Antibody-drug conjugates in breast cancer: Progress and future directions

Alexandra Bili Newman; Senthil Damodaran; Funda Meric-Bernstam

doi:10.1016/j.xcrm.2026.102742

. 2026 Apr 7;7(5):102742. doi: 10.1016/j.xcrm.2026.102742

Antibody-drug conjugates in breast cancer: Progress and future directions

Alexandra Bili Newman ¹, Senthil Damodaran ^2,³, Funda Meric-Bernstam ^3,^4,^∗

PMCID: PMC13198313 PMID: 41950928

Summary

Antibody-drug conjugates (ADCs) have transformed the treatment landscape of breast cancer, enabling targeted delivery of potent cytotoxic payloads to antigen-expressing tumor cells. These agents have demonstrated efficacy across breast cancer subtypes, including chemotherapy-refractory disease and brain metastases, with manageable side-effect profiles. However, despite significant advances, identifying predictive biomarkers for response and understanding resistance mechanisms remain critical challenges that must be addressed to guide rational sequencing strategies and optimize combination approaches. The ADC platform offers remarkable versatility through diverse antigen targeting, variable linker chemistries enabling controlled payload release, multiple cytotoxic payload classes, and adjustable drug-to-antibody ratios. Next-generation platforms including bispecific targeting constructs, immune-stimulating antibody conjugates, and novel payloads such as PROTACs and RNA polymerase II inhibitors are being developed to further expand therapeutic applications. Realizing the full potential of these agents will require integrated biomarker development, a deeper understanding of resistance mechanisms, and optimized sequencing and combination strategies.

Keywords: antibody-drug conjugates, breast cancer, systematic review, ADCs

Graphical abstract

Newman et al. review the evolving landscape of antibody-drug conjugates (ADCs) in breast cancer, including approved agents, resistance mechanisms, and combinatorial strategies. The authors highlight novel agents, antigen targets, and next-generation platforms, underscoring the need for predictive biomarkers and optimized sequencing strategies to improve patient selection and efficacy.

Introduction

The concept of a “magic bullet” for targeted therapeutic delivery to cancer cells while sparing healthy tissue was first pioneered by German Nobel Laureate Paul Ehrlich in the early 20th century. Over the subsequent decades, his idea evolved to incorporate monoclonal antibodies as delivery vehicles to preferentially target tumor cells. In 2000, gemtuzumab ozogamicin became the first modern antibody-drug conjugate (ADC) to receive Food and Drug Administration (FDA) approval for use in acute myeloid leukemia. This paved the way for 14 approved ADCs across the field of oncology over the past 25 years.¹ These agents merge the targeting precision of monoclonal antibodies with the potency of chemotherapy, thereby addressing the long-standing challenge in oncology of maximizing therapeutic efficacy while reducing systemic toxicity.²^,³ The breast cancer treatment landscape has been fundamentally reshaped by ADCs, beginning with the approval of trastuzumab emtansine (T-DM1) in 2013 followed by trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd), firmly establishing ADCs as part of standard of care across all breast cancer subtypes (Figure 1).³^,⁴^,⁵ Interestingly, meaningful clinical responses have emerged even in tumors with low target antigen expression, a finding that has substantially expanded treatment options for patients with advanced disease.⁶^,⁷^,⁸ ADCs are now being integrated throughout the treatment continuum, from neoadjuvant and adjuvant approaches through management of metastatic disease (Table S1).⁹^,¹⁰ This rapid adoption has necessitated the development of toxicity mitigation strategies and predictive biomarkers that guide patient selection and raises important questions regarding optimal ADC sequencing, combination strategies, and cost-effectiveness and accessibility.⁴^,¹¹^,¹²^,¹³ With next-generation ADCs now entering clinical development and incorporating bispecific platforms, novel targets, and advanced engineering strategies, it is essential to comprehensively review the current state of ADC therapy in breast cancer, examine mechanisms of action and resistance, and explore promising directions for future innovation.

Timeline of ADC approvals in breast cancer

Structure and mechanisms of ADCs

Fundamentally, ADCs are composed of three components; an antibody backbone, a cytotoxic payload, and a chemical linker that attaches the two together. The antibody backbone is most commonly a human/humanized immunoglobulin G1 (IgG1) antibody, chosen due to its longer serum half-life, small molecular weight, effector function leading to enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), and ease of manufacturing. The antibody backbone is conjugated to the toxic payload through a linker molecule, enabling precise attachment of a predetermined number of payload molecules. The number of payload molecules attached to each antibody is referred to as the drug-to-antibody ratio (DAR) and ranges between 2 and 8 in FDA-approved ADCs.

Though the basic components of an ADC remain consistent across agents, variability exists in the design of the various components to optimize drug delivery and enhance the cytotoxic effects while limiting the toxicity profile (Figure S1). Design of the first four ADCs approved for breast cancer is shown in Figure 2. In a traditional ADC, the antibody binds with high specificity to the target surface antigen on the tumor cell, is internalized and processed through the lysosomal/endosomal pathway where the linker is cleaved and the ADC is broken down, and the cytotoxic payload is released into the cell. Upon ADC breakdown, if the payload is membrane permeable, it can be released into surrounding cells, causing localized cytotoxicity in cells without target expression, often referred to as the “bystander effect.” Accumulating evidence demonstrates that extracellular proteases in the tumor microenvironment (TME), including cathepsins B and L, can cleave ADC linkers and release cytotoxic payloads independent of antibody internalization.¹⁴^,¹⁵ These multiple processing routes contribute to both direct tumor cell killing and bystander effects, which are critical for the efficacy of ADCs, especially in heterogeneous tumor environments. Additionally, the antibody backbone can trigger binding of the Fc receptors on immune effector cells, thereby stimulating ADCC, providing an alternative mechanism for death of the target cell.

Ideally, the ADC preferentially delivers the toxic payload to tumor cells while sparing damage to surrounding normal tissue. While the DAR controls the payload concentration delivered per antibody, the linker, either cleavable or non-cleavable, determines the payload release kinetics within the target cell. A cleavable linker can undergo degradation under conditions present in the TME, including acidic pH or exposure to tumor-associated enzymes. Non-cleavable linkers require proteolytic degradation within the acidic lysosomal environment following antibody internalization. This enhanced stability reduces premature ADC breakdown during systemic circulation, thereby minimizing off-target toxicity. However, non-cleavable linkers may exhibit reduced efficacy in heterogeneous tumors where target antigen expression varies across cell populations.

The effectiveness of an ADC also depends on cytotoxic payload potency, which is typically able to be higher than conventional chemotherapy due to its targeted delivery mechanism. An ideal cytotoxic payload should exhibit high potency and strong activity against the disease of interest, low molecular weight, stability in circulation along with the low pH environment of the lysosome, and water solubility and should have a side group that can be used to couple to the linker. Examples of payloads that have been utilized include microtubule inhibitors (e.g., monomethyl auristatin E [MMAE]), agents that induce DNA damage (e.g., topoisomerase inhibitors, govitecan, and deruxtecan). Many of these agents have been found to have unacceptable toxicity profiles and narrow therapeutic indices when given systemically, but when used as part of an ADC, their high potency allows for more effective cell killing, while limiting toxicity.

ADCs with regulatory approval for breast cancer

Trastuzumab emtansine

T-DM1, the first ADC approved for breast cancer, combines the HER2-targeting antibody trastuzumab with the microtubule inhibitor DM1 (a maytansine derivative) via a non-cleavable thioether linker, with a DAR of 3.5. FDA granted initial approval in 2013 based on the pivotal EMILIA trial, a phase III study comparing T-DM1 versus lapatinib plus capecitabine in patients with metastatic HER2-positive breast cancer previously treated with trastuzumab and taxanes. T-DM1 demonstrated superior efficacy with a median progression-free survival (PFS) of 9.6 versus 6.4 months (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.55–0.77, p < 0.001) and overall survival (OS) of 30.9 versus 25.1 months (HR 0.68, 95% CI 0.55–0.85, p < 0.001).¹⁶ The TH3RESA trial further validated T-DM1’s efficacy in heavily pretreated patients who had progressed on at least two prior anti-HER2 regimens, showing improved PFS of 6.2 versus 3.3 months (HR 0.52, p < 0.001) and OS of 22.7 versus 15.8 months (HR 0.68, p < 0.001) compared to physician’s choice therapy.¹⁷ However, first-line studies have been less encouraging, with the MARIANNE trial failing to demonstrate T-DM1 superiority over standard trastuzumab plus taxane therapy.¹⁸ In 2019, T-DM1 received adjuvant approval based on the KATHERINE trial, which showed a 50% reduction in disease recurrence or death at 3 years, compared to adjuvant trastuzumab, among patients with residual disease following neoadjuvant taxane and trastuzumab-based therapy. Long-term follow-up from this trial found improved overall survival with T-DM1 compared with trastuzumab (HR 0.66; 95% CI, 0.51–0.87; p = 0.003), with 7-year overall survival rates of 89.1% versus 84.4%.¹⁹ T-DM1’s toxicity profile, while generally more tolerable than conventional chemotherapy, includes thrombocytopenia (grade ≥3, 4%–14%), hepatotoxicity (grade ≥3, 3%–9%), anemia (grade ≥3, 3%–4%), fatigue (grade ≥3, 2%–11%), peripheral neuropathy (grade ≥3, 2%)¹⁶^,¹⁸^,²⁰^,²¹(Figure 2).

Trastuzumab deruxtecan

T-DXd represents a significant advancement in HER2-targeted therapy, featuring the trastuzumab antibody conjugated to deruxtecan, a potent topoisomerase-I inhibitor from the camptothecin class. With a DAR of 8, T-DXd employs a novel tetrapeptide-based cleavable linker that undergoes cathepsin-mediated cleavage within tumor cell lysosomes and, to a lesser extent, in the TME. The membrane-permeable deruxtecan payload exhibits the “bystander effect,” allowing diffusion into neighboring tumor cells to induce cytotoxicity regardless of their HER2 expression status. T-DXd received initial FDA approval in 2019 for heavily pretreated HER2-positive metastatic breast cancer based on the DESTINY-Breast01 phase II trial. T-DXd achieved a 62% objective response rate (ORR), with median PFS of 19.4 months (95% CI, 14.1–25.0) and OS of 29.1 months (95% CI, 24.6–36.1).²² The pivotal DESTINY-Breast03 trial established T-DXd’s superiority over T-DM1 in patients with metastatic disease following prior trastuzumab and taxane therapy. T-DXd demonstrated remarkable efficacy with median PFS of 29.0 versus 7.2 months (HR 0.30, 95% CI 0.24–0.38) and OS of 52.6 versus 42.7 months (HR 0.73, 95% CI 0.56–0.94), positioning T-DXd as the preferred second-line therapy for metastatic HER2-positive disease.²³ The recent DESTINY-Breast09 study demonstrated that T-DXd combined with pertuzumab significantly improved outcomes for patients with advanced HER2-positive breast cancer in the frontline setting, achieving a median PFS of 40.7 months versus 26.9 months with THP (trastuzumab, pertuzumab, and docetaxel), although OS data remain immature.²⁴ T-DXd has also demonstrated significant clinical activity in patients who had progressed on T-DM1 with a PFS of 18.8 versus 6.9 months in the physician’s choice group.²⁵ The significant bystander effect of T-DXd led to its investigation in “HER2-low” patients (IHC 1+ or 2+/FISH-negative). In the DESTINY-Breast04 study, T-DXd showed superior PFS of 10.1 versus 5.4 months (HR 0.51, 95% CI 0.40–0.64, p < 0.001) and OS of 23.9 versus 17.5 months (HR 0.64, 95% CI 0.48–0.85, p = 0.003) compared to physician’s choice therapy in patients who had progressed on one to two prior chemotherapy lines or recurrence within 6 months of adjuvant therapy, regardless of hormone receptor (HR) status.⁸ DESTINY-Breast06 further expanded T-DXd’s utility in HR-positive, HER2-low, and ultra-low (IHC 0 with membrane staining) patients who had received endocrine therapy but no prior chemotherapy, showing improved PFS of 13.2 versus 8.1 months (HR 0.62, 95% CI 0.52–0.75, p < 0.001), leading to FDA approval in this population.²⁶ The DAISY study evaluated T-DXd efficacy across the spectrum of HER2 expression levels and demonstrated that response rates and duration of response were highest in patients with HER2 overexpression compared to those with low or ultralow expression. Intriguingly, T-DXd also showed clinical response in patients without detectable HER2 expression, suggesting that T-DXd may possess mechanisms that involve alternative internalization pathways or enhanced bystander effects in the TME, regardless of HER2 expression.²⁷ T-DXd’s rates of grade ≥3 toxicity includes neutropenia (14%–24%), anemia (8%–10%), nausea (2%–8%), and fatigue (4%–8%).²⁴^,²⁶^,²⁸^,²⁹ The most serious concern is interstitial lung disease (ILD) pneumonitis, occurring in up to 16% of patients, with up to 2.7% experiencing grade 3 or higher toxicity, requiring vigilant clinical monitoring with serial chest imaging, as mandated by newer studies. Treatment protocols include immediate therapy discontinuation with steroid administration for grade 1 asymptomatic ILD and permanent drug discontinuation for grade 2 ILD.³⁰

Sacituzumab govitecan

SG is a trophoblast cell surface antigen-2 (TROP2)-targeted ADC that utilizes a topoisomerase-I inhibitor payload (SN-38) that is an active metabolite of irinotecan with a high DAR (7.6). TROP2 is a transmembrane glycoprotein and calcium signal transducer that is normally expressed at low levels in epithelial tissues but is significantly overexpressed in many solid tumors. SG utilizes a CL2A hydrolysable linker that is broken down by the low pH environment of the intracellular lysosome or the acidic TME, thereby enabling the “bystander effect.” SG was first approved in 2021 for patients with metastatic TNBC who had received two or more prior therapies, based on the results of the ASCENT trial that showed a median PFS of 5.6 versus 1.7 months (HR 0.41, 95% CI 0.32–0.52) with treatment of physician’s choice (TPC) and OS of 12.1 versus 6.7 months (HR 0.51, 95% CI 0.422–0.625). While the observed PFS and ORR were more in patients with high/medium TROP2 expression compared to low TROP2 expression, SG demonstrated significant activity in patients with low TROP2 expression compared to TPC. As such, routine testing for TROP2 expression has not been recommended for treatment selection.³¹^,³² In 2023, SG was approved in patients with HR-positive HER2-negative breast cancer who had received endocrine-based therapy and at least two additional systemic lines of treatment in the metastatic setting based on data from the TROPiCS-02 study, demonstrating OS of 14.4 months compared to 11.2 months with physician’s choice single-agent chemotherapy (HR 0.79, 95% CI 0.65–0.96, p = 0.02).³³ Like in TNBC, survival benefit was seen across TROP2 expression levels.³⁴ The recent ASCENT-04 study showed that in patients with treatment-naive advanced TNBC with PD-L1 positivity (CPS≥10), SG in combination with pembrolizumab significantly improved median PFS to 11.2 versus 7.8 months with pembrolizumab plus chemotherapy (HR 0.65, 95% CI 0.51–0.84, p = 0.0009), though OS data have not yet matured.³⁵ Similarly, the ASCENT-03 trial found a significant improvement in median PFS with SG monotherapy compared with chemotherapy in first-line metastatic TNBC patients who were not candidates for PD-L1 inhibitors (either due to being PD-L1 CPS<10 or ineligible due to medical co-morbidities) with a median PFS of 9.7 months versus 6.9 months (HR 0.62, 95% CI 0.50–0.77, p < 0.001).³⁶ Given responses to SG seen in the advanced disease setting, efforts are underway to evaluate SG in early-stage disease TNBC.¹⁷ The most common side effects are neutropenia (grade ≥3, 51%), with febrile neutropenia observed in 6%, diarrhea (grade ≥3.10%), leukopenia (grade ≥3, 10%), and anemia (grade ≥3, 8%). Patients who are homozygous for the UGT1A1∗28 allele have a significantly higher incidence of grade 3 or 4 neutropenia. The FDA has issued a black box warning for severe or life-threatening neutropenia along with diarrhea, and it has been recommended to consider G-CSF primary prophylaxis for patients at higher risk of developing febrile neutropenia, including older adults.

Datopotamab deruxtecan

Dato-DXd is a TROP2-directed IgG1 monoclonal antibody conjugated with a topoisomerase-I inhibitor payload DXd, with a DAR of four molecules per antibody. It utilizes a tetrapeptide-based cleavable linker. The drug was initially tested in the phase I TROPION-PanTumor01 study that demonstrated an ORR of 26.8% in HR-positive HER2-negative breast cancers and 31.8% in TNBC.³⁷ In 2025, the FDA approved Dato-DXd for patients with HR-positive HER2-negative metastatic or unresectable breast cancer who had received prior endocrine-based therapy along with chemotherapy. This approval was based on the TROPION-Breast01 trial which compared Dato-DXd to investigator choice chemotherapy and found an improved PFS of 6.9 versus 4.9 months (HR 0.63, 95% CI 0.52–0.76, p < 0.0001), though there was no improvement in OS detected at 18.6 versus 18.3 months (HR 1.01, 95% CI 0.83–1.22). Notably, <5% of patients in both arms of this study had received prior ADC therapy.³⁸ The TROPION-Breast02 phase III trial found that first-line Dato-DXd demonstrated significant improvement over chemotherapy in patients with metastatic TNBC ineligible for immunotherapy, with a median PFS of 10.8 versus 5.6 months (HR 0.57, 95% CI 0.47–0.69, p <0 .0001) and a median OS of 23.7 versus 18.7 months (HR 0.79, 95% CI 0.64–0.98, p = 0.0291).³⁹ The most common grade ≥3 side effects were stomatitis (6.4%), nausea (1.4%), anemia (1.1%), and fatigue (1.7%). Due to high rates of stomatitis, prophylaxis with dexamethasone mouthwash is recommended. Additionally, due to risk of ocular surface abnormalities, ophthalmologic assessment at baseline is recommended. Notably, there was a low rate of ILD/pneumonitis (3.3%), with <1% of patients developing grade 3 or higher disease.⁴⁰^,⁴¹

Sacituzumab tirumotecan

Sacituzumab tirumotecan (sac-TMT) is an ADC that utilizes a pyrimidine-thiol linker conjugated to a belotecan-derivative TOP1 inhibitor, with an average DAR of 7.4. The OptiTROP-Breast01 phase III trial evaluated sac-TMT in previously treated metastatic triple-negative breast cancer patients, showing a median PFS of 6.7 versus 2.5 months with chemotherapy (HR 0.32, p < 0.00001) and an ORR of 45.4% versus 12.0% with chemotherapy.⁴² Based on the results of this trial, sac-TMT was approved for use in China for patients with advanced TNBC who had received at least two prior lines of systemic treatment. The subsequent OptiTROP-Breast02 phase III trial demonstrated efficacy in previously treated HR+/HER2− metastatic breast cancer, with sac-TMT achieving a median PFS of 8.3 months versus 4.1 months with chemotherapy (HR 0.35; 95% CI, 0.26–0.48; p < 0.0001), along with a favorable trend in overall survival.⁴³

Biomarkers of response and resistance

Identification of biomarkers to guide ADC selection has become increasingly important considering increasing number of agents available. Quantification of target antigen expression can play an important role in predicting response, though the degree of effect is variable depending on antigen target and ADC design. Variable ADC efficacy can be attributed to multiple factors including spatial and temporal heterogeneity of antigen expression within each tumor and across metastatic lesions, differences in cellular internalization and intracellular trafficking efficiency, emergence of resistance through target antigen modulation or payload-specific mechanisms, and TME barriers that impede both drug penetration and immune cell engagement.⁴⁴

When examining the role of antigen expression, higher response rates to T-DM1 have been noted in patients whose tumors maintained HER2 expression compared to those whose tumors lost HER2 expression on reassessment (33.8% vs. 4.8%).⁴⁵ An association between response and expression was observed with T-DXd, where HER2 expression levels have been subdivided into “HER2-low” and “HER2-ultralow” groups, and the DAISY study demonstrated a correlation between HER2 surface expression and T-DXd response rates.²⁷ However, clinically meaningful activity was observed even with ultralow HER2 expression.²⁶ For TROP2-targeted ADCs, TROP2 expression may be a relevant biomarker, though clinical benefit has been observed even in tumors with lower expression, suggesting a broader therapeutic window.³²^,³⁴ Pre-clinical patient-derived xenograft models do indicate enhanced anti-tumoral activity both in vitro and in vivo with Dato-DXd in samples with higher TROP2 expression.⁴⁶ As such, the role of quantitative analysis of target antigen expression remains uncertain and is not routinely implemented outside of HER2 testing in breast cancers.

Beyond antigen quantification, predictive biomarkers of ADC response include molecular determinants of intracellular trafficking and drug resistance. RAB5A, a small GTPase that serves as a master regulator of early endosome formation and maturation, has emerged as a predictive biomarker with high expression correlating with increased T-DM1 sensitivity and, to a lesser extent, T-DXd sensitivity. This observed effect underscores the important role of efficient receptor-mediated endocytosis and intracellular trafficking in ADC efficacy.⁴⁷^,⁴⁸

Acquired TOP1 mutations, detected in 12.9% of patients treated with TOP1 inhibitor-containing ADCs, conferred cross-resistance to sequential ADC therapies.⁴⁹ A study of RNA expression and whole-exome sequencing in pre- and post-progression tumor samples found that acquired resistance can arise through parallel genomic alterations affecting either the target, TACSTD2/TROP2, or the topoisomerase-I inhibitor (TOP1) payload in distinct metastatic subclones within the same patient.⁵⁰ Pre-clinical work has identified SLFN11, a putative DNA/RNA helicase that regulates cellular responses to replication stress by destabilizing replication forks and blocking homologous recombination repair, as an important biomarker of sensitivity to TOP1 payloads.⁵¹ Low SLFN11 expression, largely driven by epigenetic silencing through promoter methylation, has been associated with decreased response across tumor subtypes.⁵²^,⁵³ Interestingly, demethylating agents like decitabine have been shown to epigenetically upregulate SLFN11 expression, potentially presenting a way to overcome this resistance mechanism.⁵⁴ Additional strategies to address SLFN11-loss-mediated resistance include combination approaches with PARP inhibitors that create synthetic lethality in SLFN11-low tumors.⁵⁵

SLX4 is a DNA repair scaffold protein involved with repair of double-strand breaks during replication stress. SLX4 loss-of-function mutations represent an emerging mechanism of resistance to ADCs, as cells become deficient in processing DNA damage induced by ADC payloads, which paradoxically can lead to resistance rather than enhanced sensitivity.⁵⁶ Evidence from the DAISY trial identified SLX4 mutations as one of the first documented resistance mechanisms to T-DXd, highlighting the complexity of ADC resistance mechanisms and suggesting that combination strategies targeting DNA repair pathways may be necessary to overcome this form of therapeutic escape.²⁷

Another mechanism of payload resistance is impaired intracellular drug trafficking, often involving compromise of endocytosis and impaired intracellular transport or disruption to lysosomal function. Cells can also adopt drug efflux pumps and modifications to cytotoxic agents.⁵⁷ There is increasing interest in ABCC1 (ATP binding Cassette Subfamily C Member 1), a drug efflux pump that has been associated with ADC resistance, with lower ABCC1 mRNA expression associated with improved survival with T-DXd.⁵⁸ Gain-of-function mutations in NFE2L2 and loss-of-function mutations in KEAP1, both transcriptional regulators of ABCC1 expression, have been identified in post-T-DXd genomic sequencing samples, implicating ABCC1 upregulation as a potential resistance mechanism. This provides rationale for comprehensive molecular profiling with platforms that assess transcriptomics as well as genomics post-progression.

Additionally, novel strategies including molecular-imaging-based approaches using radiolabeled antibodies to quantify in vivo target expression and tumor heterogeneity, AI-enhanced digital pathology platforms that simultaneously assess multiple predictive markers with spatial resolution, and serial ctDNA monitoring to detect emerging resistance mutations in real time are currently being studied to enable more precise patient selection and early detection of therapeutic resistance.⁵⁹^,⁶⁰^,⁶¹

Brain and leptomeningeal metastases

TOP1-inhibitor-based ADCs have demonstrated clinically meaningful intracranial activity in patients with brain metastases, particularly in HER2-positive disease where brain metastases are most prevalent. T-DXd has shown robust intracranial objective response rates (ORR-IC) in prospective and retrospective studies, with a pooled analysis of the DEBBRAH, TUXEDO-1, and DFCI/Duke/MDACC cohorts reporting an ORR-IC of 64.9% and a median intracranial PFS of 13.3 months in heavily pretreated patients with active brain metastases.⁶² These findings were prospectively validated in a larger patient cohort, which achieved a 12-month CNS PFS rate of 58.9%.⁶³ A cohort analysis of the DEBBRAH trial in patients with leptomeningeal disease (LMD) showed a median PFS and OS of 8.9 and 13.3 months, respectively. These findings suggest T-DXd has promising antitumor activity in this highly morbid and difficult-to-treat population.⁶⁴ SG has also shown intracranial activity, with a disease control rate of 42% and median intracranial PFS of 2.7 months in a real-world cohort, including patients with both stable and active brain metastases.⁶⁵

Systematic reviews and meta-analyses confirm that ADCs, especially T-DXd, provide superior survival outcomes compared to other systemic therapies including TKIs in HER2-positive brain metastases.⁶⁶ The pharmacology of CNS activity in ADCs is an active area of investigation, but permeability of the blood-tumor barrier, ADC homogeneity, and drug-antibody-ratio are all thought to be important factors in CNS drug delivery. Cleavable linkers and lipophilic payloads that enable “bystander effect” may be particularly important for CNS efficacy where permeability through the blood-brain barrier is variable.⁶⁷

Early breast cancer

ADCs are rapidly advancing in the management of early-stage breast cancer, and multiple trials are ongoing evaluating their utility in the neoadjuvant and adjuvant setting. Since 2019, T-DM1 has been considered the standard of care for patients with residual disease after neoadjuvant systemic therapy in HER2-positive breast cancer based on the KATHERINE study, which showed improved invasive DFS and later OS compared to adjuvant trastuzumab. More recently, data from the DESTINY-Breast05 study comparing the efficacy and safety of T-DXd with T-DM1 in HER2-positive patients with residual disease after neoadjuvant therapy significantly improved iDFS (HR 0.47, 95% CI 0.34–0.66, p < 0.001).¹⁰^,⁶⁸ The TRIO-US B-12 (TALENT) study evaluated T-DXd alone or in combination with endocrine therapy in patients with stage 2/3 HR-positive, HER2-low breast cancers and found an ORR of 68% with T-DXd compared to 58% with T-DXd and anastrozole in combination.⁶⁹ The ongoing SASCIA trial is evaluating adjuvant SG in patients with high-risk, HER2-negative early breast cancer, including those with minimal residual disease (MRD) after neoadjuvant therapy, to improve DFS.⁷⁰

In the neoadjuvant setting, DESTINY-Breast11 showed that neoadjuvant T-DXd followed by THP achieved a 67.3% pCR rate compared with 56.3% for standard ddAC-THP in high-risk HER2-positive early breast cancer.⁹ The NeoSTAR trial found a pCR rate of 30% in patients with early-stage TNBC with four cycles of SG alone, with baseline tumor elevations in Ki-67 and tumor-infiltrating lymphocytes (TILs) serving as predictive biomarkers for response.⁷¹ In the I-SPY2.2 phase II trial, among patients with immune-positive, HER2-negative, early-stage breast cancer, neoadjuvant Dato-DXd plus durvalumab alone achieved a pCR rate of 56%, which increased to 92% when subsequent taxane therapy was added. While Dato-DXd alone did not meet the predefined graduation threshold as a single-agent, 18.5% of patients who received single-agent neoadjuvant Dato-DXd achieved pCR with an associated reduction in toxicity.⁷² The ongoing TROPION-Breast04 study is evaluating neoadjuvant Dato-DXd with durvalumab followed by adjuvant durvalumab with or without chemotherapy for treatment-naive early-stage TNBC for HR-low/HER2-neg breast cancer.⁷³ Primary results from the VALENTINE trial showed that neoadjuvant patritumab deruxtecan (HER3-DXd) with or without letrozole achieved similar pCR rates (2%–4%) and ORRs (70%–81%) compared to standard chemotherapy in high-risk HR+/HER2− early breast cancer, but with dramatically fewer grade ≥3 adverse events (14%–18% vs. 54% with chemotherapy).⁷⁴ MRD-directed strategies are a focus of several ongoing studies, leveraging the potent activity of ADCs to eradicate subclinical disease and reduce recurrence risk.

Rational ADC combinations

Approved ADCs in breast cancer are being actively investigated in combination with targeted therapies, immunotherapies, PARP inhibitors, and other ADCs to enhance efficacy and overcome resistance mechanisms (Figure 3).⁷⁵^,⁷⁶^,⁷⁷^,⁷⁸

Combining ADCs with targeted therapies may enhance drug internalization, modulate tumor antigen expression, and overcome acquired resistance mechanisms.⁷⁹ For example, pre-clinical studies identified the presence of HER3 ligand NRG-1β as a mechanism of resistance to T-DM1, which can be overcome by adding pertuzumab.⁸⁰ Although the MARIANNE trial failed to show superiority of the T-DM1/pertuzumab combination compared with T-DM1 alone in the metastatic setting, the DESTINY-Breast09 trial demonstrated superiority of the combination of T-DXd + Pertuzumab over standard-of-care chemotherapy, and this combination has been approved by FDA for first-line use in advanced HER2-positive disease.²⁴ HER2-directed TKIs have also been shown to synergize with T-DM1 by stabilizing HER2 receptor expression and enhancing receptor ubiquitination, leading to increased drug internalization.⁸¹^,⁸² The phase II TEAL study showed improvement in pCR rates with neoadjuvant T-DM1 + lapatinib + nab-paclitaxel compared with trastuzumab + pertuzumab + paclitaxel in early-stage HER2-positive breast cancer (85.7% vs. 62.5%).⁸³ The phase III HER2CLIMB-02 study found that the combination of T-DM1 + tucatinib significantly improved PFS in patients with previously treated HER2-positive advanced breast cancer compared to T-DM1 alone (PFS 9.5 months vs., 7.4 months, 95% CI 0.61–0.95, p = 0.0163), including patients with brain metastases.⁸⁴ The TBCRC-022 trial further corroborated the intracranial activity for neratinib + T-DM1 in HER2-positive breast cancer, even in heavily pretreated patients with prior T-DM1 exposure, suggesting that the addition of neratinib may help overcome T-DM1 resistance.⁸⁵ Additionally, combining ADCs with targeted therapies such as PI3K/AKT/mTOR pathway inhibitors is under investigation, given the frequent activation of these pathways in breast cancer and their role in resistance to both endocrine therapy and ADCs. A phase I trial combined SG with α-specific PI3K inhibitor alpelisib in patients with HER2-negative advanced breast cancer who had received at least one prior line of chemotherapy. The trial enrolled patients regardless of PI3K pathway alteration status and found a manageable safety profile with an ORR of 36%.⁸⁶

The addition of immune checkpoint inhibitors to ADCs leverages ADC-induced immunogenic cell death to expose neoantigens and recruit dendritic cells, which can then migrate to lymph nodes to prime and activate cytotoxic T cells, inducing tumor cell killing. This innate immune activation can work in concert with PD-1/PD-L1 blockade to enhance the anti-tumoral immune response.⁸⁷ Early-phase clinical studies, including the open-label platform BEGONIA trial, have demonstrated that combining ADCs with immunotherapy is generally safe and well-tolerated, with preliminary evidence of durable responses. The combination of Dato-DXd with durvalumab in first-line metastatic TNBC exhibited an ORR of 79% (95% CI 67%–88%) regardless of PD-L1 expression, with a median DOR of 15.5 months.⁸⁸ The combination of T-DXd with durvalumab in first-line HR-negative HER2-low advanced breast cancer showed a confirmed ORR 57% (95% CI 41%–71%) and an mPFS of 12.6 months (95% CI 8%–NC).⁸⁹ In the ASCENT-04 trial, SG + pembrolizumab as first-line therapy for metastatic PD-L1-positive TNBC resulted in an mPFS of 11.2 months, compared to 7.8 months with chemotherapy + pembrolizumab (HR 0.65, 95% CI 0.51–0.84; p = 0.0009), with a favorable safety profile.⁷⁵ Interim analysis from the MORPHEUS-panBC trial similarly found that ORR was higher with SG plus atezolizumab compared with traditional chemotherapy plus atezolizumab (ORR 76.7% vs. 66.7%).⁷⁶ In the neoadjuvant setting, Dato-DXd is being tested with durvalumab in a sequential adaptive trial design and has shown a pCR rate of 54% in patients with an immune-positive subtype.⁷²

Combining ADCs bearing TOP1 inhibitor payloads with PARP inhibitors has strong mechanistic rationale, as TOP1 inhibitors trap TOP1 on DNA following strand cleavage during supercoil relief, leading to DNA double-strand breaks and S-phase cell death. Pre-clinical studies have demonstrated synergism through both catalytic inhibition and PARP trapping, producing synthetic lethality in both BRCA1 wild-type and mutant tumors.⁷⁷ Unfortunately, clinical implementation of this combination strategy has been limited by overlapping toxicities, particularly bone marrow suppression, prompting investigation of alternative approaches like sequential dosing.⁷⁸

EZH2 plays a role in epigenetic silencing through methylation of tumor suppressor genes and is thought to play a role in resistance to HER2-targeted therapies. Valemetostat is a dual EZH1/2 inhibitor, which has been shown in pre-clinical studies to upregulate SLFN11, thereby increasing cell sensitivity to TOP1 inhibitors. These studies laid the foundation for early clinical trials combining valemetostat and T-DXd.⁹⁰

Combining ADCs is an attractive strategy, but overlapping toxicities pose a major challenge. The combination of ADCs utilizing different payload classes and molecular targets may enhance therapeutic efficacy through non-overlapping pathways while reducing the potential for overlapping toxicities.⁹¹

Emerging ADCs

HER2

Beyond the approved agents, several novel ADCs are in advanced clinical trials that target the HER2 receptor. Disitamab vedotin (RC48), a novel anti-HER2 antibody (hertuzumab) conjugated to monomethyl auristatin E (MMAE) has shown promising activity in HER2-positive and HER2-low metastatic breast cancer in phase I/II studies (Table 1). It is currently undergoing evaluation for both metastatic and early-stage disease, and in combination with other HER2 directed agents, even demonstrating efficacy in tumors resistant to T-DM1 and/or T-DXd.¹⁴^,⁶⁸^,⁹²^,⁹³ ARX788 is an ADC composed of a site-specific anti-HER2 antibody conjugated to a potent tubulin inhibitor (AS269). A recent phase III trial (ACE-Breast-02) demonstrated improved PFS of 11.3 versus 8.2 months with lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer (HR 0.64, p = 0.0006).⁹⁴^,⁹⁵ Early-phase trials have shown activity in heavily pretreated HER2-positive breast cancer, including T-DM1 and T-DXd-resistant populations. Ongoing studies are assessing its role in earlier lines and in combination regimens. Trastuzumab duocarmazine (SYD985, T-Duo) links trastuzumab to a duocarmazine payload, which is a DNA minor groove binder. The phase III TULIP trial demonstrated efficacy of T-Duo in a heavily pre-treated population, though tolerability was limited by ocular toxicity, which led to a higher rate of discontinuation in the T-Duo arm.⁹⁶ Trastuzumab rezetecan (SHR-A1811), a humanized anti-HER2 antibody conjugated to a cleavable tetrapeptide linker and TOP1 inhibitor payload, was found to have superior efficacy compared with oral pyrotinib plus capecitabine in pre-treated patients with advanced HER2-positive BC, demonstrating an mPFS of 30.6 versus 8.3 months (HR 0.22, 95% CI 0.15–0.34, p < 0.0001).⁹⁷ A phase III trial of trastuzumab botidotin (A166), an anti-HER2 antibody with a protease-cleavable valine-citrulline linker conjugated to an anti-microtubule agent (Duo-5), was found to have superior efficacy in patients with pretreated HER2-positive advanced BC compared with T-DM1 alone with a median PFS of 11.1 versus 4.4 months (HR 0.39, 95% CI 0.30–0.51, p < 0.0001) and a consistent benefit regardless of prior lines of anti-HER2 treatment.⁹⁸ Additional agents in development—such as DHES0815A, FS-1502, MEDI4276, SHR-A1811, and BAT8001—explore diverse antibody backbones, linkers, and cytotoxic payloads to optimize therapeutic windows and address resistance.

Table 1.

Selected ADCs in development in breast cancer

Target	Biological function	Novel ADC drug name	ADC structure	Key clinical data & recent updates
HER2	EGFR family member; overexpressed in around 20% of breast cancer	Disitamab vedotin (RC48)	hertuzumab + MMAE, cleavable linker, DAR 4	ORR 34.4%, mPFS 3.5 months (PAM pathway activation, HER2-pos BC)⁹²
		ARX788	HER2 mAb site-specific conjugation + MMAF, DAR 2	ACE-Breast-02: mPFS 11.3 vs. 8.2 months (vs. lapatinib + capecitabine, HER2-pos BC, HR 0.64, p = 0.0006)⁹⁴
		JSKN003	biparatopic HER2 mAb + TOP1i + tetrapeptide linker	ORR 73.3% (at RD), ORR 54.7%, DOR 18.4 months (overall), T-DXd-naive, HER2-pos BC⁹⁹
		Trastuzumab Rezetecan (SHR-A1811)	HER2 mAb + TOP1i + tetrapeptide linker, DAR 6	HORIZON-Breast01: mPFS 30.6 vs. 8.3 months (vs. pyrotinib + capecitabine, pre-treated HER2-pos BC)⁹⁷
		Trastuzumab botidotin (A166)	HER2 mAb + TOP1i + tetrapeptide linker	mPFS 11.1 vs. 4.4 months (vs. T-DM1, pre-treated HER2-pos BC, HR 0.39, p < 0.0001), ORR 76.9% vs. 53.0%, DOR 12.2 vs. 5.7 months⁹⁸
		Zanidatamab Zovodotin (ZW49)	HER2 bispecific (non-overlapping epitopes) + auristatin toxin + protease-cleavable linker	ORR 31%, DCR 72% (at RD in HER2-pos solid tumors)¹⁰⁰
TROP2	glycoprotein involved with cell proliferation, epithelial-mesenchymal transition, and cell migration/invasion	Sacituzumab Tirumotecan (Sac-TMT)	humanized TROP2 mAb + TOP1i + pyrimidine-thiol linker, DAR 7.4	OptiTROP-Breast01: mPFS 6.7 vs. 2.5 months (vs. physician choice chemotherapy, TNBC, HR 0.32, p < 0.00001), ORR 45.5% vs. 12%, DOR 7.1 vs. 3.0⁴² OptiTROP-Breast02: mPFS 8.3 vs. 4.1 mo (vs. physician choice chemotherapy, pre-treated HR+/HER2- BC, HR 0.35, p < 0.00001), ORR 41.5% vs. 24.1%⁴³
		ESG401	humanized TROP2 mAb + TOP1i + Val-Cit (VC) dipeptide linker, DAR 8	ORR 78.6%, DCR 100%, CBR 85.7% (treatment-naive TNBC)¹⁰¹
		DB1305	humanized TROP2 mAb + TOP1i + tetrapeptide linker	ORR 30.4%, DCR 87% (solid tumors, no BC included, clinical trials including BC ongoing)¹⁰²
		LCB84	human Top2 mAb + MMAE payload + beta-glucuronidase linker, DAR 4	improved anti-tumor activity compared with SG and Dato-DXd in xenograft model with favorable safety profile. Early-stage clinical trials ongoing¹⁰³
B7-H4	immunoregulatory transmembrane glycoprotein driving T cell suppression and tumor progression in immune “cold” tumors	Puxitatug samrotecan (P-Sam, AZD8205)	B7-H4 mAb + TOP1i payload	ORR 40%, mPFS 5.6 months (1.6 mg/kg), 29.6%, mPFS 8.1 mo (2.4 mg/kg) in HR+/HER2- BC¹⁰⁴
		XMT-1660 (Emi-Le)	dolasynthen ADC + auristatin payload, DAR 6	ORR 23% heavily pre-treated TNBC, higher response with B7-H4 high, fewer prior treatment lines¹⁰⁵
		BG-C9074	B7-H4 mAb + TOP1i payload, DAR 6	ORR 16.1% confirmed across solid tumors¹⁰⁶
HER3	EGFR family member; heterodimerizes with HER2 to activate PI3K/AKT pathway; plays role in oncogenic signaling, tumor progression, and treatment resistance	Patritumab deruxtecan (HER3-DXd)	fully humanized anti-HER3 mAb + TOP1i payload + tetrapeptide-based cleavable linker	ORR 30.1%, mPFS 7.4 months (HR+/HER2−), ORR 42.9%, mPFS 11.0 months (HER2+), ORR 22.6%, mPFS 5.5 months (TNBC)¹⁰⁷ responses across HER3 high/low expression
		YL202/BNT326	HER3 mAb + TOP1i + tripeptide linker, DAR 8	ORR 54.5%, DCR 100% (DL 3 to DL5, HR+/HER2− BC)¹⁰⁸
		AMT-562, DB-1310	novel ant-HER3 Ab (Ab562) + modified self-immolative PACB spacer + exatecan	potent and durable anti-tumor activity in patient derived xenograft/organoid models with synergism with other targeted therapies¹⁰⁹
Nectin-4	cell adhesion molecule involved in cell-cell junctions; validated target from urothelial cancer	Bulumtatug Fuvedotin (9MW2821)	site-specific conjugated humanized Ab, interchain-disulfide drug conjugate technology + MMAE	ORR 50% in TNBC, pivotal trials ongoing¹¹⁰
Nectin-4		Enfortumab Vedotin	fully human mAb + MMAE + protease-cleavable linker	ORR 19%, mPFS 3.5 months (TNBC), ORR 15.6%, mPFS 5.4 months (HR+/HER2- BC), heavily pre-treated population¹¹¹
LIV-1	zinc transporter overexpressed in epithelial tumors including ER+ and TNBC subtypes	BRY812	humanized LIV-1 mAb + MMAE, CysLink conjugation method	ORR 23.5%, enhanced efficacy with higher LIV-1 expression¹¹²
		SDP03923-000-9106	humanized LIV-1 mAb + novel TOP1i w/improved cell permeability + cleavable linker, DAR 6	robust anti-tumor activity in LIV1-expressing patient-derived xenograft models, pending IND application¹¹³
		Ladiratuzumab vedotin	humanized LIV-1 mAb + MMAE + protease-cleavable linker	ORR 28% (weekly dosing, 2L TNBC), ORR 54% (+pembrolizumab, 1L TNBC)¹¹⁴^,¹¹⁵
PTK7	Wnt signaling pseudokinase linked to aggressive behavior/treatment resistance	Cofetuzumab pelidotin	humanized PTK-7 mAb + auristatin + cleavable valine-citrulline-based linker, DAR 4	ORR 16.7%, CBR 27.8% + gedatolisib (PI3K/mTOR inhibitor) in TNBC, highest response in PI3K/PTK7 pathway alterations¹¹⁶
B7-H3	immune checkpoint molecule associated with aggressive phenotype, angiogenesis, and immune tolerance	YL201	human B7-H3 mAb + TOP1i payload + protease-cleavable linker	ORR 40.8%, limited BC data (n = 1 patient)¹¹⁷
B7-H3		DualADC	anti-CD276 mAb conjugated with both a cytotoxic drug + immune boosting reagent	dual-payload design effectively targets TNBC and enhances immune cell infiltration in pre-clinical models¹¹⁸
FRα	folate uptake receptor with variable expression in breast cancer subtypes	Mirvetuximab soravtansine	FRα-binding mAb + cleavable linker + maytansinoid DM4 payload	TNBC trial terminated early due to low FRα expression (10.8%), no OR in 2 pts treated¹¹⁹
FRα		MORAb-202	farletuzumab (FRα-binding mAb) + eribulin + cathepsin-B cleavable linker	in vivo efficacy in TNBC-patient-derived xenograft models proportional to tumor FRα expression¹²⁰

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RD, recommended dose. This list is not intended to be comprehensive of all ADCs currently under development, but rather selected examples. Up to date as of 08/2025.

TROP2

Several TROP2-targeting ADCs are currently in clinical development. In addition to Saci-TMT, which has been approved for use in pre-treated patients with triple-negative breast cancer in China, additional agents in early clinical development include IBI130, which utilizes a camptothecin derivative NT1 payload and has demonstrated a favorable safety profile in early trials, ESG401, which employs a S-38 payload with a stable cleavable linker, and LCB84, which utilizes an ADAM10-activated TROP2 antibody along with a stable cleavable linker and MMAE payload.¹²¹^,¹²²^,¹²³

HER3

Overexpression of HER3 across major breast cancer subtypes along with its central role in tumor progression, metastasis, and therapeutic resistance has also made it an interesting target for ADC development. Patritumab deruxtecan (HER3-DXd) is a HER3-targeted ADC that has demonstrated promising activity in heavily pretreated metastatic breast cancer. In a phase I/II trial, HER3-DXd achieved an ORR of 30.1% in HR-positive/HER2-negative, 22.6% in triple-negative, and 42.9% in HER2-positive breast cancer, with a manageable safety profile. Responses were observed across both high and low HER3 expression levels.¹⁰⁷ In the phase II ICARUS BREAST01 study, patients with ER-positive/HER2-negative breast cancer previously treated with chemotherapy and adjuvant CDK4/6 inhibition achieved an ORR of 53.5%. Exploratory biomarker analyses suggested that HER3 spatial distribution and absence of ESR1 mutations were associated with improved response.¹²⁴ The follow up phase III HERTHENA-Breast04 trial will further evaluate HER3-DXd in this patient population. The SOLTI-1805 TOT-HER3 trial, a window-of-opportunity study, demonstrated that a single pre-operative dose of HER3-DXd significantly reduced tumor cellularity and immune infiltration in treatment-naive patients with early-stage HR-positive/HER2-negative breast cancer. Notably, response to HER3-DXd was independent of baseline HER3 expression levels but correlated with high proliferation signatures, low luminal gene expression, TP53 mutations, and low ERBB2 mRNA levels, suggesting that chemosensitivity determinants rather than target expression may predict therapeutic benefit.¹²⁵^,¹²⁶ Finally, the ongoing phase II HERTHENA-Breast03 trial will evaluate neoadjuvant HER3-DXd plus pembrolizumab administered either before or after chemotherapy with pembrolizumab.¹²⁷ Additional HER3-targeted ADCs, such as AMT-562, YL-202, and DB-1310, are in preclinical and early clinical development.¹⁰⁹

B7H4

B7H4 is an immunoregulatory protein that drives tumor progression through T cell suppression in immune “cold” tumors and cancer cell migration and proliferation. The B7H4-directed ADC AZD8205 (puxitatug samrotecan) has demonstrated impressive activity in pre-clinical models using TNBC-patient-derived xenograft models, with a single dose resulting in a 69% ORR and 36% complete remission rate.¹²⁸ It is now being evaluated in the phase I/IIa BLUESTAR trial and has demonstrated an ORR of 40% in the 1.6 mg/kg cohort and 29.6% in the 2.4 mg/kg cohort among patients with HR-positive/HER2-negative advanced breast cancer.¹⁰⁴ XMT 1660 (Emi-Le) is a B7-H4-directed Dolasynthen ADC that has shown clinical activity (ORR 23%) in a heavily pre-treated group of patients with advanced TNBC and prior TOP1 inhibitor ADC.¹²⁹ BG-C9074 is also under investigation across several advanced solid tumor subtypes including breast cancer (ORR 16.1%).¹⁰⁶

LIV-1

LIV-1 is a transmembrane zinc transporter protein found to be overexpressed in both HR-positive and triple-negative disease. Ladiratuzumab vedotin has been evaluated alone and in combination with pembrolizumab as first-line therapy for metastatic TNBC. Early-phase studies indicated tolerability and encouraging antitumor activity, though further clinical development has been paused at this time.¹¹⁴ A phase I study demonstrated that BRY812, an LIV-1-targeted ADC with an MMAE payload, exhibited a favorable safety and tolerability profile and achieved an ORR of 23.5%, with enhanced efficacy observed in patients exhibiting higher LIV-1 expression levels.¹¹² An additional LIV-1-targeted ADC SDP03923-000-9106 is currently in early development and has shown promising activity in in vitro models.¹¹³

B7-H3

B7-H3, an immune checkpoint molecule involved in immune regulation and tumor growth, can be overexpressed in breast cancer and is frequently associated with a more aggressive tumor phenotype, angiogenesis, immune tolerance, and poor prognosis. A phase I trial of YL20, a B7-H3-targeted ADC featuring a TOP1 inhibitor payload and protease-cleavable linker, demonstrated safety with early signs of efficacy across advanced solid tumor types. However, the trial included only one breast cancer patient, limiting conclusions for this indication.¹¹³ Dual-payload B7-H3-targeted ADCs are in early development, featuring both cytotoxic and immune-activating components designed to overcome resistance mechanisms and address tumor heterogeneity for improved therapeutic efficacy.¹¹⁸

Folate receptor alpha

Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeted ADC, showed no objective responses in a phase II trial in TNBC, likely due to low FRα expression in this population and was terminated early. AZD5335, an FRα-targeting antibody with a TOP1-inhibitor payload, has shown early signs of clinical activity in patients with high FRα expression, though no breast-specific efficacy data are available.¹³⁰ MORAb-202, another FRα-targeted ADC, has shown preclinical activity but lacks clinical efficacy data in TNBC.¹¹⁹

Nectin-4

Nectin-4 is a validated target in urothelial carcinoma and is now being explored in breast cancer.¹³¹ Enfortumab vedotin (EV), a Nectin-4-directed ADC, demonstrated an ORR of 19% when evaluated in heavily pretreated patients with advanced TNBC and HR-positive/HER2-negative breast cancer, many of whom had previously received SG.¹¹¹ 9MW2821, a next-generation Nectin-4-targeted ADC, demonstrated an ORR of 50% in TNBC in a phase I/II study, with a tolerable safety profile and ongoing trials.¹¹⁰

PTK7

PTK7 is a pseudokinase transmembrane receptor involved with the Wnt signaling pathway, and its expression on tumor cells has been linked to aggressive tumor behavior, poor prognosis, and treatment resistance. Cofetuzumab pelidotin, targeting PTK7, has shown clinical activity in TNBC, particularly when combined with the PI3K/mTOR inhibitor gedatolisib. In a phase I trial, the combination yielded an ORR of 16.7% and a clinical benefit rate of 27.8%, with enrichment in patients harboring PI3K/PTK7 pathway alterations.¹¹⁶^,¹³²

CEACAM5 (carcinoembryonic-antigen-related cell adhesion molecule 5)

CEACAM5 is a cell surface glycoprotein that regulates the mesenchymal-to-epithelial transition. Its up-regulation has been linked to metastatic progression, and preclinical data support the antitumor activity of CEACAM5-directed ADCs in epithelial tumors, including breast.¹³³^,¹³⁴

Future strategies in ADC development

Bispecific ADCs

Bispecific ADCs are designed to simultaneously target two distinct antigens or non-overlapping epitopes, thereby enhancing tumor selectivity, internalization, and efficacy.¹³⁵ Early clinical evidence indicates that the toxicity profile of bispecific ADCs is largely dictated by the cytotoxic payload, with no added toxicities attributable to the bispecific format itself. Several bispecific HER2 ADCs targeting non-overlapping HER2 epitopes have shown promise in early-phase trials and are also being tested in combination with immune checkpoint blockade.¹⁰⁰^,¹³⁶^,¹³⁷ HER2×HER3 bispecific ADCs, such as MM-111, are being developed to address resistance mechanisms related to HER2/HER3 dimerization and signaling, with preclinical studies demonstrating enhanced efficacy in models resistant to prior HER2 therapies. BL-B01D1 is an EGFR-HER3 bispecific ADC that utilizes a TOP1 inhibitor payload, with phase I data demonstrating an ORR of 42.1% in patients with HER2-negative advanced breast cancer, with consistent effect across different levels of HER2 expression (HER2 0 versus HER2 1+/2+).¹³⁸ In a first-in-human trial, JSKN016, a TROP2-HER3 bispecific ADC, achieved an 80% ORR among five evaluable patients with advanced TNBC with manageable toxicity, prompting planned combination studies with an oral selective estrogen receptor degrader (SERD) in ER-positive disease.¹³⁹ Additionally, several NECTIN4-TROP2-targeted bispecific ADCs such as AVZO-103 are in clinical development, aiming to increase specificity for tumor cells co-expressing these transmembrane proteins while reducing off-target payload release in normal tissues with lower rates of co-expression.¹⁴⁰^,¹⁴¹

Immuno-stimulating ADCs

Immune stimulator antibody conjugates (ISACs) are a novel class of ADCs that contain immune activating payloads (such as TLR agonists) to activate anti-tumor immunity. Pre-clinical and early-phase clinical data suggest that ISACs can induce innate and adaptive immune responses within the TME, thereby activating local inflammatory cytokine production along with myeloid and CD8⁺ T cells within the TME, while minimizing toxicity due to systemic inflammation. NJH395 is a first-in-class ISAC that conjugates an anti-HER2 antibody to a Toll-like receptor 7 (TLR7) agonist. In a phase I trial, NJH395 demonstrated successful payload delivery and immune activation, but these effects did not translate into clinical responses, and there was a high incidence of low-grade cytokine release syndrome (CRS) events along with neuroinflammation and anti-drug antibody development, highlighting challenges of developing this class of drugs.¹⁴² BDC-1001 (trastuzumab imbotolimod) is an alternative ISAC that uses a trastuzumab biosimilar conjugated to a TLR7/8 agonist. Early phase I/II studies, both as monotherapy and in combination with nivolumab or pertuzumab, showed good tolerability with biomarker evidence of myeloid and T cell recruitment to the TME, with some early clinical responses observed.¹⁴³ Additional approaches, such as antibody-STING (Simulator of Interferon Genes) agonist conjugates, are being explored to activate innate immunity via type I/III interferon production and dendritic cell maturation. Several early phase I/II trials have utilized tumor-specific antibodies conjugated to STING agonists both alone and in combination with immune checkpoint inhibitors or alternative agents. Similarly, there has been interest in development of a dual PD-L1/TLR7 dual-targeting therapy, with the goal of activating innate immunity through TLR7 agonism and increasing PD-L1 expression, thereby enhancing response to PD-L1 targeted therapy. An alternative strategy to enhance tumor immune infiltration is the delivery of a TLR9 agonist payload to B-cells via an anti-CD22 antibody, which activates both innate and adaptive immune responses.¹⁴⁴^,¹⁴⁵

Novel payload designs

Novel cytotoxic payloads under clinical evaluation include RNA polymerase II inhibitors, advantageous due to their cell-cycle-independent mechanism, allowing for effective targeting of senescent or slowly proliferating cell populations, topoisomerase-II inhibitors, and Bcl-xL inhibitors. Proteolysis-targeting chimeras (PROTACs) represent another innovative payload class, enabling targeted protein degradation and modulation of oncogenic signaling pathways at the protein level. Kinesin spindle protein inhibitors, which induce mitotic arrest, offer a cell-cycle-specific mechanism and may be effective in tumors resistant to tubulin-targeting agents.

Conditionally active ADCs (or probody-drug conjugation) are under investigation as a way of reducing on-target but off-tumor effects, thereby broadening the therapeutic window, especially for targets that are highly expressed on normal tissues. They are designed to be activated by proteolytic enzymes or other conditions that are specific to the TME, reducing erroneous binding of the drug to healthy tissue and pre-mature payload release.¹⁴⁶ Dual-drug ADCs are engineered to carry two distinct cytotoxic payloads on a single antibody, enabling simultaneous disruption of multiple cellular pathways, thereby addressing tumor heterogeneity and resistance mechanisms that limit the efficacy of single-payload ADCs.¹⁴⁷

Collectively, these novel engineering approaches are poised to expand the clinical utility of ADCs, particularly in tumors with heterogeneous antigen expression or acquired resistance to conventional ADCs. Ongoing and future clinical trials will be critical to defining the optimal patient populations and sequencing strategies for these next-generation agents.

Future directions

Beyond developing novel ADC agents, the optimal sequence of approved therapies remains an open question. While multiple studies have demonstrated that PFS is highest with first-line ADC agents, whether sequencing impacts overall survival in the metastatic setting and the best way to sequence to overcome mechanisms of resistance is an active area of research.¹¹^,¹⁴⁸^,¹⁴⁹^,¹⁵⁰ Additionally, as agents such as T-DXd are moved into the early-stage setting, the utility of re-challenge in the metastatic setting remains unknown.

Important questions also remain regarding the cost-effectiveness of ADCs relative to traditional chemotherapy, and marginal clinical benefit must be balanced with the substantial additional costs. Additionally, accessibility to these novel agents, particularly outside of large academic medical centers, warrants careful consideration. This concern is especially relevant for therapies requiring intensive monitoring and in some cases inpatient admission. The impact of these monitoring requirements and their associated costs on accessibility to care outside of tertiary care centers must be taken into consideration.

Conclusion

The clinical success of T-DM1, T-DXd, SG, and Dato-DXd across diverse breast cancer subtypes demonstrates the versatility and potency of the ADC platform. The expanding understanding of mechanisms of action, particularly the bystander effect, has broadened treatment eligibility beyond traditional biomarker-defined populations, as evidenced by the efficacy of T-DXd in HER2-low and HER2-ultralow tumors. However, the emergence of resistance mechanisms and challenges in optimal sequencing underscore the need for continued innovation. Next-generation ADCs incorporating novel targets, bispecific platforms, immunostimulatory payloads, and advanced conjugation technologies represent promising strategies to overcome current limitations and extend therapeutic benefits to previously intractable patient populations. As the field advances toward precision medicine approaches guided by predictive biomarkers and molecular profiling, ADCs are poised to play an increasingly central role in both metastatic and early-stage breast cancer management, with the potential to improve long-term outcomes across all molecular subtypes while minimizing treatment-related toxicity.

Acknowledgments

This work was supported in part by the Nellie B Connelly Breast Cancer Research Fund, MD Anderson Cancer Center Support grant (NIH/NCI award #: P30 CA016672), a METAvivor Foundation Translational Research Award, and Center for Clinical and Translational Science (award #: 5UL1TR003167).

Declaration of interests

S.D. reports grant or research support to institution from Guardant Health, Taiho, EMD Serono, Novartis, CPRIT, Sermonix, Edgewood Oncology, AstraZeneca, MediLink, and Daiichi Sankyo; and serves on an Advisory panel for AstraZeneca, Sermonix, and Eli Lilly.

F.M.-B. reports personal fees from AstraZeneca Pharmaceuticals, Becton Dickinson, Biocartis NV, Boehringer Ingelheim International GmbH, Calibr (a division of Scripps Research), Crossbridge Bio, Daiichi Sankyo, Dava Oncology, Debiopharm, DEM BioPharma, EcoR1 Capital, eFFECTOR Therapeutics, Elevation Oncology, Exelixis, GT Aperion, Incyte, Jazz Pharmaceuticals, LigaChem Biosciences, Menarini Group, Molecular Templates, Precede Biosciences, Protai Bio, Ribometrix, SystImmune, TEMPUS, Vir Biotechnology, and Zymeworks; serves on an advisory role for Cybrexa Therapeutics, DEM BioPharma, go Therapeutics, Guardant Health, Harbinger Health, Illumen Therapeutics, Kivu Biosciences, LOXO-Oncology, OnCusp Therapeutics, Seagen (formerly Seattle Genetics), Sutro BioPharma Inc., Theratechnologies Inc., and Zentalis Pharmaceuticals; sponsored research support has been provided to the institution from AstraZeneca, Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Guardant Health Inc., Jazz Pharmaceuticals, and Zymeworks; received honoraria from Dava Oncology and Physician Education Resource (PER); travel-related support has been provided by Cholangiocarcinoma Foundation, Dava Oncology, European Society for Medical Oncology (ESMO), and Physician Education Resource (PER).

Footnotes

Supplemental information can be found online at https://doi.org/10.1016/j.xcrm.2026.102742.

Supplemental information

Document S1. Figure S1

mmc1.pdf^{(72.4KB, pdf)}

Document S2. Table S1

mmc2.pdf^{(181.4KB, pdf)}

Document S3. Article plus supplemental information

mmc3.pdf^{(3.1MB, pdf)}

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Supplementary Materials

Document S1. Figure S1

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Document S2. Table S1

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Document S3. Article plus supplemental information

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PERMALINK

Antibody-drug conjugates in breast cancer: Progress and future directions

Alexandra Bili Newman

Senthil Damodaran

Funda Meric-Bernstam

Summary

Graphical abstract

Introduction

Figure 1.

Structure and mechanisms of ADCs

Figure 2.

ADCs with regulatory approval for breast cancer

Trastuzumab emtansine

Trastuzumab deruxtecan

Sacituzumab govitecan

Datopotamab deruxtecan

Sacituzumab tirumotecan

Biomarkers of response and resistance

Brain and leptomeningeal metastases

Early breast cancer

Rational ADC combinations

Figure 3.

Emerging ADCs

HER2

Table 1.

TROP2

HER3

B7H4

LIV-1

B7-H3

Folate receptor alpha

Nectin-4

PTK7

CEACAM5 (carcinoembryonic-antigen-related cell adhesion molecule 5)

Future strategies in ADC development

Bispecific ADCs

Immuno-stimulating ADCs

Novel payload designs

Future directions

Conclusion

Acknowledgments

Declaration of interests

Footnotes

Supplemental information

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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