancers 2024,16, 800 4 of 21
Cancers 2024, 16, x FOR PEER REVIEW 4 of 22
Figure 2. Mechanism of action of ADCs.
2. Current Landscape of HER2-Targeted ADCs
To date, two ADCs directed against HER2—trastuzumab emtansine (T-DM1,
Kadcyla) [15] and trastuzumab deruxtecan (T-DXd, DS-8201a, Enhertu) [16]—have been
approved by the Food and Drug Administration (FDA) and other regulatory agencies
throughout the world for the management of HER2-positive breast cancer. In addition, T-
DXd was approved for patients with HER2-Low metastatic breast cancer (IHC score 1 or
IHC 2 with negative FISH) (Table 1) [17]. The DESTINY-Breast06 trial is testing the ecacy
of T-DXd in patients with HER2-Ultra-Low breast cancer (IHC score 0, with 110% cells
staining weakly).
Table 1. Key characteristics of selected HER2 ADCs.
ADC Name mAb Payload Linker DAR Clinical Phase References
Trastuzumab
emtansine
(T-DM1)
Trastuzumab DM1
Non-
cleavable
SMCC linker
3.5
Approved for
metastatic
HER2-positive
breast cancer,
residual disease
after
neoadjuvant
therapy
[18,19]
Figure 2. Mechanism of action of ADCs.
2. Current Landscape of HER2-Targeted ADCs
To date, two ADCs directed against HER2—trastuzumab emtansine (T-DM1, Kad-
cyla) [
15
] and trastuzumab deruxtecan (T-DXd, DS-8201a, Enhertu) [
16
]—have been ap-
proved by the Food and Drug Administration (FDA) and other regulatory agencies through-
out the world for the management of HER2-positive breast cancer. In addition, T-DXd
was approved for patients with HER2-Low metastatic breast cancer (IHC score 1 or IHC
2 with negative FISH) (Table 1) [
17
]. The DESTINY-Breast06 trial is testing the efficacy
of T-DXd in patients with HER2-Ultra-Low breast cancer (IHC score 0, with 1–10% cells
staining weakly).
Table 1. Key characteristics of selected HER2 ADCs.
ADC Name mAb Payload Linker DAR Clinical Phase References
Trastuzumab
emtansine
(T-DM1)
Trastuzumab DM1 Non-cleavable
SMCC linker 3.5
Approved for
metastatic
HER2-positive breast
cancer, residual disease
after neoadjuvant
therapy
[18,19]
Cancers 2024,16, 800 5 of 21
Table 1. Cont.
ADC Name mAb Payload Linker DAR Clinical Phase References
Trastuzumab
deruxtecan
(DS-8201a)
Trastuzumab DXd Cleavable GGFG
linker 8
Metastatic
HER2-positive and
HER2-Low breast
cancer
[16,20]
Trastuzumab
duocarmazine
(SYD985)
Trastuzumab seco-DUBA Cleavable vc linker 2.7 Phase I/II—advanced
breast cancer [21]
ARX-788
Anti-
HER2 mAb
(ARX269)
MMAF
Non-cleavable
linker conjugated
to pAcF
1.9 Phase II—advanced
breast cancer [22]
ALT-P7 Trastuzumab
biobetter (HM2)
MMAE Cleavable cysteine-
containing peptide 2 Phase I [23]
BL-M07D1 Trastuzumab Ed-04 Cathepsin B
cleavable linker 8Phase I—advanced
breast cancer [24]
Disitamab
vedotin (RC48) Hertuzumab MMAE mc-val-cit PABC
linker 4 Phase I [25]
Zanidatamab
zovodotin Zanidatamab Zovodotin Cleavable vc linker 2–4
(variable) Phase II [26]
Abbreviations: mAb: monoclonal antibody; DAR: drug-to-antibody ratio; DM1: derivative of maytansine 1;
SMCC: succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate; DXd: derivative of exatecan; GGFG:
glycine–glycine–phenylalanine–glycine; vc: valine–citrulline; seco-DUBA: seco-duocarmycin hydroxybenzamide
azaindole; MMAF: monomethyl auristatin F; pAcF: para-acetylphenylalanine; MMAE: monomethyl auristatin E;
mc-val-cit PABC: maleimidocaproyl–valine–citrulline–p-aminobenzylcarbamate.
2.1. Trastuzumab Emtansine (T-DM1)
Trastuzumab emtansine (T-DM1) represents a seminal advancement in the treatment of
HER2-positive breast cancer. T-DM1 (Kadcyla) was the first ADC to receive FDA approval
in the U.S. in 2013 for single-agent treatment for advanced HER2-positive breast cancer
(following treatment with trastuzumab and a taxane). Its approval was expanded in
2019 for the use of T-DM1 for patients with early-stage high-risk HER2-positive breast
cancer with residual disease after neoadjuvant therapy with trastuzumab and taxane-based
treatment [19].
The T-DM1 molecule consists of a cytotoxic component (Emtansine) attached to the
antibody trastuzumab through a stable linker. Maytansine is a highly potent cytotoxic
agent derived from the Ethiopian plant Maytenus serrata. Due to its high toxicity, it is not
used directly as a cancer treatment but rather as a part of a targeted therapy. Emtansine
(also known as DM1) is a derivative of maytansine that has been chemically modified to
be less toxic and more stable in the bloodstream. T-DM1 retains trastuzumab’s inhibitory
functions—especially the blockade of the PI3K/AKT pathway. In addition, trastuzumab
facilitates T-DM1
s internalization and subsequent disintegration to unleash the potent
microtubule-inhibitory action of the MCC-DM1 complex [27].
The EMILIA trial showcased the superiority of T-DM1, demonstrating its ability
to improve progression-free survival (PFS) rates compared to a regimen that combined
lapatinib and capecitabine in patients with HER2-positive metastatic breast cancer who had
received a prior taxane [
15
]. In this trial, median progression-free survival was improved
from 6.4 months with lapatinib–capecitabine to 9.6 months with T-DM1. Overall survival
and objective response rates were also improved with T-DM1. The KATHERINE trial
showed improvement in disease-free survival (DFS) rates in patients with early-stage
HER2-positive breast cancer with residual disease following neoadjuvant trastuzumab-
based treatment [
19
]. At a follow-up of 3 years, the percentage of patients who were free of
invasive disease was 88.3% in the T-DM1 group compared with 77.0% in the trastuzumab
Cancers 2024,16, 800 6 of 21
group. This randomized trial validated the role of T-DM1 for patients with residual disease
after neoadjuvant therapy when compared to continued trastuzumab therapy.
Furthermore, in the KRISTINE trial, T-DM1 therapy was compared to sequential
anthracycline-based chemotherapy followed by taxane in combination with trastuzumab
and pertuzumab, or the TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab) regimen
in the neoadjuvant setting. In this study, T-DM1 demonstrated a reduced pathologic
complete response rate compared to the other regimens [
28
]. Nevertheless, the KRISTINE
trial linked it to a more favorable safety profile, achieving pathologic complete responses in
44% of patients without conventional chemotherapy.
2.1.1. Mechanisms of Resistance to T-DM1
The mechanisms of resistance to T-DM1 in breast cancer are multifactorial and occur
via various different pathways.
1.
Antigen-Related Resistance Mechanisms. T-DM1 resistance can develop via vari-
ous pathways, particularly in JIMT1 cells, which are inherently resistant to first-line
trastuzumab [
29
]. These cells, upon TM-ADC treatment, showed resistance while
remaining sensitive to other chemotherapeutics. It suggests that prolonged exposure
to HER2-targeted therapy could decrease HER2 levels, leading to treatment-resistant
cells [
30
]. Additionally, heterogeneity in HER2 expression, as observed in the KRIS-
TINE and ZEPHIR trials, correlated with lower efficacy of T-DM1, marked by no
pathologic complete responses and shorter progression-free survival (PFS) and overall
survival (OS) [
31
,
32
]. Truncated forms of the antigen ectodomain, like P95HER2,
and antigen masking by molecules such as MUC4 have also been implicated in re-
sistance [
33
]. Furthermore, ligand-induced heterodimerization of HER2 with other
receptors can impair T-DM1’s effectiveness [29].
2.
Payload-Related Resistance. Tumor cells may develop resistance to the cytotoxic drug
(DM1). T-DM1-resistant cells with upregulated ABC transporter expressions (ABCC2,
ABCG2) exhibited reduced sensitivity, which could be countered by inhibiting these
transporters [
34
]. The diversity in payloads, conjugation sites, and drug-to-antibody
ratios (DAR) also significantly impacts ADC efficacy, suggesting that ADC resistance
can be payload specific [35,36].
3.
Internalization and Trafficking Pathways. T-DM1 is internalized into cancer cells via
endocytosis. Variations in endocytic routes, regulated by specific proteins, can affect
ADC delivery and processing. For instance, some T-DM1-resistant cells have been
shown to internalize ADCs into caveolin-1-coated vesicles, indicating an alternative
trafficking pathway. Proteins like Endophilin A2 also play a role in HER2 internaliza-
tion, affecting T-DM1 sensitivity [37].
4.
Lysosomal Dysfunction. After T-DM1 internalization, lysosomal cleavage releases
the cytotoxic drug. Any disruption in lysosomal function, such as altered pH or pro-
teolytic activity, can hinder this process. Resistant clones with higher lysosomal pH
and accumulated T-DM1 have been documented, indicating impaired ADC process-
ing [
38
]. The transport of cytotoxic drugs from lysosomes to the cytoplasm, especially
relevant for non-cleavable linkers, is another potential resistance mechanism [
39
]. In
the DAISY trial, a phase II multicenter, open-label study, researchers investigated
resistance to T-DXd in three distinct patient groups: HER2-positive, HER2-zero, and
low-HER2. Participants received T-DXd at 5.4 mg/kg triweekly, aiming for the best ob-
jective response rate as the primary measure of success. When the cancer progressed,
whole-genome sequencing was employed to uncover potential resistance mechanisms.
The findings indicated that apart from reduced HER2 expression, alterations in the
SLX4 gene could contribute to resistance. SLX4 is integral to DNA damage repair,
overseeing three endonucleases. The evidence showed that a deficit in SLX4 correlated
with resistance to T-DXd, suggesting that loss-of-function mutations in SLX4 could be
implicated in the development of resistance to the drug [40].
Cancers 2024,16, 800 7 of 21
5.
Drug-Efflux Mechanisms. Overexpression of ABC transporters, which increase drug
efflux from cells, can contribute to resistance. For example, maytansinoids, T-DM1’s
payload, are known substrates of ABC transporters like MDR1, linking resistance to
increased expression of these transporters [41].
6.
Cell Cycle Dependencies. The cell cycle status affects T-DM1 effectiveness. Resistance
to T-DM1 has been linked to variations in cyclin B levels, a cell cycle regulator. Accu-
mulation of cyclin B1 in sensitive cells, as opposed to resistant ones, suggests that cell
cycle dysregulation can modulate T-DM1 efficacy [42].
7.
Activation of Survival Signaling Pathways. Activation of pathways like PI3K/AKT/
mTOR, which are involved in cell survival, can decrease sensitivity to trastuzumab-
based therapy. PTEN loss or PIK3CA hyperactivation can lead to reduced trastuzumab
sensitivity [
43
]. However, T-DM1 may remain effective even with these mutations, as indi-
cated by the EMILIA trial results [44]. Therefore, this is an area of ongoing investigation.
8.
Apoptosis Dysregulation. Finally, changes in apoptosis regulation, such as the over-
expression of proteins like BCL-2 and BCL-XL, have been correlated with resistance
to ADCs like gemtuzumab ozogamicin [
45
] and brentuximab vedotin [
46
], indicat-
ing a potential mechanism of resistance to other ADCs like T-DM1, although this
mechanism of resistance is not well defined in breast cancer.
2.1.2. T-DM1 Combination Therapies
Current research strives to devise approaches to surmount these resistance mecha-
nisms to improve patient prognosis. Personalized medicine strategies, including targeted
and immune-based therapies, are under exploration to effectively counter resistance. In
efforts to surmount resistance to T-DM1 in treating HER2-positive breast cancer, the inte-
gration of T-DM1 with diverse therapeutic agents has been extensively investigated. This
strategy targets specific resistance mechanisms, proposing alternate modalities to boost
treatment efficacy.
Many agents have been assessed for their potential synergistic effects with T-DM1, in-
cluding monoclonal antibodies (e.g., pertuzumab), tyrosine kinase inhibitors (e.g., lapatinib,
neratinib, tucatinib), PI3K pathway inhibitors (e.g., alpelisib), PD1/PDL1 checkpoint in-
hibitors (e.g., pembrolizumab, atezolizumab) as well as CDK4/6 inhibitors (e.g., palbociclib,
ribociclib, abemaciclib) [4751].
The logic behind these combinations is to mount a diversified onslaught on HER2-
positive breast cancer cells, targeting various pathways and resistance mechanisms. Utiliz-
ing T-DM1 with these agents is anticipated to improve treatment results and confront the
hurdles posed by drug resistance. Future clinical studies will shed light on the success of
these combination treatments for patients with HER2-positive breast cancer.
2.1.3. T-DM1 Toxicities and Safety Profile
With the development of new ADCs comes specific toxicities. In the landmark EMILIA
trial [
15
], 15.5% of patients experienced a grade 3 adverse event (compared with 18% in the
lapatinib–capecitabine arm). The most common grade 3 and 4 events with T-DM1 were
thrombocytopenia (12.9%) and liver enzyme elevations of aspartate aminotransferase (4.3%)
and alanine aminotransferase (2.9%). In the EMILIA trial, the occurrence of grade 3 or
4 thrombocytopenia was most common during the first two cycles of T-DM1 treatment, and
the majority of patients were able to continue treatment with dose modifications. Overall,
the incidence of bleeding was more common among patients treated with T-DM1 (29.8%)
compared with lapatinib–capecitabine (15.8%), but rates of grade 3 or 4 bleeding were
low in both groups (1.4% and 0.8%, respectively). One grade 4 gastrointestinal bleed did
occur in a patient on T-DM1 but whose platelet count was within the normal range at that
time. Additionally, most patients were able to continue treatment with dose modifications
for elevated liver enzymes as well. These side effects highlight the importance of vigilant
laboratory monitoring throughout the therapy [15,19,28].
Cancers 2024,16, 800 8 of 21
Cardiotoxicity was also evaluated in the EMILIA trial, and the majority of patients
treated with T-DM1 maintained an ejection fraction greater than or equal to 45% while on
therapy (97.1%) [
15
]. Only one patient treated at the time of publication had developed
grade 3 left ventricular systolic dysfunction after treatment with T-DM1. Baseline ejection
fraction should be assessed and monitored throughout treatment while on T-DM1.
2.2. Trastuzumab Deruxtecan (T-DXd)
Trastuzumab deruxtecan (T-DXd) is a novel ADC that has transformed the treatment of
breast cancer. T-DXd distinguishes itself by utilizing a topoisomerase I inhibitor derivative
(i.e., deruxtecan) as its payload, connected via a cleavable tetrapeptide-based linker [
20
].
This cleavable linker is selectively severed within tumor cells, reducing off-target release
and associated toxicities. T-DXd possesses a notably higher drug-to-antibody ratio (DAR)
relative to T-DM1, an attribute that contributes to its potent efficacy [52].
Clinical investigations, including the pivotal DESTINY-Breast01 and DESTINY-Breast03
trials, have demonstrated T-DXd’s efficacy in significantly prolonging progression-free
survival (PFS) over T-DM1, leading to its endorsement by the FDA as a second-line therapy
for HER2-positive metastatic breast cancer [
16
,
53
]. Furthermore, T-DXd’s approval for
HER2-Low breast cancer signals the recognition of a new subset within the breast cancer
spectrum, expanding the therapeutic landscape [54].
While T-DXd has shown promising clinical efficacy in HER2-positive breast cancer, its
use is accompanied by potential adverse effects that require vigilant monitoring. Paramount
among these is the risk of drug-related interstitial lung disease (ILD) or pneumonitis, inflam-
matory conditions that may progress to severe impairment of lung function and significant
respiratory compromise. Other toxicities include gastrointestinal symptoms, hematological
abnormalities, and rare cardiac toxicities. Regular monitoring and appropriate supportive
treatments are essential for managing these side effects [16].
2.2.1. T-DXd: Mechanisms of Resistance
Trastuzumab deruxtecan (T-DXd) has emerged as a significant therapeutic agent in
the treatment of HER2-positive and HER2-Low metastatic breast cancer. Nonetheless, resis-
tance to T-DXd poses a significant obstacle in clinical settings. A thorough understanding
of the resistance mechanisms is crucial to improving therapeutic strategies and subsequent
patient outcomes.
1.
HER2 Receptor Modifications: Modifications of the HER2 receptor are a primary
resistance mechanism, including mutations, gene amplification, or structural alter-
ations, which can diminish the receptor’s affinity for T-DXd. These modifications may
reduce the drug’s efficacy by impairing target binding, necessitating the investigation
of methods to overcome these changes in HER2 [55].
2.
ADC Internalization and Intracellular Trafficking: The internalization and intracel-
lular trafficking of T-DXd are critical to its cytotoxic action. Resistance may develop
from disruptions in these processes, impeding the delivery of the cytotoxic payload.
Enhancing T-DXd internalization and trafficking could be a strategic approach to
bypass this resistance mechanism [56].
3.
Drug-Efflux Transporters: The expression of efflux transporters, such as P-glycoprotein
(P-gp), which expel the payload (deruxtecan) from cells, can decrease its intracellular
concentration and cytotoxic impact. Inhibition or circumvention of these transporters
is under investigation to enhance deruxtecan’s intracellular retention [34].
4.
Tumor Microenvironment and Stromal Factors: The tumor microenvironment, includ-
ing stromal cell-secreted factors, can confer survival advantages to cancer cells, foster-
ing resistance to T-DXd. Targeting the tumor microenvironment through combination
therapies or immune-modulating agents may address this resistance mechanism [
57
].
In the DAISY trial evaluating the efficacy of T-DXd in breast cancer patients at dif-
ferent levels of HER2 expression, researchers evaluated the impact of T-DXd on the
tumor microenvironment. This exploratory study included samples collected from
Cancers 2024,16, 800 9 of 21
31 patients. No significant changes in immune cell levels were observed at the 3-week
or 6-week mark following treatment. However, a notable reduction in PD-L1 expres-
sion among the first cohort of patients was attributed to T-DXd’s cytotoxic effects on
PD-L1-positive tumor cells. Additionally, a decline in the presence of macrophages
close to tumor cells was reported in the same cohort [40].
5.
Alternative Signaling Pathways: The activation of alternative signaling pathways,
such as the PI3K/AKT/mTOR pathway, can provide survival advantages to cancer
cells, undermining T-DXd’s effectiveness. Co-targeting HER2 and these alternative
pathways may be essential to counteract resistance [7,43,58,59].
6.
Tumor Heterogeneity: The intrinsic heterogeneity of tumors, both among patients
and within a single tumor, can result in cancer cell populations with varying sen-
sitivities to T-DXd, contributing to the complex nature of resistance. Personalized
treatments, considering the unique molecular and phenotypic profiles of tumors, may
be promising in overcoming resistance [60].
In summary, resistance to T-DXd in breast cancer is complex and involves diverse
interactions between the tumor cells and their surrounding microenvironment. Current
research is focused on elucidating these mechanisms in detail and developing targeted
strategies to counter resistance. Anticipated advancements in T-DXd-based treatments for
HER2-positive and HER2-Low breast cancer include personalized medicine, combination
therapies, and an enhanced understanding of tumor biology.
2.2.2. T-Dxd Combination Therapies
Therapeutic combinations are being rigorously evaluated to surmount resistance to
T-DXd in breast cancer therapy. These research efforts aim to refine treatment regimens
and enhance patient prognoses. A range of combinations are in various stages of clinical
trials, following the same paradigm as T-DM1 above. The objectives of these clinical trials
are to establish the safety profiles, efficacy, and appropriate dosing regimens for these
combination treatments. The forthcoming results are expected to yield critical insights
into the most efficacious combinations and patient demographics best suited for these
therapies. The overarching aim is to personalize treatment approaches, thereby advancing
the care and outcomes for patients with HER2-positive breast cancer who exhibit resistance
to T-DXd.
2.2.3. T-DXd in HER2-Low Breast Cancer
In the realm of breast cancer treatment, the categorization of tumors as HER2-positive
or HER2-negative has been traditionally binary. However, a subset of tumors exhibit low
levels of HER2 (“HER2-Low”), which is found in 45–60% of cases without HER2 amplifi-
cation or overexpression [
5
]. These HER2-Low tumors are identified by an immunohisto-
chemical (IHC) score of 1+ or a score of 2+ accompanied by a negative in situ hybridization
(ISH) result. In the pivotal DESTINY-Breast 04 trial, trastuzumab deruxtecan (T-DXd)
showed significant effectiveness in treating HER2-Low metastatic breast cancer, achieving
a 52.6% objective response rate among patients who had undergone one or two prior lines
of therapy [17].
While HER2-0 breast cancers are often less amenable to monoclonal antibody ther-
apy, a subset known as HER2-Ultra-Low has been recognized, characterized by minimal
HER2 protein expression. Ongoing studies are exploring the use of ADCs for this group.
For example, the DESTINY-Breast06 trial is investigating the efficacy of T-DXd in patients
with HER2-Ultra-Low metastatic breast cancer. Additionally, certain genetic mutations,
like the V777L ERBB2 mutation and MutL deficiency—related to mismatch repair system
changes—suggest potential responsiveness to anti-HER2 therapies, even in HER2-negative
breast cancers.
Ongoing research is assessing T-DXd versus chemotherapy in hormone receptor-
positive, HER2-Low metastatic breast cancer and exploring its combination with immune
checkpoint inhibitors. Early data indicate favorable safety and efficacy, with high response
Cancers 2024,16, 800 10 of 21
rates [
61
]. The combination of T-DXd with immune therapies such as PD-L1 and PD-1
inhibitors is being evaluated, showing promising activity, although questions about the
incremental benefit over T-DXd alone persist. These studies underscore the potential
of T-DXd as a key therapeutic for HER2-Low breast cancer, offering hope for improved
outcomes in this diverse patient population.
2.2.4. T-Dxd Toxicities and Safety Profile
In the DESTINY-Breast03 trial, 45.1% of patients receiving T-DXd experienced any
grade 3 or 4 adverse effects. The most common drug-related toxicities in the T-DXd arm
were nausea (72.8%), fatigue (44.7%), and vomiting (44%). Overall, T-DM1 was better
tolerated. Drug-related alopecia was also common, occurring in 36.2% of patients who
received T-DXd (compared with 2.3% in patients treated with T-DM1). Neutropenia (19.1%),
thrombocytopenia (7%), and leukopenia (6.6%) were also noted. Cardiotoxicity, as with
T-DM1, appeared to be a rare event, but echocardiograms should be monitored.
The most concerning of the adverse events associated with T-DXd remains interstitial
lung disease (ILD), or pneumonitis, which occurred in 10.5% of patients treated with
T-DXd. The median time to onset of ILD/pneumonitis was 168 days (range: 33 to 507).
Treatment was discontinued in 8.2% of patients treated with T-DXd due to pneumonitis.
Fatal cases of ILD had occurred in earlier trials; however, most patients experience grade
1 or 2 events. Increased awareness has led to improved monitoring and treatment of
this rare but serious side effect. Risk factors for the development of pneumonitis/ILD
include dose >6.4 mg/kg, age <65, baseline oxygen saturation <95%, moderate to severe
kidney impairment, pulmonary comorbidities (asthma, COPD, prior ILD/pneumonitis,
pulmonary fibrosis, emphysema, and radiation pneumonitis) and >4 years since initial
diagnosis [62].
Experts recommend high-resolution chest CT every 6 months for monitoring for
pneumonitis and ILD in patients undergoing treatment with T-DXd, if available. If ILD
is suspected, the drug must be held, and steroids should be promptly administered, in
addition to pulmonary consultation and evaluation. If grade 1 toxicity occurs, the patient
can be rechallenged with the drug. If grade 2 (symptomatic) toxicity occurs, the drug must
be held permanently.
3. New HER2-Targeting ADCs on the Horizon
Emerging ADCs are being developed to enhance the therapeutic landscape of HER2-
positive breast cancer treatments [
63
]. The advent of such ADCs has been revolution-
izing the field, particularly by expanding the potential applications beyond traditional
HER2-positive cancers to include tumors with lower expression levels of HER2 or with
ERBB2 mutations. These novel ADCs are designed with modifications that optimize the
delivery and release of cytotoxic agents within tumor cells, aiming to leverage the tumor
microenvironment to enhance antitumor activity. Advancements in ADC technology are
not only improving the effectiveness of these therapies but also aiming to reduce resistance
and adverse effects. These improvements are the result of meticulous engineering that
includes the selection of high-affinity antibodies, the development of potent payloads, and
the creation of stable linkers that bind the payload until it reaches the tumor site.
The research and development of HER2 ADCs are expected to continue improving the
therapeutic index, offering a broader spectrum of treatment options for patients with HER2-
positive and HER2-Low breast cancer. These advancements signal a shift toward precision
medicine, where treatment strategies can be personalized for better clinical outcomes and
an enhanced quality of life for patients with breast cancer (Table 2).
Cancers 2024,16, 800 11 of 21
Table 2. Clinical trials of investigational antibody–drug conjugates for HER2-positive breast cancer.
ADC Study Title Key
Eligibility Primary Endpoint Phase N Efficacy and Results References
ALT-P7
(HM2-MMAE)
Clinical Study of ALT-P7 to Determine
Safety, Tolerability and Pharmacokinetics in
Breast Cancer Patients [NCT03281824]
HER2-positive MBC DLT, MTD I 27 ORR: 77%
mPFS: 6.2 months [23]
ARX788
Phase I Trial of a Novel
Anti-HER2 Antibody-Drug Conjugate, for
the Treatment of HER2-Positive Metastatic
Breast Cancer
HER2-positive MBC
Safety,
pharmacokinetics,
and antitumor
activity
I 69
ORR: 65%
DCR 100%
mPFS 17.02 months
[64]
ARX788
Phase 1 Dose Escalation Study of ARX788, a
Next-Generation Anti-HER2 Antibody
Drug Conjugate, in Heavily Pretreated
Breast Cancer Patients
[ACE-PanTumor-01 trial (ARX788-1711;
NCT03255070]
HER2-positive and
HER2-Low MBC
Safety,
pharmacokinetics,
and antitumor
activity
I 42
HER2-positive
ORR 36%
HER2-Low ORR 17%
[65]
ARX788
Efficacy and Safety of Pyrotinib Maleate
Combined with ARX788 Neoadjuvant
Treatment in Breast Cancer Patients
[NCT04983121]
Stage II-III
HER2-positive breast
cancer patients
experiencing a poor
efficacy of
trastuzumab and
pertuzumab
Residual tumor
burden (RCB) II 30 N/A Recruiting
ARX788
ARX788 in HER2-positive, Metastatic
Breast Cancer Subjects (ACE-Breast-03)
[NCT04829604]
HER2-positive MBC
previously treated
with T-DXd
ORR II 71 ORR: 57% [66]
ARX788
ARX788 in HER2-positive Breast Cancer
Patients with Brain Metastases
[NCT05018702]
HER2-positive,
MBC-resistant, or
refractory to tyrosine
kinase inhibitors
(TKI)
Central nervous
system (CNS) clinical
benefit rate (CBR)
II 32 N/A Recruiting
ARX788 ARX788 in Breast Cancer with Low
Expression of HER2 [NCT05018676] HER2-Low MBC ORR II 54 N/A Recruiting
Cancers 2024,16, 800 12 of 21
Table 2. Cont.
ADC Study Title Key
Eligibility Primary Endpoint Phase N Efficacy and Results References
BL-M07D1
A Study of BL-M07D1 in Patients with
Locally Advanced or Metastatic
HER2 Positive Breast Cancer and Other
Solid Tumors [NCT05461768]
Locally advanced or
metastatic
HER2-positive/low-
expression breast
cancer and other
solid tumors
DLT, MTD I 15 HER2-positive
MBC-ORR 60%
[67]
(Recruiting)
Disitamab
vedotin (RC48)
RC48-ADC, a HER2-targeting
antibody-drug conjugate, in patients with
HER2-positive and HER2-low expressing
advanced or metastatic breast cancer: A
pooled analysis of two studies
[NCT02881138; NCT03052634]
HER2-positive
metastatic solid
tumors
ORR I 118
HER2-positive ORR
42.9%, mPFS
6.3 months
HER2-Low ORR 39%,
mPFS 5.7 months
[68]
SYD985 vs. PC
SYD985 vs. Physician’s Choice in
Participants with HER2-positive Locally
Advanced or Metastatic Breast Cancer
(TULIP) [NCT03262935]
HER2-positive MBC PFS III 437
mPFS
SYD985: 7 months
PC: 4.9 months
[69]
TQB2102
A Study of TQB2102 for Injection in
Patients with Recurrent/Metastatic Breast
Cancer [NCT06115902]
HER2-positive MBC Toxicity, ORR I 150 N/A Recruiting
XMT-1522
Study of Antibody Drug Conjugate in
Patients with Advanced Breast Cancer
Expressing HER2 [NCT02952729]
HER2-positive MBC
Dose
escalation/objective
response
Ib 120 Discontinued due to
toxicity [23]
Abbreviations: MMAE: monomethyl auristatin E; DLT: dose-limiting toxicity; MTD: maximum tolerated dose; RCB: residual cancer burden; T-DXd: trastuzumab deruxtecan; ORR:
objective response rate; DCR: disease control rate; TKI: tyrosine kinase inhibitor; CNS: central nervous system; CBR: clinical benefit rate; mPFS: median progression-free survival; PC:
physician’s choice; mo: months; N/A: data not available.
Cancers 2024,16, 800 13 of 21
3.1. Disitamab Vedotin (RC48)
Disitamab vedotin (DV), known as RC48, is a novel ADC directed against HER2-
expressing cancer cells. The architecture of DV is characterized by a humanized anti-
HER2 monoclonal antibody linked to the cytotoxic agent monomethyl auristatin E (MMAE)
through a cleavable linker [
70
]. This design ensures that the monoclonal antibody binds
selectively to the HER2 epitope, facilitating the internalization of MMAE, which then
mediates cell death. DV’s binding affinity for HER2, which is higher than that of other ther-
apeutic agents like trastuzumab, potentially increases its therapeutic impact. Furthermore,
DV can induce cytotoxicity in adjacent cells—a phenomenon known as the bystander effect.
Early clinical evaluations of DV have shown promising efficacy, particularly in patients
with HER2 2+/ISH-negative status, indicating a potential for tailored therapy based on
HER2 expression levels [71].
The safety and tolerability of RC48 have been evaluated in cancer patients in early-
stage clinical trials. The most common mild adverse events (AEs) included fever, fatigue,
and hematologic toxicity. The most common grade 3 or higher AEs were neutropenia,
leukopenia, hypesthesia, and increased conjugated bilirubin levels. The incidence of serious
AEs and dose-limiting toxicity were observed in the high-dose groups (2.5 mg/kg and
3.0 mg/kg); therefore, it appears the AEs of RC48 were dose dependent. Importantly, no
drug-related pulmonary toxicity was seen with RC48 [25].
Disitamab vedotin and similar next-generation ADCs represent a significant advance
in cancer therapeutics, combining precise tumor targeting with innovative payload mecha-
nisms and improved linker technologies. These developments contribute to ADCs with
variable DARs, refined safety profiles, and expanded potential for treating diverse cancer
types and disease stages. It should be noted that DV is currently approved in China for
gastric cancers [24].
3.2. ARX788
ARX788 represents an innovative ADC comprising an anti-HER2 monoclonal anti-
body, a non-cleavable linker, and a modified monomethyl auristatin F (MMAF), known as
Amberstatin 269 (AS269) [
22
]. This ADC exhibits a DAR of 1.9. Preclinical studies, includ-
ing those reported by Barok et al. in 2020, demonstrate ARX788’s superior efficacy over
T-DM1 in trastuzumab-resistant breast cancer xenograft models [
72
]. A phase I trial showed
ARX788 is well tolerated and has promising antitumor activity in patients with HER2-
positive advanced gastric adenocarcinoma (ChinaDrugTrials.org.cn: CTR20190639) [73].
In the phase I ACE-Breast-01 study, the safety and antitumor activity of ARX788 was
tested in patients with advanced HER2-positive breast cancer in China. The most common
AEs occurring in more than 30% of patients were increased AST, increased ALT, corneal
epitheliopathy, alopecia, hypokalemia, and ILD/pneumonitis (34.8%), which were mainly
grades 1–2. Of note, grade 3–4 ILD/pneumonitis occurred in 2.9% of patients in this trial,
and these were mainly late events after >100 days of treatment. Ocular toxicities were
managed by a special task force and were primarily grades 1–2. Fortunately, all of these
ocular AEs were reversible. Mild hypokalemia was an additional common toxicity (all
grades 1–2) and was managed with oral potassium supplementation. Prolonged Qtc was
observed in 20% of patients and recovered with observation in most cases. No drug-related
deaths occurred. Based upon these results, the phase 2 recommended drug dosing was
determined to be 1.5 mg/kg every 3 weeks [64].
Current phase II clinical trials are evaluating ARX788’s efficacy in various HER2-
positive breast cancer contexts. Trial NCT05018676 is investigating its impact on HER2-Low
breast cancers, while NCT05018702 focuses on patients with HER2-positive cancers with
brain metastases. Additionally, NCT04829604, known as ACE-Breast-03, aims to determine
the effectiveness of ARX-788 in patients with HER2-positive metastatic breast cancer who
have previously undergone treatment with T-DXd [24].
Cancers 2024,16, 800 14 of 21
3.3. Trastuzumab Duocarmazine (SYD985)
Trastuzumab duocarmazine (SYD985) is a novel ADC that combines trastuzumab
with a cleavable valine–citrulline linker and a duocarmycin derivative, seco-DUBA, which
is activated by proteases to cause DNA alkylation and cell death. It exhibits a bystander
effect and has a DAR of 2.7 [
21
]. It showed efficacy in HER2-Low breast cancer models,
surpassing T-DM1. In a phase 1 trial, it demonstrated antitumor activity with an objective
response rate (ORR) of 28% for HR-positive and 40% for HR-negative metastatic breast
cancer [24].
The phase III TULIP
®
study compared SYD985 with physicians’ choice of treatment in
participants with HER2-positive locally advanced or metastatic breast cancer. The trial met
its primary endpoint, showing a statistically significant improvement in progression-free
survival (PFS) for SYD985 over the physicians’ choice (7.0 months versus 4.9 months in
favor of the trastuzumab duocarmazine group). PFS is the duration from randomization to
disease progression or death from any cause. Additionally, the study reported preliminary
supportive results for overall survival (OS) [69].
Safety data from this phase III trial were also collected. The most commonly reported
adverse events were ocular events, including conjunctivitis (38.2%) and keratitis (38.2%), as
well as fatigue (33.3%). Adverse events that led to discontinuation of the study drug were
eye disorders (20.8%) and respiratory disorders (6.3%). There were no treatment-related
deaths caused by trastuzumab duocarmazine [69].
3.4. BL-M0701
BL-M07D1 is a new ADC-targeting HER2 with a structure comprising the humanized
antibody trastuzumab, a cathepsin B cleavable linker, and Ed-04, a camptothecin-derived
topoisomerase I inhibitor. This inhibitor impedes the cell cycle in the S phase, inducing
apoptosis. BL-M07D1 has a DAR of 8:1, akin to T-DXd, but with a more stable linker.
Preclinical evaluations using xenograft models revealed BL-M07D1’s superior tumor
inhibition, outperforming T-DXd in low HER2-expressing models and both T-DM1 and T-
DXd in HER2-positive models. Notably, BL-M07D1 demonstrated potent bystander effects,
suggesting an enhanced efficacy against mixed HER2-positive/negative tumors [
74
]. These
findings posit BL-M07D1 as a promising candidate in the treatment of a wider spectrum of
breast cancers, surpassing the current HER2-targeting ADCs.
A phase I trial is ongoing in patients with metastatic breast cancer. The preliminary
safety profile of BL-M07D1 from this study indicates that treatment-related AEs were
mostly low-grade, with keratitis, anemia, and neutropenia being the most common. Grade
3 adverse events were noted at 42%, with anemia (23%) and neutropenia (17%) being
more prevalent. There was one case of grade 4 neutropenia. No dose-limiting toxicities
were reported at the recommended dose, and there were no treatment-related deaths [
75
].
Further studies are needed to fully assess the safety and efficacy of BL-M07D1.
3.5. Zanidatamab Zovodotin
Zanidatamab zovodotin, also referred to as ZW49, is an innovative bispecific ADC
aimed at treating HER2-expressing or HER2-amplified cancers, including breast cancer. It
is currently undergoing clinical evaluation to determine its efficacy and safety profile. The
first-in-human phase I trial was designed to determine the maximum tolerated dose, char-
acterize its safety and tolerability, and evaluate its antitumor activity as monotherapy [
26
].
The phase 1 study of zanidatamab zovodotin (ZW49) in patients with HER2-positive
solid cancers found it to have an acceptable safety profile, with the majority of AEs being
low-grade and manageable. The most common treatment-related AEs included keratitis,
alopecia, and diarrhea, primarily of grade 1 or 2 severity. No dose-limiting toxicities were
observed for the selected dosing regimens in the dose-escalation phase, and no treatment-
related deaths occurred. Among eight patients with breast cancer, zanidatamab zovodotin
achieved a confirmed ORR of 13%, which included a partial response (PR) rate of 13% and
a stable disease (SD) rate of 38%. The recommended dose for further studies was identified
Cancers 2024,16, 800 15 of 21
as 2.5 mg/kg every 3 weeks, showing promising antitumor activity in heavily pretreated
patients [76].
3.6. Other ADCs in Clinical Trials
There are many other ADCs in clinical trials, including ALT-P7, SHR-A1811, and
TQB2102 (Table 2). The safety and therapeutic benefit of these molecules will be determined
by the results of these trials and additional future clinical trials.
4. Future Directions
Antibody–drug conjugates (ADCs) represent a sophisticated class of therapeutic agents
that have transformed the treatment landscape for HER2-positive and HER2-Low breast
cancer. The successful development of novel HER2-targeted ADCs will require not only
advancements in technology but also predictive preclinical models and well-designed
clinical trials.
The conjugation process, particularly site-specific conjugation, is at the forefront of
ADC technology advancements [
22
]. Traditional conjugation methods may result in het-
erogeneous ADC populations, leading to variability in efficacy and safety. The industry
trend is shifting toward site-specific conjugation methods to produce more uniform ADCs,
which could lead to improved therapeutic outcomes. Site-specific conjugation involves
precise and consistent attachment of payloads to the antibodies, ensuring a uniform drug-
to-antibody ratio (DAR), which is a critical quality attribute of ADCs [
77
]. Several methods
facilitate site-specific conjugation. Antibody engineering techniques such as THIOMABs
utilize engineered cysteine residues in antibodies to attach payloads at specific sites. Chem-
ical methods, like AJICAP, leverage distinct functional groups on antibodies for consistent
conjugation. Enzymatic methods offer another layer of specificity by using enzymes that
recognize specific peptide or carbohydrate motifs on antibodies for payload attachment.
Among the most exciting advancements are Tag-free enzymatic methods that negate the
need for engineered tags on antibodies, simplifying the process and potentially improv-
ing the manufacturability and scalability of ADC production [
78
80
]. These methods
utilize naturally occurring glycan sites on antibodies for the attachment of payloads using
glycan-specific enzymes, allowing for a homogeneous product without the need for genetic
modification of the antibody. In a recent publication, Fujii et al. [
81
] introduced the AJICAP
method, a novel “second-generation” technology designed to precisely link therapeutic
agents to antibodies. This method circumvents the commonly encountered issue of protein
aggregation during such conjugation processes. Unlike traditional methods that necessitate
altering an antibody’s structure through redox treatments, AJICAP simplifies the process
by utilizing a “one-pot” reaction that maintains the antibody’s integrity. This innovation
significantly bolsters the stability of the compounds involved in coupling drugs to antibod-
ies, which facilitates the generation of antibody–drug conjugates (ADCs) with a uniform
and exact drug-to-antibody ratio. The team has refined the process to enable dual-site drug
attachment on the antibody, resulting in the synthesis of over 20 distinct ADC formulations.
The versatility of the AJICAP technology is further demonstrated by its application in
formulating other conjugate types, such as antibody–protein and antibody–oligonucleotide
conjugates. The advancements offered by this technique hold the promise for the creation
of ADCs that are not only more efficacious but also safer for oncological applications, all
without the necessity for genetic modification of the antibodies. The evolution of these
component technologies demonstrates a deliberate move toward precision in ADC design,
aiming to enhance efficacy, reduce off-target effects, and improve patient outcomes. A
comprehensive understanding of these technologies is essential to advancing the field and
optimizing the therapeutic potential of ADCs.
Although efficacy is the main goal in the development of ADCs, ensuring their safety
profile is essential. Preclinical models are not infallible in predicting human toxicity, which
can lead to unexpected challenges during clinical trials. For instance, DHES0815A, an ADC
that initially demonstrated considerable promise with its high effectiveness and apparent
Cancers 2024,16, 800 16 of 21
tolerability in preclinical assessments, encountered a significant setback. Despite the
encouraging preclinical results, it exhibited severe dermatological, ocular, and pulmonary
toxicities in the first phase of human trials, resulting in its failure to proceed further [
82
].
This discrepancy underscores the need to delve into the potential causes behind such
unpredicted outcomes and to strategize on enhancing the predictive accuracy of preclinical
models for ADC development.
There are numerous biological obstacles that arise in ADC clinical development,
including resistance mechanisms such as antigen downregulation and impaired drug
internalization (Figure 3). Novel strategies like alternative linkers and checkpoint inhibitors
are being explored to tackle these challenges. Pharmacokinetic and pharmacodynamic
optimization are pivotal for ensuring that therapeutic drug levels are maintained with
minimal toxicity. Additionally, technical and manufacturing complexities, such as intricate
production processes and limited manufacturing capabilities, pose significant barriers.
Regulatory frameworks also demand rigorous adherence to ensure ADC quality and safety.
Financial constraints further complicate ADC development due to the costly nature of their
specialized production. To surmount these challenges, strategies such as the selection of
preclinical models mirroring human pathology, identification of predictive biomarkers,
integrated PK/PD modeling, and iterative learning from clinical trials are essential.
Cancers 2024, 16, x FOR PEER REVIEW 17 of 22
Figure 3. ADC internalization and targeting specicity. IV refers to Domain IV of the extracellular
domain of the HER2 protein.
Additionally, the exploration of ADC sequencing for disease progression and the
combination with other targeted therapies hold promise for overcoming resistance and
enhancing treatment ecacy. Tailoring treatments based on individual molecular and ge-
netic proles, facilitated by next-generation sequencing, signies a shift toward more per-
sonalized and potent combination therapies in cancer treatment.
5. Conclusions
HER2-positive breast cancer remains an aggressive disease with historically poor
outcomes. HER2-targeted ADCs have emerged as a promising strategy for breast cancer
treatment, with a particular focus on enhancing outcomes for both patients with HER2-
positive and HER2-Low breast cancer. The development of T-DM1 and T-DXd has signif-
icantly improved patient outcomes, but resistance and progression still occur. Addition-
ally, with these novel drug mechanisms come additional side eects and toxicities that
must be carefully monitored, specically thrombocytopenia and elevated liver function
enzymes for T-DM1 and gastrointestinal eects, alopecia, and pneumonitis for T-DXd.
In this review, we provide an updated summary of the current state of approved
HER2-targeted ADCs as well as a detailed review of selected investigational agents on the
Figure 3. ADC internalization and targeting specificity. IV refers to Domain IV of the extracellular
domain of the HER2 protein.
Cancers 2024,16, 800 17 of 21
Additionally, the exploration of ADC sequencing for disease progression and the
combination with other targeted therapies hold promise for overcoming resistance and
enhancing treatment efficacy. Tailoring treatments based on individual molecular and
genetic profiles, facilitated by next-generation sequencing, signifies a shift toward more
personalized and potent combination therapies in cancer treatment.
5. Conclusions
HER2-positive breast cancer remains an aggressive disease with historically poor
outcomes. HER2-targeted ADCs have emerged as a promising strategy for breast cancer
treatment, with a particular focus on enhancing outcomes for both patients with HER2-
positive and HER2-Low breast cancer. The development of T-DM1 and T-DXd has signifi-
cantly improved patient outcomes, but resistance and progression still occur. Additionally,
with these novel drug mechanisms come additional side effects and toxicities that must be
carefully monitored, specifically thrombocytopenia and elevated liver function enzymes
for T-DM1 and gastrointestinal effects, alopecia, and pneumonitis for T-DXd.
In this review, we provide an updated summary of the current state of approved
HER2-targeted ADCs as well as a detailed review of selected investigational agents on the
horizon. We have discussed the characteristics and available efficacy and safety data on the
novel molecules RC48, ARX-788, SYD985, BL-M0701, and the bispecific ADC zanidatamab
zovodotin (ZW25). Clinical trials are crucial in determining the optimal dosing regi-
mens, understanding resistance mechanisms, and identifying patient populations that
would derive the most benefit from these treatments. With a focus on innovation and
precision, these novel ADCs are at the forefront of a new era in targeted cancer therapy,
holding the potential to improve outcomes for patients with HER2-positive and HER2-Low
breast cancer.
The exploration of novel sequences and combinations incorporating ADCs represents
another promising frontier in cancer therapy. These combinations have the potential to
expand the therapeutic reach, overcome resistance mechanisms, modulate the immune
system, and offer tailored treatments to specific patient subgroups. Ongoing clinical trials
and research efforts are essential in advancing our understanding of optimal sequential
approaches and combinations and their potential to improve patient outcomes in the
complex landscape of cancer treatment.
Author Contributions: Conceptualization, B.S.Z. and F.J.E.; literature review, B.S.Z. and F.J.E.;
writing—original draft preparation, review and editing, B.S.Z. and F.J.E. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: F.J.E. has served as a consultant for AstraZeneca, Genentech, and Novartis for
activities unrelated to this manuscript. B.S.Z. has no conflicts of interest to disclose.
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... Importantly, no deaths or severe toxicities were reported during the dose-escalation phase, and there were no dose-limiting toxicities. In terms of effectiveness, zanidatamab-zovodotin showed an objective response rate (ORR) of 13%, with a partial response (PR) rate of 13%, indicating promising anticancer activity [101]. ...
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Introduction: ARX788 is a next-generation anti-HER2 antibody-drug conjugate (ADC) conjugated to amberstatin269 (AS269), a potent cytotoxic tubulin inhibitor. ARX788 is highly stable with nearly identical PK profiles for the total ADC and the total antibody due to proprietary site-specific oxime conjugation chemistry. The stability of ARX788 results in limited systemic toxicity and increased targeted delivery of payload to tumor cells. Clinical benefit of ARX788 has been observed in patients (pts) with HER2-positive (HER2-pos) breast cancer (BC) in multiple clinical trials and recently in a randomized, controlled, phase 3 registrational trial conducted in China. Methods: ARX788-1711 (NCT03255070)was a phase 1 dose-escalation study of ARX788 monotherapy in pts with advanced solid tumors with HER2 expression. There was no limit to the number of prior therapies. An objective of the trial was investigating the safety and tolerability of ARX788 in pts with BC. Results: Between August 2020 and June 2023, 42 pts with HER2-pos and HER2-low BC with a median of 6 prior lines of therapy received intravenous ARX788 at either 1.5, 1.6, or 1.7 mg/kg every 21 days (Q3W) or every 28 days (Q4W). Treatment regimens were combined for these analyses. ARX788 was generally well tolerated. Most adverse events (AEs) were grade (Gr) 1 or 2, the most common being ocular, alopecia, nausea, and fatigue. Gr3 treatment-related AEs (TRAEs) occurred in 23.8% of pts and included nausea, ocular, AST and ALP increase (4.8% each); one pt (2.4%) had Gr3 pneumonitis/interstitial lung disease. A Gr3 ocular SAE occurred 48 days after the pt’s last study dose and was resolving 9 days after onset. There were no Gr4 or Gr5 events. Treatment discontinuation due to drug-related AEs occurred in 7.1% of pts. Overall response rate (ORR) per RECIST v1.1 was analyzed in groups by HER2-low or HER2-pos tumor status. In pts with HER2-pos BC (n=11) the ORR was 54.5% (4 confirmed, 2 unconfirmed); in pts with HER2-low BC (n=30) the ORR was 23.3% (5 confirmed, 2 unconfirmed). The disease control rate (confirmed complete or partial response + stable disease) was 81.8% and 76.7%, for HER2-pos and HER2-low BC, respectively. Six of 9 pts with confirmed responses had a duration of response greater than 5 months. Six of eight pts with prior trastuzumab deruxtecan (T-DXd) exposure also had prior trastuzumab emtansine (T-DM1). Two pts with prior T-DM1 and T-DXd had significant target lesion reductions of 55% and 32%; these were a HER2-low pt with 6 prior cancer therapy regimens and a HER2-pos pt with 9 prior cancer therapy regimens, respectively. Both pts came off treatment before response confirmation. As of the data cut-off (19 Jun 2023), 4 of 9 confirmed responders remain on treatment and continue to experience clinical benefit including one pt with prior T-DM1 exposure with a durable response of 15.8 months. Importantly, significant target lesion reductions were observed in heavily pretreated pts who also received prior T-DXd and T-DM1. Discussion: Based on the promising safety and antitumor activity of ARX788 in this heavily pretreated pt population, a phase 2 study is open (NCT04829604) and enrolling pts with HER2-pos BC who have been previously treated with T-DXd. Citation Format: Sophia Frentzas, Haesong Park, George Budd, Vinod Ganju, Catherine Shannon, Sara Hurvitz, Katharine Cuff, Peter Lau, Richard Eek, Joyce O'Shaughnessy, Fran Boyle, Sandra Aung, Colin Hessel, Janice Lu. Phase 1 dose escalation study of ARX788, a next-generation anti-HER2 antibody drug conjugate, in heavily pretreated breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-01.
Article
HER2 is a member of the epidermal growth factor receptor family. Activation of the HER2 signaling pathway has been shown to strongly promote carcinogenesis. It is therapeutically targeted in cancer owing to its overexpression and pathway dependence in a variety of human carcinomas, especially human breast cancers. We created a promising therapeutic anti-tumor agent, BL-M07D1, an anti-HER2-Ed-04 ADC. It is comprised of a humanized anti-HER2 antibody Trastuzumab, a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent (Ed-04), which is a derivative of the alkaloid camptothecin, driving cell cycle arrest at the S phase and subsequent apoptosis. The BL-M07D1 drug-to-antibody-ratio is 8:1 (DAR=8), similar to Trastuzumab Deruxotecan (DS-8201), while possessing a more stable linker. To evaluate the pharmacological potential of BL-M07D1, xenograft tumor inhibition assays were used to compare BL-M07D1 with the commercialized HER2-targeting ADCs, T-DM1 and DS-8201, which have been approved worldwide for patients with HER2-expressing tumors. Results from the in vivo murine studies show that BL-M07D1 has strong tumor inhibition effects in multiple cell line-derived xenograft (CDX) tumor models. 1) BL-M07D1 exhibited better anti-tumor efficacy than DS-8201 in CDX with low HER2 expression, human epidermal cancer A431 and human non-small cell lung cancer NCI-H1975. Both models are considered be T-DM1-insensitive. 2) BL-M07D1 exhibited better anti-tumor efficacy in comparison to either T-DM1 or DS-8201 in a CDX with JIMT-1, a HER2-positive human breast cancer cell line. 3) BL-M07D1 exhibits potent bystander effects in a heterogeneous xenograft model of HER2-positive and HER2-negative tumor cells composed of NCI-N87 and MDA-MB-468 cells. In this model, BL-M07D1 exhibited stronger tumor inhibition than T-DM1, consistent with bystander effects that are also exhibited by DS-8201. In conclusion, in vivo studies suggest that BL-M07D1, a novel HER2-targeting ADC, is potentially more efficacious in a broader patient population than T-DM1, and mediate superior anti-tumor efficacy than DS-8201. The clinical phase I is under way and the available data exhibit excellent efficacy in breast cancer therapy with acceptable tolerability. Citation Format: Weili Wan, Shuwen Zhao, Shi Zhuo, Yong Zhang, Lan Chen, Gangrui Li, Jahan Salar Khalili, Sa Xiao, Yongqi Yan, Xuejiao Shen, Yi Zhu. BL-M07D1, a novel HER2-targeting ADC, demonstrates potent anti-tumor efficacy in preclinical pharmacodynamic models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2643.